<?xml version="1.0" encoding="UTF-8"?><title>These highlights do not include all the information needed to use <content styleCode="bold">LYNPARZA </content>safely and effectively. See full prescribing information for <content styleCode="bold">LYNPARZA</content>.<br/> <br/>LYNPARZA^® (olaparib) tablets, for oral use<br/>Initial U.S. Approval: 2014</title>

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<?xml version="1.0" encoding="UTF-8"?><section ID="ID_712ba609-9eee-48f2-a075-477f7cd59f2d"> <id root="d42b1974-09d9-4b38-ad9d-3e18f144c051"/> <code code="43683-2" codeSystem="2.16.840.1.113883.6.1" displayName="RECENT MAJOR CHANGES SECTION"/> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <paragraph/> <paragraph>Indications and Usage <linkHtml href="#ID_b2dde63f-c71a-4997-a942-4a9e3cf6bcbc">(1)</linkHtml>                                                                                                           05/2020</paragraph> <paragraph>Dosage and Administration <linkHtml href="#ID_5b27e16b-f933-4ea6-9a3a-43220aba2224">(2)</linkHtml>                                                                                                   12/2020</paragraph> <paragraph>Warnings and Precautions, Myelodysplastic Syndrome/Acute Myeloid Leukemia <linkHtml href="#ID_ddb21fce-152b-4f6c-8c2a-e181418a068c">(5.1)</linkHtml>          03/2021</paragraph> <paragraph>Warnings and Precautions, Venous Thromboembolic Events <linkHtml href="#ID_9d7c095f-cd4c-4495-bd4a-2ca07305f94f">(5.4)</linkHtml>                                           05/2020</paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_b2dde63f-c71a-4997-a942-4a9e3cf6bcbc"> <id root="3b41f286-fec0-4f7a-9af7-abd50b129c58"/> <code code="34067-9" codeSystem="2.16.840.1.113883.6.1" displayName="INDICATIONS &amp; USAGE SECTION"/> <title>1 INDICATIONS AND USAGE</title> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <paragraph>Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:</paragraph> <paragraph>Ovarian cancer</paragraph> <list listType="unordered"> <item> <caption>•</caption>for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic <content styleCode="italics">BRCA</content>-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (<linkHtml href="#ID_b7079e94-84c3-48a6-b732-aa32bc1afeef">1.1</linkHtml>, <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">2.1</linkHtml>) </item> <item> <caption>•</caption>in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:<list listType="unordered"> <item> <caption>•</caption>a deleterious or suspected deleterious <content styleCode="italics">BRCA</content> mutation, and/or </item> <item> <caption>•</caption>genomic instability. </item> </list> </item> <item> <caption> </caption>Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza (<linkHtml href="#ID_e2abba15-4cf2-4454-8819-6da3cfbc146b">1.2</linkHtml>, <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">2.1</linkHtml>).</item> <item> <caption>•</caption>for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy. <linkHtml href="#ID_5c661c5d-a054-4fa7-b2e9-098ecdf2af2f">(1.3)</linkHtml> </item> <item> <caption>•</caption>for the treatment of adult patients with deleterious or suspected deleterious germline <content styleCode="italics">BRCA</content>-mutated (g<content styleCode="italics">BRCA</content>m) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (<linkHtml href="#ID_13aef49f-108f-458a-854a-960b33828048">1.4</linkHtml>, <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">2.1</linkHtml>)</item> </list> <paragraph>Breast cancer</paragraph> <list listType="unordered"> <item> <caption>•</caption>for the treatment of adult patients with deleterious or suspected deleterious g<content styleCode="italics">BRCA</content>m, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (<linkHtml href="#ID_564420c7-9264-45b3-bad7-2b9661c8397e">1.5</linkHtml>, <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">2.1</linkHtml>)</item> </list> <paragraph>Pancreatic cancer</paragraph> <list listType="unordered"> <item> <caption>•</caption>for the maintenance treatment of adult patients with deleterious or suspected deleterious g<content styleCode="italics">BRCA</content>m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (<linkHtml href="#ID_72bb290e-7fbe-4335-8a27-7a85e648ab6d">1.6</linkHtml>, <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">2.1</linkHtml>)</item> </list> <paragraph>Prostate cancer</paragraph> <list listType="unordered"> <item> <caption>•</caption>for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza. (<linkHtml href="#ID_41d54f23-bedc-4cb0-ad31-ff0ccaec1002">1.7</linkHtml>, <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">2.1</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_b7079e94-84c3-48a6-b732-aa32bc1afeef"> <id root="1f8fbd38-bcd0-4b35-93e5-f83d573cf1af"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.1 First-Line Maintenance Treatment of <content styleCode="italics">BRCA</content>-mutated Advanced Ovarian Cancer </title> <text> <paragraph>Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic <content styleCode="italics">BRCA</content>-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza <content styleCode="italics">[see </content> <content styleCode="italics"> <linkHtml href="#ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71">Dosage and Administration (2.1)</linkHtml> </content> <content styleCode="italics">]</content>.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_e2abba15-4cf2-4454-8819-6da3cfbc146b"> <id root="15e07b08-1be9-4e8b-b0db-bcb68f4a9271"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab </title> <text> <paragraph> <content styleCode="xmChange">Lynparza is indicated in combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:</content> </paragraph> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>•</caption> <content styleCode="xmChange">a deleterious or suspected deleterious <content styleCode="italics">BRCA</content> mutation, and/or</content> </item> <item> <caption>•</caption> <content styleCode="xmChange">genomic instability.</content> </item> </list> </item> </list> <paragraph> <content styleCode="xmChange">Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza <content styleCode="italics">[see <linkHtml href="#">Dosage and Administration (2.1)</linkHtml>]</content>.</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_5c661c5d-a054-4fa7-b2e9-098ecdf2af2f"> <id root="f1d18356-a06d-44e1-b615-377e2d011d17"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.3 Maintenance Treatment of Recurrent Ovarian Cancer</title> <text> <paragraph>Lynparza is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_13aef49f-108f-458a-854a-960b33828048"> <id root="5153e9dc-8f0f-4eb6-8f3a-cf1caa8b69f4"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.4 Advanced Germline <content styleCode="italics">BRCA</content>-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy </title> <text> <paragraph>Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline <content styleCode="italics">BRCA</content>-mutated (g<content styleCode="italics">BRCA</content>m) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza <content styleCode="italics">[see </content> <content styleCode="italics"> <linkHtml href="#_2.2_Patient_Selection">Dosage and Administration (2.1)</linkHtml> </content> <content styleCode="italics">].</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_564420c7-9264-45b3-bad7-2b9661c8397e"> <id root="a66206c0-9cd4-4956-9bbc-185733505f16"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.5 Germline BRCA-mutated HER2-negative Metastatic Breast Cancer </title> <text> <paragraph> <content styleCode="xmChange">Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious <content styleCode="italics">gBRCA</content>m, HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza <content styleCode="italics">[see Dosage and Administration (2.1)]</content>.</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_72bb290e-7fbe-4335-8a27-7a85e648ab6d"> <id root="bfaf86d7-7514-41f6-9dd8-1f1cb7386194"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.6 First-Line Maintenance Treatment of Germline BRCA-mutated Metastatic Pancreatic Adenocarcinoma </title> <text> <paragraph> <content styleCode="xmChange">Lynparza is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious <content styleCode="italics">gBRCA</content>m metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza <content styleCode="italics">[see <linkHtml href="#">Dosage and Administration (2.1)</linkHtml>]</content>.</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_41d54f23-bedc-4cb0-ad31-ff0ccaec1002"> <id root="3f8e06c9-b77e-4b10-9de8-ef81f33ce9ae"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>1.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer </title> <text> <paragraph> <content styleCode="xmChange">Lynparza is indicated for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for Lynparza <content styleCode="italics">[see <linkHtml href="#">Dosage and Administration (2.1)</linkHtml>].</content> </content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_5b27e16b-f933-4ea6-9a3a-43220aba2224"> <id root="3001a2e1-9194-4b00-8627-5e9fc4bbded5"/> <code code="34068-7" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE &amp; ADMINISTRATION SECTION"/> <title>2 DOSAGE AND ADMINISTRATION</title> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption>Recommended dosage is 300 mg taken orally twice daily with or without food. See Full Prescribing Information for the recommended duration. <linkHtml href="#ID_75e18f13-f28a-4bd0-9e31-89546b86a498">(2.2)</linkHtml> </item> <item> <caption>•</caption>Patients receiving Lynparza for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. <linkHtml href="#ID_75e18f13-f28a-4bd0-9e31-89546b86a498">(2.2)</linkHtml> </item> <item> <caption>•</caption>For moderate renal impairment (CLcr 31-50 mL/min), reduce Lynparza dosage to 200 mg orally twice daily. <linkHtml href="#ID_a7348257-58ce-4f6f-a756-64f8ca4e9ed4">(2.5)</linkHtml> </item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_2a9e21af-cccb-4aba-8ef6-57b1f908da71"> <id root="1cffb47b-7558-46d2-b60f-a1863fd399be"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.1 Patient Selection</title> <text> <paragraph> <content styleCode="xmChange">Information on FDA-approved tests for the detection of genetic mutations is available at <linkHtml href="http://www.fda.gov/companiondiagnostics">http://www.fda.gov/companiondiagnostics</linkHtml>.</content> </paragraph> <paragraph> <content styleCode="xmChange">Select patients for treatment with Lynparza based on the presence of deleterious or suspected deleterious HRR gene mutations, including BRCA mutations, or genomic instability based on the indication, biomarker, and sample type (Table 1).</content> </paragraph> <table width="100%"> <caption>Table 1 Biomarker Testing for Patient Selection<footnote ID="_Ref66442768">Where testing fails or tissue sample is unavailable/insufficient, or when germline testing is negative, consider using an alternative test, if available.</footnote> </caption> <col width="40%"/> <col width="29%"/> <col width="9%"/> <col width="11%"/> <col width="11%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Indication</content> </paragraph> </td> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Biomarker</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Sample type</content> </paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Tumor</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Plasma</content> </paragraph> <paragraph> <content styleCode="bold">(ctDNA)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>First-line maintenance treatment of germline or somatic <content styleCode="italics">BRCAm</content> advanced ovarian cancer</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics">BRCA1</content>m, <content styleCode="italics">BRCA2</content>m</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>First-line maintenance treatment of HRD-positive advanced ovarian cancer in combination with bevacizumab</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics">BRCA1</content>m, <content styleCode="italics">BRC</content>A2m and/or genomic instability</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Maintenance treatment of recurrent ovarian cancer</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>No requirement for biomarker testing</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>Advanced g<content styleCode="italics">BRCA</content>m ovarian cancer</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics">gBRCA1</content>m, <content styleCode="italics">gBRCA2</content>m</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>g<content styleCode="italics">BRCA</content>m HER2-negative metastatic breast cancer</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics">gBRCA1</content>m, <content styleCode="italics">gBRCA2</content>m</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>First-line maintenance treatment of germline <content styleCode="italics">BRCA</content>-mutated metastatic pancreatic adenocarcinoma</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics">gBRCA1</content>m, <content styleCode="italics">gBRCA2</content>m</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td rowspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>Germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics">ATM</content>m, <content styleCode="italics">BRCA1</content>m<content styleCode="italics">, BRCA2</content>m, <content styleCode="italics">BARD1</content>m, <content styleCode="italics">BRIP1</content>m, <content styleCode="italics">CDK12</content>m, <content styleCode="italics">CHEK1</content>m, <content styleCode="italics">CHEK2</content>m, <content styleCode="italics">FANCL</content>m, <content styleCode="italics">PALB2</content>m, <content styleCode="italics">RAD51B</content>m, <content styleCode="italics">RAD51C</content>m, <content styleCode="italics">RAD51D</content>m, <content styleCode="italics">RAD54L</content>m</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph> <content styleCode="italics"> <content styleCode="underline">g</content>BRCA1</content>m, g<content styleCode="italics">BRCA2</content>m</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>X</paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="italics">ATM</content>m<content styleCode="italics">, BRCA1</content>m, <content styleCode="italics">BRCA2</content>m</paragraph> </td> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/> <td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>X</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_75e18f13-f28a-4bd0-9e31-89546b86a498"> <id root="bfacdc54-cad0-4586-b879-37c45048f864"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.2 Recommended Dosage </title> <text> <paragraph>The recommended dosage of Lynparza is 300 mg taken orally twice daily, with or without food.</paragraph> <paragraph>If a patient misses a dose of Lynparza, instruct patient to take their next dose at its scheduled time. </paragraph> <paragraph>Instruct patients to swallow tablets whole. Do not chew, crush, dissolve, or divide tablet.</paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="underline">First-Line Maintenance Treatment of <content styleCode="italics">BRCA</content>-mutated Advanced Ovarian Cancer </content> </content> </paragraph> <paragraph> <content styleCode="xmChange">Continue treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous treatment, can be treated beyond 2 years.</content> </paragraph> <paragraph> <content styleCode="xmChange"> <content styleCode="underline">First-Line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab</content> </content> </paragraph> <paragraph> <content styleCode="xmChange">Continue Lynparza treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment. Patients with a complete response (no radiological evidence of disease) at 2 years should stop treatment. Patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider can derive further benefit from continuous Lynparza treatment, can be treated beyond 2 years. </content> </paragraph> <paragraph> <content styleCode="xmChange">When used with Lynparza, the recommended dose of bevacizumab is 15 mg/kg every three weeks. Bevacizumab should be given for a total of 15 months including the period given with chemotherapy and given as maintenance. Refer to the Prescribing Information for bevacizumab when used in combination with Lynparza for more information.</content> </paragraph> <paragraph> <content styleCode="underline">Recurrent Ovarian Cancer, Germline <content styleCode="italics">BRCA</content>m Advanced Ovarian Cancer, HER2-negative Metastatic Breast Cancer, Metastatic Pancreatic Adenocarcinoma, and HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer</content> </paragraph> <paragraph>Continue treatment until disease progression or unacceptable toxicity for:</paragraph> <list listType="unordered"> <item> <caption> </caption> <list listType="unordered"> <item> <caption>•</caption>Maintenance treatment of recurrent ovarian cancer</item> <item> <caption>•</caption>Advanced germline <content styleCode="italics">BRCA</content>-mutated ovarian cancer</item> <item> <caption>•</caption> <content styleCode="xmChange">Germline <content styleCode="italics">BRCA</content>-mutated HER-2 negative metastatic breast cancer</content> </item> <item> <caption>•</caption> <content styleCode="xmChange">First-line maintenance treatment of germline <content styleCode="italics">BRCA</content>-mutated metastatic pancreatic adenocarcinoma.</content> </item> <item> <caption>•</caption> <content styleCode="xmChange">HRR gene-mutated metastatic castration-resistant prostate cancer</content> </item> </list> </item> </list> <paragraph> <content styleCode="xmChange">Patients receiving Lynparza for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_c08157e3-323f-4d20-aa33-895f4bbe6d59"> <id root="934ce008-3898-48c7-8358-9dae5d23dbf9"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.3 Dosage Modifications for Adverse Reactions </title> <text> <paragraph>To manage adverse reactions, consider interruption of treatment or dose reduction. The recommended dose reduction is 250 mg taken twice daily.</paragraph> <paragraph>If a further dose reduction is required, then reduce to 200 mg taken twice daily.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_6fbd0e2a-f3c4-47b1-9654-a235e09236f8"> <id root="b13c4417-042e-4df4-b68f-05a04384bc51"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.4 Dosage Modifications for Concomitant Use with Strong or Moderate CYP3A Inhibitors </title> <text> <paragraph>Avoid concomitant use of strong or moderate CYP3A inhibitors with Lynparza. </paragraph> <paragraph>If concomitant use cannot be avoided, reduce Lynparza dosage to:</paragraph> <list listType="unordered"> <item> <caption>•</caption>100 mg twice daily when used concomitantly with a strong CYP3A inhibitor.</item> <item> <caption>•</caption>150 mg twice daily when used concomitantly with a moderate CYP3A inhibitor.</item> </list> <paragraph>After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Lynparza dose taken prior to initiating the CYP3A inhibitor <content styleCode="italics">[see <linkHtml href="#ID_234fa3d4-b847-4ab5-a73b-8b5807c75f9e">Drug Interactions (7.2)</linkHtml> and <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">Clinical Pharmacology (12.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_a7348257-58ce-4f6f-a756-64f8ca4e9ed4"> <id root="074058a9-a84a-4b83-b473-5019e838b984"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>2.5 Dosage Modifications for Renal Impairment </title> <text> <paragraph> <content styleCode="underline">Moderate Renal Impairment</content> </paragraph> <paragraph>In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the Lynparza dosage to 200 mg orally twice daily <content styleCode="italics">[see <linkHtml href="#ID_cb156c67-c307-4a85-a1f2-ccacbc188d60">Use in Specific Populations (8.6)</linkHtml> and <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">Clinical Pharmacology (12.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_8fd50637-140b-457f-9fd0-373df41f5fd7"> <id root="eff2b58b-bbfe-4501-8bb8-b8ad10ca1a07"/> <code code="43678-2" codeSystem="2.16.840.1.113883.6.1" displayName="DOSAGE FORMS &amp; STRENGTHS SECTION"/> <title>3 DOSAGE FORMS AND STRENGTHS</title> <text> <paragraph>Tablets:</paragraph> <list listType="unordered"> <item> <caption>•</caption>150 mg: green to green/grey, oval, bi-convex, film-coated, with debossment ‘OP150’ on one side and plain on the reverse side.</item> <item> <caption>•</caption>100 mg: yellow to dark yellow, oval, bi-convex, film-coated, with debossment ‘OP100’ on one side and plain on the reverse side.</item> </list> </text> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <paragraph>Tablets: 150 mg, 100 mg <linkHtml href="#ID_8fd50637-140b-457f-9fd0-373df41f5fd7">(3)</linkHtml> </paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_92dc1934-d748-45f3-905b-e0918962a2b3"> <id root="597bf443-24fd-41e5-a0f8-902583500a44"/> <code code="34070-3" codeSystem="2.16.840.1.113883.6.1" displayName="CONTRAINDICATIONS SECTION"/> <title>4 CONTRAINDICATIONS</title> <text> <paragraph>None.</paragraph> </text> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <paragraph>None. <linkHtml href="#ID_92dc1934-d748-45f3-905b-e0918962a2b3">(4)</linkHtml> </paragraph> </text> </highlight> </excerpt> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_e883c46f-49b2-41dc-b3d0-5e2ebc8ea9b7"> <id root="9b2617cd-b671-4b12-bdf9-5733a9ee4999"/> <code code="43685-7" codeSystem="2.16.840.1.113883.6.1" displayName="WARNINGS AND PRECAUTIONS SECTION"/> <title>5 WARNINGS AND PRECAUTIONS</title> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption>Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to Lynparza monotherapy and the majority of events had a fatal outcome. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. <linkHtml href="#ID_ddb21fce-152b-4f6c-8c2a-e181418a068c">(5.1)</linkHtml> </item> <item> <caption>•</caption>Pneumonitis: Occurred in 0.8% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. <linkHtml href="#ID_77122f3a-5030-4c60-a986-fa38152f1aa7">(5.2)</linkHtml> </item> <item> <caption>•</caption>Embryo-Fetal Toxicity: Can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. (<linkHtml href="#ID_a784e1ea-98c0-4c96-8486-32353c47e4c5">5.3</linkHtml>, <linkHtml href="#ID_929586ba-127d-4cc0-bd5a-dfdea42c2b87">8.1</linkHtml>, <linkHtml href="#ID_aefb7be1-5ba8-4334-8dcc-19abb24c2cad">8.3</linkHtml>)</item> <item> <caption>•</caption>Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. (<linkHtml href="#ID_9d7c095f-cd4c-4495-bd4a-2ca07305f94f">5.4</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_ddb21fce-152b-4f6c-8c2a-e181418a068c"> <id root="8a11af87-701b-405d-90ba-cd9178a25a5d"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia</title> <text> <paragraph>Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Lynparza and some cases were fatal.</paragraph> <paragraph>In clinical studies enrolling 2901 patients with various cancers who received Lynparza as a single agent <content styleCode="italics">[see <linkHtml href="#ID_45e158de-cdf6-4826-8ae8-946e0ee65930">Adverse Reactions (6.1)</linkHtml>]</content>, the cumulative incidence of MDS/AML was approximately 1.5% (43/2901). Of these, 51% (22/43) had a fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was 2 years (range: &lt; 6 months to &gt; 10 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.</paragraph> <paragraph>Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_77122f3a-5030-4c60-a986-fa38152f1aa7"> <id root="b8f9f441-6532-44aa-b215-f067b1ece292"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.2 Pneumonitis</title> <text> <paragraph>In clinical studies enrolling 2901 patients with various cancers who received Lynparza as a single agent <content styleCode="italics">[see <linkHtml href="#ID_45e158de-cdf6-4826-8ae8-946e0ee65930">Adverse Reactions (6.1)</linkHtml>]</content>, the incidence of pneumonitis, including fatal cases, was 0.8% (24/2901). If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_a784e1ea-98c0-4c96-8486-32353c47e4c5"> <id root="774374ac-97f4-44da-872b-d3616e82364c"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.3 Embryo-Fetal Toxicity</title> <text> <paragraph>Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza <content styleCode="italics">[see Use in Specific Populations (<linkHtml href="#ID_929586ba-127d-4cc0-bd5a-dfdea42c2b87">8.1</linkHtml>, <linkHtml href="#ID_aefb7be1-5ba8-4334-8dcc-19abb24c2cad">8.3</linkHtml>)]</content>.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_9d7c095f-cd4c-4495-bd4a-2ca07305f94f"> <id root="8fb09c96-f835-48dd-87a4-2eca03021b27"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>5.4 Venous Thromboembolic Events </title> <text> <paragraph> <content styleCode="xmChange">Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic castration resistant prostate cancer who received Lynparza plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving Lynparza and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_7cc0bf6f-632e-4948-8b75-b8e69d0e3549"> <id root="e1d8e087-b876-4b91-9a36-ef3a26e8834b"/> <code code="34084-4" codeSystem="2.16.840.1.113883.6.1" displayName="ADVERSE REACTIONS SECTION"/> <title>6 ADVERSE REACTIONS</title> <text> <paragraph>The following adverse reactions are discussed elsewhere in the labeling:</paragraph> <list listType="unordered"> <item> <caption>•</caption>Myelodysplastic Syndrome/Acute Myeloid Leukemia <content styleCode="italics">[see <linkHtml href="#ID_ddb21fce-152b-4f6c-8c2a-e181418a068c">Warnings and Precautions (5.1)</linkHtml>]</content> </item> <item> <caption>•</caption>Pneumonitis <content styleCode="italics">[see <linkHtml href="#ID_77122f3a-5030-4c60-a986-fa38152f1aa7">Warnings and Precautions (5.2)</linkHtml>]</content> </item> <item> <caption>•</caption>Venous Thromboembolic Events <content styleCode="italics">[see <linkHtml href="#ID_9d7c095f-cd4c-4495-bd4a-2ca07305f94f">Warnings and Precautions (5.4)</linkHtml>]</content> </item> </list> </text> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <paragraph>Most common adverse reactions (≥10%) in clinical trials:</paragraph> <list listType="unordered"> <item> <caption>•</caption>as a single agent were nausea, fatigue (including asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, and thrombocytopenia. <linkHtml href="#ID_45e158de-cdf6-4826-8ae8-946e0ee65930">(6.1)</linkHtml> </item> <item> <caption>•</caption>in combination with bevacizumab were nausea, fatigue (including asthenia), anemia, lymphopenia, vomiting, diarrhea, neutropenia, leukopenia, urinary tract infection, and headache. (<linkHtml href="#ID_45e158de-cdf6-4826-8ae8-946e0ee65930">6.1</linkHtml>)</item> </list> <paragraph> <content styleCode="bold">To report SUSPECTED ADVERSE REACTIONS, contact </content> <content styleCode="bold">AstraZeneca at 1-800-236-9933</content> <content styleCode="bold"> or FDA at 1-800-FDA-1088 or <linkHtml href="http://www.fda.gov/medwatch">www.fda.gov/medwatch.</linkHtml> </content> </paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_45e158de-cdf6-4826-8ae8-946e0ee65930"> <id root="e3eeae88-33e2-42f8-b2fd-fb108833bf55"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>6.1 Clinical Trial Experience</title> <text> <paragraph>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.</paragraph> <paragraph>The data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose including five controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses. In these trials, 56% of patients were exposed for 6 months or longer and 28% were exposed for greater than one year in the Lynparza group. </paragraph> <paragraph>In this pooled safety population, the most common adverse reactions in ≥10% of patients were nausea (60%), fatigue (55%), anemia (36%), vomiting (32%), diarrhea (24%), decreased appetite (22%), headache (16%), dysgeusia (15%), cough (15%), neutropenia (14%), dyspnea (14%), dizziness (12%), dyspepsia (12%), leukopenia (11%), and thrombocytopenia (10%).</paragraph> <paragraph> <content styleCode="underline">First-Line Maintenance Treatment of <content styleCode="italics">BRCA</content>-mutated Advanced Ovarian Cancer</content> </paragraph> <paragraph> <content styleCode="italics">SOLO-1</content> </paragraph> <paragraph>The safety of Lynparza for the maintenance treatment of patients with <content styleCode="italics">BRCA</content>-mutated advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO-1 <content styleCode="italics">[see <linkHtml href="#ID_1cd4967a-8800-4f31-9795-c91580895e7e">Clinical Studies (14.1)</linkHtml>]</content>. Patients received Lynparza tablets 300 mg orally twice daily (n=260) or placebo (n=130) until disease progression or unacceptable toxicity. The median duration of study treatment was 25 months for patients who received Lynparza and 14 months for patients who received placebo.</paragraph> <paragraph>Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 52% and dose reductions due to an adverse reaction occurred in 28%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (23%), nausea (14%), and vomiting (10%). Discontinuation due to adverse reactions occurred in 12% of patients receiving Lynparza. The most frequent adverse reactions that led to discontinuation of Lynparza were fatigue (3.1%), anemia (2.3%), and nausea (2.3%).</paragraph> <paragraph>Tables 2 and 3 summarize adverse reactions and laboratory abnormalities in SOLO-1.</paragraph> <table cellpadding="0pt" width="100%"> <caption>Table 2 Adverse Reactions<footnote ID="_Ref38455000">Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.</footnote> in SOLO-1 (≥10% of Patients Who Received Lynparza)</caption> <col width="50%"/> <col width="13%"/> <col width="12%"/> <col width="14%"/> <col width="12%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Lrule Toprule " valign="top"> <content styleCode="bold">Adverse Reaction</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Lynparza tablets</content> <br/> <content styleCode="bold">n=260</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Placebo</content> <br/> <content styleCode="bold">n=130</content> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">All Grades</content> <br/> <content styleCode="bold">(%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Grades</content> <br/> <content styleCode="bold">3 – 4 (%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">All</content> <br/> <content styleCode="bold">Grades<br/>(%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Grades</content> <br/> <content styleCode="bold">3 – 4 (%)</content> </th> </tr> </thead> <tbody> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>77</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>38</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Abdominal pain<footnote ID="_Ref38455024">Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, and abdominal tenderness. </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Diarrhea<footnote ID="_Ref38455040">Includes colitis, diarrhea, and gastroenteritis. </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Constipation</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Stomatitis<footnote ID="_Ref38455058">Includes stomatitis, aphthous ulcer; and mouth ulceration.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Fatigue<footnote ID="_Ref38455073">Includes asthenia, fatigue, lethargy, and malaise. </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>67</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic System Disorders </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Anemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>38</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Neutropenia<footnote ID="_Ref38455087">Includes neutropenia, and febrile neutropenia.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Leukopenia<footnote ID="_Ref38455102">Includes leukopenia, and white blood cell count decreased.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Thrombocytopenia<footnote ID="_Ref38455135">Includes platelet count decreased, and thrombocytopenia. </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Upper respiratory tract<br/>     infection/influenza/nasopharyngitis/bronchitis </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     UTI<footnote ID="_Ref38455252">Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Dysgeusia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Decreased appetite</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Dyspnea<footnote ID="_Ref38455271">Includes dyspnea, and dyspnea exertional.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph>In addition, the adverse reactions observed in SOLO-1 that occurred in &lt;10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), hypersensitivity (2%), MDS/AML (1%), dermatitis (1%), and increased mean cell volume (0.4%).</paragraph> <table width="100%"> <caption>Table 3 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-1</caption> <col width="50%"/> <col width="13%"/> <col width="13%"/> <col width="12%"/> <col width="12%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Laboratory </content> </paragraph> <paragraph> <content styleCode="bold">Parameter</content> <footnote ID="_Ref522754567">Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref522754583">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">=260</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnoteRef IDREF="_Ref522754583"/> <content styleCode="bold">=130</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>87</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>63</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in mean corpuscular volume</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>87</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>43</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>70</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>52</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>67</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>51</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>38</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in platelets</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Increase in serum creatinine</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab</content> </paragraph> <paragraph> <content styleCode="italics">PAOLA-1</content> </paragraph> <paragraph>The safety of Lynparza in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer following first-line treatment containing platinum-based chemotherapy and bevacizumab was investigated in PAOLA-1 <content styleCode="italics">[see <linkHtml href="#ID_5a17802b-5c8c-4312-99af-7dddee79b3ea">Clinical Studies (14.2)</linkHtml>]</content>. This study was a placebo-controlled, double-blind study in which 802 patients received either Lynparza 300 mg BID in combination with bevacizumab (n=535) or placebo in combination with bevacizumab (n=267) until disease progression or unacceptable toxicity. The median duration of treatment with Lynparza was 17.3 months and 11 months for bevacizumab post-randomization on the Lynparza/bevacizumab arm.</paragraph> <paragraph>Fatal adverse reactions occurred in 1 patient due to concurrent pneumonia and aplastic anemia. Serious adverse reactions occurred in 31% of patients who received Lynparza/bevacizumab. Serious adverse reactions in &gt;5% of patients included hypertension (19%) and anemia (17%).</paragraph> <paragraph>Dose interruptions due to an adverse reaction of any grade occurred in 54% of patients receiving Lynparza/bevacizumab and dose reductions due to an adverse reaction occurred in 41% of patients who received Lynparza/bevacizumab.</paragraph> <paragraph>The most frequent adverse reactions leading to dose interruption in the Lynparza/bevacizumab arm were anemia (21%), nausea (7%), vomiting (3%), and fatigue (3%), and the most frequent adverse reactions leading to reduction in the Lynparza/bevacizumab arm were anemia (19%), nausea (7%), and fatigue (4%). </paragraph> <paragraph>Discontinuation due to adverse reactions occurred in 20% of patients receiving Lynparza/bevacizumab. Specific adverse reactions that most frequently led to discontinuation in patients treated with Lynparza/bevacizumab were anemia (4%) and nausea (3%). </paragraph> <paragraph>Tables 4 and 5 summarize adverse reactions and laboratory abnormalities in PAOLA-1, respectively.</paragraph> <table width="100%"> <caption>Table 4 Adverse Reactions<footnote ID="_Ref40094079">Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.</footnote> Occurring in ≥10% of Patients Treated with Lynparza/bevacizumab in PAOLA-1 and at ≥5% Frequency Compared to the Placebo/bevacizumab Arm</caption> <col width="39%"/> <col width="14%"/> <col width="14%"/> <col width="17%"/> <col width="16%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reactions</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza/bevacizumab </content> </paragraph> <paragraph> <content styleCode="bold">n=535</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo/bevacizumab <br/>n=267</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Fatigue (including asthenia)<footnote ID="_Ref38534392">Includes asthenia, and fatigue.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>53</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.5</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>53</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Anemia<footnote ID="_Ref38534400">Includes anemia, anemia macrocytic, erythropenia, haematocrit decreased, haemoglobin decreased, normochromic anemia, normochromic normocytic anemia, normocytic anemia, and red blood cell count decreased. </footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>41</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Lymphopenia<footnote ID="_Ref66440937">Includes B-lymphocyte count decreased, lymphocyte count decreased, lymphopenia, and T-lymphocyte count decreased.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1.1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Leukopenia<footnote ID="_Ref38534415">Includes leukopenia, and white blood cell count decreased.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>1.9</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>1.5</paragraph> </td> </tr> </tbody> </table> <paragraph>The most common adverse reactions (≥ 10%) for patients receiving Lynparza/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), diarrhea (18%), neutropenia (18%), leukopenia (18%), urinary tract infection (15%), and headache (14%).</paragraph> <paragraph>The adverse reactions that occurred in &lt;10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%), hypersensitivity (1.7%) and MDS/AML (0.7%).</paragraph> <paragraph>In addition, venous thromboembolic events occurred more commonly in patients receiving Lynparza/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).</paragraph> <table width="100%"> <caption>Table 5 Laboratory Abnormalities Reported in ≥25% of Patients in PAOLA-1<footnote ID="_Ref40095548">Reported within 30 days of the last dose.</footnote> </caption> <col width="47%"/> <col width="15%"/> <col width="13%"/> <col width="13%"/> <col width="12%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Laboratory Parameter</content> <footnote ID="_Ref40095697">Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza/bevacizumab <br/>n</content> <footnoteRef IDREF="_Ref40095697"/> <content styleCode="bold">=535</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo/bevacizumab <br/>n</content> <footnote ID="_Ref23949789">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">=267</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>79</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>55</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>63</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3.0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in serum creatinine</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>61</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>59</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2.2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in platelets</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>2.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0.4</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">Maintenance Treatment of Recurrent Ovarian Cancer</content> </paragraph> <paragraph> <content styleCode="italics">SOLO-2</content> </paragraph> <paragraph>The safety of Lynparza for the maintenance treatment of patients with platinum sensitive g<content styleCode="italics">BRCA</content>m ovarian cancer was investigated in SOLO-2 <content styleCode="italics">[see <linkHtml href="#ID_b383168c-2afc-46a7-b1ec-09e1d4930470">Clinical Studies (14.3)</linkHtml>]</content>. Patients received Lynparza tablets 300 mg orally twice daily (n=195) or placebo (n=99) until disease progression or unacceptable toxicity. The median duration of study treatment was 19.4 months for patients who received Lynparza and 5.6 months for patients who received placebo. </paragraph> <paragraph>Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 45% and dose reductions due to an adverse reaction occurred in 27%. The most frequent adverse reactions leading to dose interruption or reduction of Lynparza were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation due to an adverse reaction occurred in 11% of patients receiving Lynparza.</paragraph> <paragraph>Tables 6 and 7 summarize adverse reactions and laboratory abnormalities in SOLO-2.</paragraph> <table width="100%"> <caption>Table 6 Adverse Reactions<footnote ID="_Ref40196145">Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.</footnote> in SOLO-2 (≥20% of Patients Who Received Lynparza)</caption> <col width="47%"/> <col width="14%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n=195</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">n=99</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>76</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>33</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>33</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Stomatitis<footnote ID="_Ref40196200">Represents grouped term consisting of abscess oral, aphthous ulcer, gingival abscess, gingival disorder, gingival pain, gingivitis, mouth ulceration, mucosal infection, mucosal inflammation, oral candidiasis, oral discomfort, oral herpes, oral infection, oral mucosal erythema, oral pain, oropharyngeal discomfort, and oropharyngeal pain.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Fatigue including asthenia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>66</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Anemia<footnote ID="_Ref40196219">Represents grouped term consisting of anemia, hematocrit decreased, hemoglobin decreased, iron deficiency, mean cell volume increased and red blood cell count decreased.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>44</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Nasopharyngitis/URI/sinusitis/ rhinitis/influenza</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Arthralgia/myalgia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Dysgeusia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Headache</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>    Decreased appetite</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph>In addition, the adverse reactions observed in SOLO-2 that occurred in &lt;20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), edema (8%), rash (6%), and lymphopenia (1%).</paragraph> <table width="100%"> <caption>Table 7 Laboratory Abnormalities Reported in ≥25% of Patients in SOLO-2</caption> <col width="33%"/> <col width="17%"/> <col width="17%"/> <col width="16%"/> <col width="17%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Laboratory Parameter</content> <footnote ID="_Ref23950011">Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref23950038">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">=195 </content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnoteRef IDREF="_Ref23950038"/> <content styleCode="bold">=99</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in mean corpuscular volume<footnote ID="_Ref23950055">Represents the proportion of subjects whose mean corpuscular volume was &gt; upper limit of normal (ULN).</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>89</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>52</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>83</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>69</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>69</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>48</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>67</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>51</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in serum creatinine</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>44</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in platelets</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>42</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>1</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="italics">Study 19</content> </paragraph> <paragraph>The safety of Lynparza as maintenance monotherapy was evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19 <content styleCode="italics">[see <linkHtml href="#ID_b383168c-2afc-46a7-b1ec-09e1d4930470">Clinical Studies (14.3)</linkHtml>]</content>. Patients received Lynparza capsules 400 mg orally twice daily (n=136) or placebo (n=128). At the time of final analysis, the median duration of exposure was 8.7 months in patients who received Lynparza and 4.6 months in patients who received placebo.</paragraph> <paragraph>Adverse reactions led to dose interruptions in 35% of patients receiving Lynparza; dose reductions in 26% and discontinuation in 6% of patients receiving Lynparza.</paragraph> <paragraph>Tables 8 and 9 summarize adverse reactions and laboratory abnormalities in Study 19.</paragraph> <table width="100%"> <caption>Table 8 Adverse Reactions<footnote ID="_Ref37253119">Graded according to NCI CTCAE v4.0.</footnote> in Study 19 (≥20% of Patients Who Received Lynparza)</caption> <col width="39%"/> <col width="14%"/> <col width="14%"/> <col width="17%"/> <col width="16%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza capsules</content> </paragraph> <paragraph> <content styleCode="bold">n=136</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">n=128</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>71</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Constipation</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Fatigue (including asthenia)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>63</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>46</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Anemia<footnote ID="_Ref37253137">Represents grouped terms of related terms that reflect the medical concept of the adverse reaction.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Respiratory tract infection</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Decreased appetite</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>1</paragraph> </td> </tr> </tbody> </table> <paragraph>In addition, the adverse reactions in Study 19 that occurred in &lt;20% of patients receiving Lynparza were dysgeusia (16%), dizziness (15%), dyspnea (13%), pyrexia (10%), stomatitis (9%), edema (9%), increase in creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), MDS/AML (1%) and lymphopenia (1%).</paragraph> <table width="100%"> <caption>Table 9 Laboratory Abnormalities Reported in ≥25% of Patients in Study 19</caption> <col width="34%"/> <col width="17%"/> <col width="18%"/> <col width="15%"/> <col width="16%"/> <tbody> <tr> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Laboratory Parameter</content> <footnote ID="_Ref23951377">Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza capsules</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref23951472">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">=136</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnoteRef IDREF="_Ref23951472"/> <content styleCode="bold">=129</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>82</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>58</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in mean corpuscular volume<footnote ID="_Ref23951494">Represents the proportion of subjects whose mean corpuscular volume was &gt; ULN.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>82</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>51</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>58</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>52</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>47</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in serum creatinine</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in platelets</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">Advanced Germline <content styleCode="italics">BRCA</content>-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy</content> </paragraph> <paragraph> <content styleCode="italics">Pooled Data</content> </paragraph> <paragraph>The safety of Lynparza was investigated in 223 patients (pooled from 6 studies) with g<content styleCode="italics">BRCA</content>m advanced ovarian cancer who had received 3 or more prior lines of chemotherapy <content styleCode="italics">[see <linkHtml href="#ID_9639caef-740b-4d6d-81fb-c72fa258af8d">Clinical Studies (14.4)</linkHtml>]</content>. Patients received Lynparza capsules 400 mg orally twice daily until disease progression or unacceptable tolerability. The median exposure to Lynparza in these patients was 5.2 months.</paragraph> <paragraph>There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. </paragraph> <paragraph>Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities from the pooled studies.</paragraph> <table width="100%"> <caption>Table 10 Adverse Reactions Reported in Pooled Data (≥20% of Patients Who Received Lynparza)</caption> <col width="55%"/> <col width="23%"/> <col width="22%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza capsules</content> </paragraph> <paragraph> <content styleCode="bold">n=223</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Fatigue/asthenia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>66</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>64</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>43</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Decreased appetite</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Anemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>18</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Nasopharyngitis/URI</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Arthralgia/musculoskeletal pain</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Myalgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <table width="100%"> <caption>Table 11 Laboratory Abnormalities Reported in ≥25% of Patients in Pooled Data</caption> <col width="54%"/> <col width="23%"/> <col width="23%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Laboratory Parameter</content> <footnote ID="_Ref37255152"> Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza capsules</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref37255176">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">=223</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>90</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Mean corpuscular volume elevation</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>57</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>56</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in platelets </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in creatinine</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in absolute neutrophil count </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>7</paragraph> </td> </tr> </tbody> </table> <paragraph>The following adverse reactions and laboratory abnormalities have been identified in ≥10 to &lt;20% of the 223 patients receiving Lynparza and not included in the table: cough (16%), constipation (16%), dysgeusia (16%), headache (15%), peripheral edema (14%), back pain (14%), urinary tract infection (14%), dyspnea (13%), and dizziness (11%).</paragraph> <paragraph>The following adverse reactions and laboratory abnormalities have been identified in &lt;10% of the 223 patients receiving Lynparza and not included in the table: leukopenia (9%), pyrexia (8%), peripheral neuropathy (5%), hypomagnesemia (5%), rash (5%), stomatitis (4%), MDS/AML (1.8%), and venous thrombosis (including pulmonary embolism) (1%).</paragraph> <paragraph> <content styleCode="underline">Germline <content styleCode="italics">BRCA</content>-mutated HER2-negative Metastatic Breast Cancer </content> </paragraph> <paragraph> <content styleCode="italics">OlympiAD</content> </paragraph> <paragraph>The safety of Lynparza was evaluated in g<content styleCode="italics">BRCA</content>m patients with HER2-negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD <content styleCode="italics">[see <linkHtml href="#ID_7eff5af5-ad29-4f8e-a7cc-19d136ee42ea">Clinical Studies (14.5)</linkHtml>]</content>. Patients received either Lynparza tablets 300 mg orally twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received Lynparza and 3.4 months in patients who received chemotherapy. </paragraph> <paragraph>Among patients who received Lynparza, dose interruptions due to an adverse reaction of any grade occurred in 35% and dose reductions due to an adverse reaction occurred in 25%. Discontinuation due to an adverse reaction occurred in 5% of patients receiving Lynparza. </paragraph> <paragraph>Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities in OlympiAD.</paragraph> <table width="100%"> <caption>Table 12 Adverse Reactions<footnote ID="_Ref37254486">Graded according to NCI CTCAE v4.0.</footnote> in OlympiAD (≥20% of Patients Who Received Lynparza)</caption> <col width="39%"/> <col width="14%"/> <col width="14%"/> <col width="17%"/> <col width="16%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reaction</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n=205</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Chemotherapy</content> </paragraph> <paragraph> <content styleCode="bold">n=91</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>58</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Anemia<footnote ID="_Ref37254509">Represents grouped terms consisting of anemia (anemia erythropenia, hematocrit decreased, hemoglobin decreased and red blood cell count decreased).</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>40</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Neutropenia<footnote ID="_Ref37254534">Represents grouped terms consisting of neutropenia (febrile neutropenia, granulocyte count decreased, granulocytopenia, neutropenia, neutropenic infection, neutropenic sepsis, and neutrophil count decreased).</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>50</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Leukopenia<footnote ID="_Ref40362619">Represents grouped terms consisting of leukopenia (leukopenia and white blood cell count decreased).</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Fatigue (including asthenia)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>36</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="middle"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Respiratory tract infection<footnote ID="_Ref37254577">Represents grouped terms consisting of bronchitis, influenza, lower respiratory tract infection, nasopharyngitis, pharyngitis, respiratory tract infection, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>22</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>2</paragraph> </td> </tr> </tbody> </table> <paragraph>In addition, adverse reactions in OlympiAD that occurred in &lt;20% of patients receiving Lynparza were cough (18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia (8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine (3%), and dermatitis (1%). </paragraph> <table width="100%"> <caption>Table 13 Laboratory Abnormalities Reported in ≥25% of Patients in OlympiAD</caption> <col width="39%"/> <col width="14%"/> <col width="17%"/> <col width="17%"/> <col width="14%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Laboratory Parameter</content> <footnote ID="_Ref37254723"> Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref37254748">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">= 205</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Chemotherapy</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnoteRef IDREF="_Ref37254748"/> <content styleCode="bold">= 91</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>82</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>66</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>73</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>63</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>71</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>70</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in mean corpuscular volume<footnote ID="_Ref37254809">Represents the proportion of subjects whose mean corpuscular volume was &gt; ULN.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>71</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>33</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>46</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>65</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>38</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in platelets</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>33</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>28</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">First-line Maintenance Treatment of Germline <content styleCode="italics">BRCA</content>-mutated Metastatic Pancreatic Adenocarcinoma</content> </paragraph> <paragraph> <content styleCode="italics">POLO</content> </paragraph> <paragraph>The safety of Lynparza as maintenance treatment of germline <content styleCode="italics">BRCA</content>-mutated metastatic pancreatic adenocarcinoma following first-line treatment with platinum-based chemotherapy was evaluated in POLO <content styleCode="italics">[see <linkHtml href="#ID_a1d1299e-3abe-4f12-a454-2eda60a57f56">Clinical Studies (14.6)</linkHtml>]</content>. Patients received Lynparza tablets 300 mg orally twice daily (n=90) or placebo (n=61) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 34% were exposed for 6 months or longer and 25% were exposed for greater than one year.</paragraph> <paragraph>Among patients who received Lynparza, dosage interruptions due to an adverse reaction of any grade occurred in 35% and dosage reductions due to an adverse reaction occurred in 17%. The most frequent adverse reactions leading to dosage interruption or reduction in patients who received Lynparza were anemia (11%), vomiting (5%), abdominal pain (4%), asthenia (3%), and fatigue (2%). Discontinuation due to adverse reactions occurred in 6% of patients receiving Lynparza. The most frequent adverse reaction that led to discontinuation of Lynparza was fatigue (2.2%).</paragraph> <paragraph>Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities in patients in POLO.</paragraph> <table cellpadding="0pt" width="100%"> <caption>Table 14 Adverse Reactions<footnote ID="_Ref37767241">Graded according to NCI CTCAE, version 4.0</footnote> in POLO (Occurring in ≥10% of Patients who Received Lynparza)</caption> <col width="46%"/> <col width="13%"/> <col width="15%"/> <col width="12%"/> <col width="14%"/> <thead> <tr> <th align="center" rowspan="2" styleCode="Rrule Lrule Toprule " valign="top"> <content styleCode="bold">Adverse Reaction</content> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Lynparza tablets</content> <br/> <content styleCode="bold">(n=91)</content> <footnote ID="_Ref37767491">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> </th> <th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Placebo</content> <br/> <content styleCode="bold">(n=60)</content> <footnoteRef IDREF="_Ref37767491"/> </th> </tr> <tr> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">All Grades (%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Grades</content> <br/> <content styleCode="bold">3 – 4 (%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">All</content> <br/> <content styleCode="bold">Grades</content> <br/> <content styleCode="bold"> (%)</content> </th> <th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Grades</content> <br/> <content styleCode="bold">3 – 4 (%)</content> </th> </tr> </thead> <tbody> <tr> <td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administration Site Conditions</content> </paragraph> </td> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Fatigue<footnote ID="_Ref37767513">Includes asthenia and fatigue</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>60</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>35</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>45</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Abdominal pain<footnote ID="_Ref37767543">Includes abdominal pain, abdominal pain upper, abdominal pain lower</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Constipation</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Stomatitis<footnote ID="_Ref37767564">Includes stomatitis and mouth ulceration</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and Lymphatic System Disorders </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Anemia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Thrombocytopenia<footnote ID="_Ref37767584">Includes platelets count decreased and thrombocytopenia</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Neutropenia<footnote ID="_Ref37767576">Includes neutropenia, febrile neutropenia and neutrophil count decreased</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and Nutrition Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Decreased appetite</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Back pain</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Arthralgia</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and Subcutaneous Tissue Disorder</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Rash<footnote ID="_Ref37767675">Includes rash erythematous, rash macular and rash maculo-papular</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Dyspnea<footnote ID="_Ref37767688">Includes dyspnea and dyspnea exertional</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Infections and Infestations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Nasopharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Dysgeusia</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph>In addition, the adverse reactions observed in POLO that occurred in &lt;10% of patients receiving Lynparza were cough (9%), abdominal pain upper (7%), blood creatinine increased (7%), dizziness (7%), headache (7%), dyspepsia (5%), leukopenia (5%), hypersensitivity (2%), and lymphopenia (2%).</paragraph> <table width="100%"> <caption>Table 15 Laboratory Abnormalities Reported in ≥25% of Patients in POLO</caption> <col width="46%"/> <col width="18%"/> <col width="12%"/> <col width="12%"/> <col width="12%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Laboratory</content> </paragraph> <paragraph> <content styleCode="bold">Parameter</content> <footnote ID="_Ref38535087">Patients were allowed to enter POLO with hemoglobin ≥9 g/dL (CTCAE Grade 2) and other laboratory values of CTCAE Grade 1. </footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref38535114">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">=91</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnoteRef IDREF="_Ref38535114"/> <content styleCode="bold">=60</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4 (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in serum creatinine</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>99</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>85</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>86</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>65</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increase in mean corpuscular volume<footnote ID="_Ref38535130">Represents the proportion of subjects whose mean corpuscular volume was &gt; ULN.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>71</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>61</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in platelets</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>56</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>39</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>50</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="underline">HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer</content> </paragraph> <paragraph> <content styleCode="italics">PROfound</content> </paragraph> <paragraph>The safety of Lynparza as monotherapy was evaluated in patients with mCRPC and HRR gene mutations who have progressed following prior treatment with enzalutamide or abiraterone in PROfound <content styleCode="italics">[see <linkHtml href="#ID_d17760ea-331e-411a-8649-1791b3994867">Clinical Studies (14.7)</linkHtml>]</content>. This study was a randomized, open-label, multi-center study in which 386 patients received either Lynparza tablets 300 mg orally twice daily (n=256) or investigator’s choice of enzalutamide or abiraterone acetate (n=130) until disease progression or unacceptable toxicity. Among patients receiving Lynparza, 62% were exposed for 6 months or longer and 20% were exposed for greater than one year.</paragraph> <paragraph>Fatal adverse reactions occurred in 4% of patients treated with Lynparza. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%).</paragraph> <paragraph>Serious adverse reactions occurred in 36% of patients receiving Lynparza. The most frequent serious adverse reactions (≥2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%), and urinary tract infection (2%).</paragraph> <paragraph>Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 22% of Lynparza patients. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (25%) and thrombocytopenia (6%) and the most frequent adverse reaction leading to reduction of Lynparza was anemia (16%). Discontinuation due to adverse reactions occurred in 18% of Lynparza. The adverse reaction that most frequently led to discontinuation of Lynparza was anemia (7%).</paragraph> <paragraph>Tables 16 and 17 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in PROfound.</paragraph> <table width="100%"> <caption>Table 16 Adverse Reactions<footnote ID="_Ref40249232">Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03</footnote> Reported in ≥10% of Patients in PROfound</caption> <col width="35%"/> <col width="15%"/> <col width="17%"/> <col width="16%"/> <col width="16%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Reactions</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n=256</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Enzalutamide or abiraterone </content> </paragraph> <paragraph> <content styleCode="bold">n=130</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">(%)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Blood and lymphatic disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Anemia<footnote ID="_Ref40249300">Includes anemia and hemoglobin decreased</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>46</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Thrombocytopenia<footnote ID="_Ref40249329">Includes platelet count decreased and thrombocytopenia</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Nausea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>41</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General disorders and administration site conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Fatigue (including asthenia)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>41</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>32</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and nutrition disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Decreased appetite </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory, thoracic, and mediastinal disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Cough</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>    Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> <paragraph>In addition, adverse reactions of clinical relevance in PROfound that occurred in &lt;10% of patients receiving Lynparza were neutropenia (9%), venous thromboembolic events (7%), dizziness (7%), dysgeusia (7%), dyspepsia (7%), headache (6%), pneumonia (5%), stomatitis (5%), rash (4%), blood creatinine increase (4%), pneumonitis (2%), upper abdominal pain (2%), and hypersensitivity (1%).</paragraph> <table width="100%"> <caption>Table 17 Laboratory Abnormalities Reported in ≥25% of Patients in PROfound</caption> <col width="39%"/> <col width="16%"/> <col width="14%"/> <col width="16%"/> <col width="15%"/> <tbody> <tr> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">Laboratory<br/>Parameter<footnote ID="_Ref40249509">Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.</footnote> </content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnote ID="_Ref40249547">This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.</footnote> <content styleCode="bold">= 256</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Enzalutamide or abiraterone </content> </paragraph> <paragraph> <content styleCode="bold">n</content> <footnoteRef IDREF="_Ref40249547"/> <content styleCode="bold">=130</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">n= 247 (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">n=247 (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 1-4</content> </paragraph> <paragraph> <content styleCode="bold">n=124 (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Grades 3-4</content> </paragraph> <paragraph> <content styleCode="bold">n=124 (%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in hemoglobin </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>242 (98)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>33 (13)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>91 (73)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5 (4)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in lymphocytes </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>154 (62)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>57 (23)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>42 (34)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>16 (13)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decrease in leukocytes</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>130 (53)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>9 (4)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>26 (21)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Decrease in absolute neutrophil count</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>83 (34)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>8 (3)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>11 (9)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_d93b615f-46ed-49a4-988c-59a9e5ffeb6e"> <id root="35fa6055-2298-40f3-93e6-3ff8e1b5ac63"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>6.2 Postmarketing Experience </title> <text> <paragraph>The following adverse reactions have been identified during post approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</paragraph> <paragraph> <content styleCode="italics">Immune System Disorders</content>: Hypersensitivity including angioedema.</paragraph> <paragraph> <content styleCode="italics">Skin and subcutaneous tissue disorders</content>: Erythema nodosum, rash, dermatitis.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_3fd598f8-f32a-43ef-805c-6c59b2c9492a"> <id root="c51ea947-858c-4c90-95a3-268d3b42a0d4"/> <code code="34073-7" codeSystem="2.16.840.1.113883.6.1" displayName="DRUG INTERACTIONS SECTION"/> <title>7 DRUG INTERACTIONS</title> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <list listType="unordered"> <item> <caption>•</caption>Strong or moderate CYP3A inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce Lynparza dosage. (<linkHtml href="#ID_6fbd0e2a-f3c4-47b1-9654-a235e09236f8">2.4</linkHtml>, <linkHtml href="#ID_234fa3d4-b847-4ab5-a73b-8b5807c75f9e">7.2</linkHtml>, <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">12.3</linkHtml>)</item> <item> <caption>•</caption>Strong or moderate CYP3A inducers: Avoid concomitant use. (<linkHtml href="#ID_234fa3d4-b847-4ab5-a73b-8b5807c75f9e">7.2</linkHtml>, <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">12.3</linkHtml>)</item> </list> </text> </highlight> </excerpt> <component> <section ID="ID_3a7cc754-5ab8-4628-bfcd-c04b13a60a3c"> <id root="590d916f-6dc2-47b2-9b43-769fa80f0359"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>7.1 Use with Anticancer Agents</title> <text> <paragraph>Clinical studies of Lynparza with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_234fa3d4-b847-4ab5-a73b-8b5807c75f9e"> <id root="dd76bb30-0cf6-438f-9327-e7dcfcb2047b"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>7.2 Effect of Other Drugs on Lynparza</title> <text> <paragraph> <content styleCode="underline">Strong and Moderate CYP3A Inhibitors</content> </paragraph> <paragraph>Coadministration of CYP3A inhibitors can increase olaparib concentrations, which may increase the risk for adverse reactions <content styleCode="italics">[see <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">Clinical Pharmacology (12.3)</linkHtml>]</content>. Avoid coadministration of strong or moderate CYP3A inhibitors. If the strong or moderate inhibitor must be coadministered, reduce the dose of Lynparza <content styleCode="italics">[see <linkHtml href="#ID_6fbd0e2a-f3c4-47b1-9654-a235e09236f8">Dosage and Administration (2.4)</linkHtml>].</content> </paragraph> <paragraph> <content styleCode="underline">Strong and Moderate CYP3A Inducers</content> </paragraph> <paragraph>Concomitant use with a strong or moderate CYP3A inducer decreased olaparib exposure, which may reduce Lynparza efficacy <content styleCode="italics">[see <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">Clinical Pharmacology (12.3)</linkHtml>]</content>. Avoid coadministration of strong or moderate CYP3A inducers.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_48eda289-ce49-43e5-a0ff-25be17bc2878"> <id root="a3577cb2-b7a5-4eea-9c83-623097324bbb"/> <code code="43684-0" codeSystem="2.16.840.1.113883.6.1" displayName="USE IN SPECIFIC POPULATIONS SECTION"/> <title>8 USE IN SPECIFIC POPULATIONS </title> <effectiveTime value="20210610"/> <excerpt> <highlight> <text> <paragraph>Lactation: Advise women not to breastfeed. <linkHtml href="#ID_36d256f0-3f04-4f55-9999-1d9af2481676">(8.2)</linkHtml> </paragraph> <paragraph> </paragraph> </text> </highlight> </excerpt> <component> <section ID="ID_929586ba-127d-4cc0-bd5a-dfdea42c2b87"> <id root="bc72ee58-8b4c-4174-8564-d26e88cd583e"/> <code code="42228-7" codeSystem="2.16.840.1.113883.6.1" displayName="PREGNANCY SECTION"/> <title>8.1 Pregnancy </title> <text> <paragraph> <content styleCode="underline">Risk Summary </content> </paragraph> <paragraph>Based on findings in animals and its mechanism of action <content styleCode="italics">[see <linkHtml href="#ID_af238e10-429f-4e93-8c20-da3a88f8e6b1">Clinical Pharmacology (12.1)</linkHtml>]</content>, Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug-associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 300 mg twice daily <content styleCode="italics">(see <linkHtml href="#ID_c9ebe97b-0233-452d-9d74-642cc2cda794">Data</linkHtml>).</content> Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy.</paragraph> <paragraph>The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies.</paragraph> </text> <effectiveTime value="20210610"/> <component> <section ID="ID_c9ebe97b-0233-452d-9d74-642cc2cda794"> <id root="6f6bd552-f9f5-450f-8b88-0e47575748f4"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>Data </title> <text> <paragraph> <content styleCode="italics"> <content styleCode="underline">Animal Data</content> </content> </paragraph> <paragraph>In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to Day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 7% of the human exposure (AUC_0-24h) at the recommended dose).</paragraph> <paragraph>In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.18% of human exposure (AUC_0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital), and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter, and umbilical artery. Some findings noted above in the eyes, ribs, and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section> </component> <component> <section ID="ID_36d256f0-3f04-4f55-9999-1d9af2481676"> <id root="e5053332-c4e5-4acf-8f1d-9da9f6ce8c28"/> <code code="77290-5" codeSystem="2.16.840.1.113883.6.1" displayName="LACTATION SECTION"/> <title>8.2 Lactation </title> <text> <paragraph> <content styleCode="underline">Risk Summary</content> </paragraph> <paragraph>No data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.</paragraph> </text> <effectiveTime value="20180112"/> </section> </component> <component> <section ID="ID_aefb7be1-5ba8-4334-8dcc-19abb24c2cad"> <id root="406f12fc-3a7c-4815-b28f-b0708985781d"/> <code code="77291-3" codeSystem="2.16.840.1.113883.6.1" displayName="FEMALES &amp; MALES OF REPRODUCTIVE POTENTIAL SECTION"/> <title>8.3 Females and Males of Reproductive Potential </title> <text> <paragraph> <content styleCode="underline">Pregnancy Testing</content> </paragraph> <paragraph>Recommend pregnancy testing for females of reproductive potential prior to initiating treatment with Lynparza.</paragraph> <paragraph> <content styleCode="underline">Contraception</content> </paragraph> <paragraph> <content styleCode="italics">Females</content> </paragraph> <paragraph>Lynparza can cause fetal harm when administered to a pregnant woman <content styleCode="italics">[see <linkHtml href="#_8.1_Pregnancy">Use in Specific Populations (8.1)</linkHtml>]</content>. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least 6 months following the last dose.</paragraph> <paragraph> <content styleCode="italics">Males</content> </paragraph> <paragraph>Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza <content styleCode="italics">[see <linkHtml href="#ID_929586ba-127d-4cc0-bd5a-dfdea42c2b87">Use in Specific Populations (8.1)</linkHtml> and <linkHtml href="#ID_9afb73ea-ade3-4918-8f87-3930234a80c5">Nonclinical Toxicology (13.1)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_27b6a6c4-83ae-449c-803f-8a1bb4263aa1"> <id root="3df061fc-5596-451e-8ac7-94576b148743"/> <code code="34081-0" codeSystem="2.16.840.1.113883.6.1" displayName="PEDIATRIC USE SECTION"/> <title>8.4 Pediatric Use </title> <text> <paragraph>Safety and effectiveness of Lynparza have not been established in pediatric patients.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_4d07f763-3e79-4038-a8f6-ad32f602e854"> <id root="3a4afa54-8130-43d5-9871-3809b8d1aef3"/> <code code="34082-8" codeSystem="2.16.840.1.113883.6.1" displayName="GERIATRIC USE SECTION"/> <title>8.5 Geriatric Use </title> <text> <paragraph>Of the 2351 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily as monotherapy, 596 (25%) patients were aged ≥65 years, and this included 137 (6%) patients who were aged ≥75 years. Seven (0.3%) patients were aged ≥85 years. </paragraph> <paragraph>Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab, 204 (38%) patients were aged ≥65 years, and this included 31 (6%) patients who were aged ≥75 years. </paragraph> <paragraph>No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_cb156c67-c307-4a85-a1f2-ccacbc188d60"> <id root="29fad601-3bed-4571-8f4a-a23de718473a"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.6 Renal Impairment </title> <text> <paragraph>No dosage modification is recommended in patients with mild renal impairment (CLcr 51 to 80 mL/min estimated by Cockcroft-Gault). Reduce Lynparza dosage to 200 mg twice daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min) <content styleCode="italics">[see <linkHtml href="#ID_a7348257-58ce-4f6f-a756-64f8ca4e9ed4">Dosage and Administration (2.5)</linkHtml>].</content> There are no data in patients with severe renal impairment or end-stage disease (CLcr ≤30 mL/min) <content styleCode="italics">[see <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">Clinical Pharmacology (12.3)</linkHtml>].</content> </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_e660cd39-e1bd-4f7f-9bff-69ebe85c9971"> <id root="4c980d7e-06f1-470e-a058-7e5814be609a"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>8.7 Hepatic Impairment </title> <text> <paragraph>No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C) <content styleCode="italics">[see <linkHtml href="#ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_b7fb1b56-9cab-4085-89a4-1368c526dd96"> <id root="d975d9d5-c143-4808-9f87-21ee57290157"/> <code code="34089-3" codeSystem="2.16.840.1.113883.6.1" displayName="DESCRIPTION SECTION"/> <title>11 DESCRIPTION</title> <text> <paragraph>Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one. The empirical molecular formula for Lynparza is C24H23FN4O3 and the relative molecular mass is 434.46. It has the following chemical structure:</paragraph> <renderMultiMedia ID="id219324315" referencedObject="ID_26fdf1c5-8b42-4196-9277-4dc1052601a2"/> <paragraph>Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility across the physiological pH range.</paragraph> <paragraph>Lynparza (olaparib) tablets for oral use contain 100 mg or 150 mg of olaparib. Inactive ingredients in the tablet core are copovidone, mannitol, colloidal silicon dioxide, and sodium stearyl fumarate. The tablet coating consists of hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow, and ferrosoferric oxide (150 mg tablet only).</paragraph> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="ID_26fdf1c5-8b42-4196-9277-4dc1052601a2"> <text>Checmical Structure</text> <value mediaType="image/jpeg"> <reference value="image-01.jpg"/> </value> </observationMedia> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_30e57064-80a1-41aa-be14-cabecf9aea8b"> <id root="7c4a21bf-99c0-4490-a370-6e6765f2deb5"/> <code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/> <title>12 CLINICAL PHARMACOLOGY</title> <effectiveTime value="20210610"/> <component> <section ID="ID_af238e10-429f-4e93-8c20-da3a88f8e6b1"> <id root="90ea4cb6-6dac-48b7-a0bc-ff422ce79364"/> <code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/> <title>12.1 Mechanism of Action</title> <text> <paragraph>Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer, both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in <content styleCode="italics">BRCA1/2</content>, <content styleCode="italics">ATM</content>, or other genes involved in the homologous recombination repair (HRR) of DNA damage and correlated with platinum response. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death. </paragraph> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_1f8dc4e1-7f63-4628-8218-46964d928456"> <id root="255f972b-a871-46b2-89b3-04de70d6575c"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>12.2 Pharmacodynamics </title> <text> <paragraph> <content styleCode="underline">Cardiac Electrophysiology</content> </paragraph> <paragraph>The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of olaparib on QT interval was observed.</paragraph> </text> <effectiveTime value="20180112"/> </section> </component> <component> <section ID="ID_30b0040c-2cc0-4a63-8e0a-6a2b348cfff6"> <id root="da91d146-3821-40ef-a5e1-3a2b5909a723"/> <code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/> <title>12.3 Pharmacokinetics</title> <text> <paragraph>The area under the curve (AUC) of olaparib increases approximately proportionally following administration of single doses of 25 mg to 450 mg (0.08 to 1.5 times the recommended dose) and maximal concentrations (C_max) increased slightly less than proportionally for the same dose range. Olaparib showed time-dependent pharmacokinetics and an AUC mean accumulation ratio of 1.8 is observed at steady state following a dose of 300 mg twice daily.</paragraph> <paragraph>The mean (CV%) olaparib C_max is 5.4 μg/mL (32%) and AUC is 39.2 μg*h/mL (44%) following a single 300 mg dose. The mean steady state olaparib C_max and AUC is 7.6 μg/mL (35%) and 49.2 μg*h/mL (44%), following a dose of 300 mg twice daily.</paragraph> <paragraph> <content styleCode="underline">Absorption</content> </paragraph> <paragraph>Following oral administration of olaparib, the median time to peak plasma concentration is 1.5 hours. </paragraph> <paragraph> <content styleCode="italics">Effect of Food </content> </paragraph> <paragraph>Co-administration of a high fat and high calorie meal (800-1000 kcal, 50% of the calorie content made up from fat) with olaparib slowed the rate (t_max delayed by 2.5 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 8%).</paragraph> <paragraph> <content styleCode="underline">Distribution</content> </paragraph> <paragraph>The mean (± standard deviation) apparent volume of distribution of olaparib is 158 ± 136 L following a single 300 mg dose of Lynparza. The protein binding of olaparib is approximately 82% in vitro.</paragraph> <paragraph> <content styleCode="underline">Elimination</content> </paragraph> <paragraph>The mean (± standard deviation) terminal plasma half-life of olaparib is 14.9 ± 8.2 hours and the apparent plasma clearance is 7.4 ± 3.9 L/h following a single 300 mg dose of Lynparza.</paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">Metabolism</content> </content> </paragraph> <paragraph>Olaparib is metabolized by cytochrome P450 (CYP) 3A in vitro.</paragraph> <paragraph>Following an oral dose of radiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of the circulating radioactivity in plasma. It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.</paragraph> <paragraph> <content styleCode="italics"> <content styleCode="underline">Excretion</content> </content> </paragraph> <paragraph>Following a single dose of radiolabeled olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.</paragraph> <paragraph> <content styleCode="underline">Specific Populations</content> </paragraph> <paragraph> <content styleCode="italics">Patients with Renal Impairment</content> </paragraph> <paragraph>In a renal impairment trial, the mean AUC increased by 24% and C_maxby 15%, when olaparib was dosed in patients with mild renal impairment (CLcr=51-80 mL/min defined by the Cockcroft-Gault equation; n=13) and by 44% and 26%, respectively, when olaparib was dosed in patients with moderate renal impairment (CLcr=31-50 mL/min; n=13), compared to those with normal renal function (CLcr ≥81 mL/min; n=12). There was no evidence of a relationship between the extent of plasma protein binding of olaparib and creatinine clearance. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min). </paragraph> <paragraph> <content styleCode="italics">Patients with Hepatic Impairment</content> </paragraph> <paragraph>In a hepatic impairment trial, the mean AUC increased by 15% and the mean C_max increased by 13% when olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; n=10) and the mean AUC increased by 8% and the mean C_max decreased by 13% when olaparib was dosed in patients with moderate hepatic impairment (Child-Pugh classification B; n=8), compared to patients with normal hepatic function (n=13). Hepatic impairment has no effect on the protein binding of olaparib and, therefore, total plasma exposure was representative of free drug. There are no data in patients with severe hepatic impairment (Child-Pugh classification C).</paragraph> <paragraph> <content styleCode="underline">Drug Interaction Studies </content> </paragraph> <paragraph> <content styleCode="italics">Clinical Studies</content> </paragraph> <paragraph> <content styleCode="italics">CYP3A Inhibitors:</content> Concomitant use of itraconazole (strong CYP3A inhibitor) increased olaparib C_max by 42% and AUC by 170%. Concomitant use of fluconazole (moderate CYP3A inhibitor) is predicted to increase olaparib C_max by 14% and AUC by 121%. </paragraph> <paragraph> <content styleCode="italics">CYP3A Inducers</content>: Concomitant use of rifampicin (strong CYP3A inducer) decreased olaparib C_max by 71% and AUC by 87%. Concomitant use of efavirenz (moderate CYP3A inducer) is predicted to decrease olaparib C_max by 31% and AUC by 60%.</paragraph> <paragraph> <content styleCode="italics">In vitro Studies</content> </paragraph> <paragraph> <content styleCode="italics">CYP Enzymes</content>: Olaparib is both an inhibitor and inducer of CYP3A and an inducer of CYP2B6. Olaparib is predicted to be a weak CYP3A inhibitor in humans. </paragraph> <paragraph> <content styleCode="italics">UGT Enzymes</content>: Olaparib is an inhibitor of UGT1A1.</paragraph> <paragraph> <content styleCode="italics">Transporters</content>: Olaparib is an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K. Olaparib is a substrate and inhibitor of the efflux transporter P-gp. The potential for olaparib to induce P-gp has not been evaluated.</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_d449726f-d421-48dc-b965-ec10c0a275f2"> <id root="673c5e0f-616f-486c-94df-1da1057a71f9"/> <code code="43680-8" codeSystem="2.16.840.1.113883.6.1" displayName="NONCLINICAL TOXICOLOGY SECTION"/> <title>13 NONCLINICAL TOXICOLOGY</title> <effectiveTime value="20210610"/> <component> <section ID="ID_9afb73ea-ade3-4918-8f87-3930234a80c5"> <id root="38319e5d-f50a-44e1-b9dd-9a525f388d3f"/> <code code="34083-6" codeSystem="2.16.840.1.113883.6.1" displayName="CARCINOGENESIS &amp; MUTAGENESIS &amp; IMPAIRMENT OF FERTILITY SECTION"/> <title>13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility</title> <text> <paragraph>Carcinogenicity studies have not been conducted with olaparib.</paragraph> <paragraph>Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian Chinese hamster ovary (CHO) cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test.</paragraph> <paragraph>In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 7% of the human exposure (AUC_0-24h) at the recommended dose).</paragraph> <paragraph>In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 5% of the human exposure (AUC_0-24h) at the recommended dose).</paragraph> </text> <effectiveTime value="20210610"/> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_be39be5d-9087-4fbb-8a86-e7018353bdd3"> <id root="08254f40-1386-4421-9ed0-35c8a42fe283"/> <code code="34092-7" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL STUDIES SECTION"/> <title>14 CLINICAL STUDIES</title> <effectiveTime value="20210610"/> <component> <section ID="ID_1cd4967a-8800-4f31-9795-c91580895e7e"> <id root="fb9cd6f8-bd87-4d4b-9d8f-c56d73d9eed6"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.1 First-Line Maintenance Treatment of <content styleCode="italics">BRCA</content>-mutated Advanced Ovarian Cancer </title> <text> <paragraph>The efficacy of Lynparza was evaluated in SOLO-1 (NCT01844986), a randomized (2:1), double-blind, placebo-controlled, multi-center trial in patients with <content styleCode="italics">BRCA</content>-mutated advanced ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo. Treatment was continued for up to 2 years or until disease progression or unacceptable toxicity; however, patients with evidence of disease at 2 years, who in the opinion of the treating healthcare provider could derive further benefit from continuous treatment, could be treated beyond 2 years. Randomization was stratified by response to first-line platinum-based chemotherapy (complete or partial response). The major efficacy outcome was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.</paragraph> <paragraph>A total of 391 patients were randomized, 260 to Lynparza and 131 to placebo. The median age of patients treated with Lynparza was 53 years (range: 29 to 82) and 53 years (range: 31 to 84) among patients on placebo. The ECOG performance status (PS) was 0 in 77% of patients receiving Lynparza and 80% of patients receiving placebo. Of all patients, 82% were White, 36% were enrolled in the U.S. or Canada, and 82% were in complete response to their most recent platinum-based regimen. The majority of patients (n=389) had germline <content styleCode="italics">BRCA</content> mutation (g<content styleCode="italics">BRCA</content>m), and 2 patients had somatic <content styleCode="italics">BRCA</content>m (s<content styleCode="italics">BRCA</content>m). </paragraph> <paragraph>Of the 391 patients randomized in SOLO-1, 386 were retrospectively or prospectively tested with a Myriad BRACAnalysis test and 383 patients were confirmed to have deleterious or suspected deleterious g<content styleCode="italics">BRCA</content>m status; 253 were randomized to the Lynparza arm and 130 to the placebo arm. Two out of 391 patients randomized in SOLO-1 were confirmed to have s<content styleCode="italics">BRCA</content>m based on an investigational Foundation Medicine tissue test.</paragraph> <paragraph>SOLO-1 demonstrated a statistically significant improvement in investigator-assessed PFS for Lynparza compared to placebo. Results from a blinded independent review were consistent. At the time of the analysis of PFS, overall survival (OS) data were not mature (21% of patients had died). Efficacy results are presented in Table 18 and Figure 1.</paragraph> <table width="100%"> <caption>Table 18 Efficacy Results - SOLO-1 (Investigator Assessment)</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">(n=260)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">(n=131)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> <footnote ID="_Ref523301911">Median follow up of 41 months in both treatment arms.</footnote> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>102 (39%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>96 (73%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>NR</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Hazard ratio<footnote ID="_Ref523356087">A value &lt;1 favors olaparib. Hazard ratio from a Cox proportional hazards model including response to previous platinum chemotherapy (complete response versus partial response) as a covariate.</footnote> (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.30 (0.23, 0.41)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     p-value<footnote ID="_Ref532812844">The p-value is derived from a stratified log-rank test.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>&lt;0.0001</paragraph> </td> </tr> <tr> <td colspan="3" valign="top"> <paragraph>NR not reached; CI Confidence Interval.</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 1 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival - SOLO-1 </content> </paragraph> <renderMultiMedia ID="id577561240" referencedObject="ID_1403f7ce-0549-4f6d-8a25-eeb7777034b5"/> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="ID_1403f7ce-0549-4f6d-8a25-eeb7777034b5"> <text>Figure 1</text> <value mediaType="image/jpeg"> <reference value="Figure_1.jpg"/> </value> </observationMedia> </component> </section> </component> <component> <section ID="ID_5a17802b-5c8c-4312-99af-7dddee79b3ea"> <id root="ff6f3a7b-acac-438b-87b6-094680b7bac6"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.2 First-line Maintenance Treatment of HRD-positive Advanced Ovarian Cancer in Combination with Bevacizumab </title> <text> <paragraph>PAOLA-1 (NCT02477644) was a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of Lynparza in combination with bevacizumab versus placebo/bevacizumab for the maintenance treatment of advanced high-grade epithelial ovarian cancer, fallopian tube or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab. Randomization was stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and t<content styleCode="italics">BRCA</content>m status, determined by prospective local testing. All available clinical samples were retrospectively tested with Myriad myChoice^® CDx. Patients were required to have no evidence of disease (NED) due to complete surgical resection, or who were in complete response (CR), or partial response (PR) following completion of first-line platinum-containing chemotherapy and bevacizumab. Patients were randomized (2:1) to receive Lynparza tablets 300 mg orally twice daily in combination with bevacizumab (n=537) 15 mg/kg every three weeks or placebo/bevacizumab (n=269) Patients continued bevacizumab in the maintenance setting and started treatment with Lynparza after a minimum of 3 weeks and up to a maximum of 9 weeks following completion of their last dose of chemotherapy. Lynparza treatment was continued for up to 2 years or until progression of the underlying disease or unacceptable toxicity. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond 2 years. Treatment with bevacizumab was for a total of up to 15 months, including the period given with chemotherapy and given as maintenance. </paragraph> <paragraph>The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy endpoint was overall survival (OS).</paragraph> <paragraph>The median age of patients in both arms was 61 years overall (range 26 to 87). Ovarian cancer was the primary tumor type in 86% of patients in both arms. Ninety six percent (96%) were serous histological type. The ECOG performance score was 0 in 70% of patients and 1 in 28% of patients, overall. All patients had received first-line platinum-based therapy and bevacizumab. First-line treatment outcomes at screening indicated that patients had no evidence of disease with complete macroscopic resection at initial debulking surgery (32%, both arms), no evidence of disease/ CR with complete macroscopic resection at interval debulking surgery (31%, both arms), no evidence of disease/ CR in patients who had either incomplete resection (at initial or interval debulking surgery) or no debulking surgery (15%, both arms) and patients with a partial response (22%, both arms). Thirty percent (30%) of patients in both arms had a deleterious mutation. Patients were not restricted by the surgical outcome with 65% having complete cytoreduction at initial or interval debulking surgery and 35% having residual macroscopic disease. Demographics and baseline disease characteristics were balanced and comparable between the study and placebo arms in the Intention to Treat (ITT) population and also in the HRD-positive subgroup.</paragraph> <paragraph>Efficacy results from a biomarker subgroup analysis of 387 patients with HRD-positive tumors, identified post-randomization using the Myriad myChoice^® HRD Plus tumor test, who received Lynparza/bevacizumab (n=255) or placebo/bevacizumab (n=132), are summarized in Table 19 and Figure 2. Results from a blinded independent review of PFS were consistent. Overall survival data in this subpopulation were immature with 16% deaths.</paragraph> <table width="100%"> <caption>Table 19 Efficacy Results - PAOLA-1 (HRD-positive status<footnote ID="_Ref40861909">Median follow-up of 27.4 months in Lynparza/bevacizumab arm and 27.5 months in placebo/bevacizumab arm.</footnote>, Investigator Assessment)</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza/bevacizumab</content> </paragraph> <paragraph> <content styleCode="bold">(n=255)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo/bevacizumab</content> </paragraph> <paragraph> <content styleCode="bold">(n=132)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>87 (34%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>92 (70%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>37.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17.7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Hazard ratio<footnote ID="_Ref40861987">The analysis was performed using an unstratified Cox proportional hazards model.</footnote> (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.33 (0.25, 0.45)</paragraph> </td> </tr> <tr> <td colspan="3" valign="top"> <paragraph>CI Confidence interval</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 2 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – PAOLA-1 (HRD-positive status)</content> </paragraph> <renderMultiMedia ID="id293028155" referencedObject="ID_29e5ddc8-f011-49ad-96c4-d8d6449047e0"/> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="ID_29e5ddc8-f011-49ad-96c4-d8d6449047e0"> <text>Figure 2</text> <value mediaType="image/jpeg"> <reference value="image-06.jpg"/> </value> </observationMedia> </component> </section> </component> <component> <section ID="ID_b383168c-2afc-46a7-b1ec-09e1d4930470"> <id root="d9ca9543-843d-4eec-9adc-533081136a50"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.3 Maintenance Treatment of Recurrent Ovarian Cancer </title> <text> <paragraph>The efficacy of Lynparza was investigated in two randomized, placebo-controlled, double-blind, multi-center studies in patients with recurrent ovarian cancers who were in response to platinum-based therapy.</paragraph> <paragraph> <content styleCode="underline">SOLO-2</content> </paragraph> <paragraph>The efficacy of Lynparza was evaluated in SOLO-2 (NCT01874353), a randomized (2:1) double-blind, placebo-controlled trial in patients with g<content styleCode="italics">BRCA</content>m ovarian, fallopian tube, or primary peritoneal cancer. Patients were randomized to Lynparza tablets 300 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete versus partial) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 months versus &gt;12 months). All patients had received at least two prior platinum-containing regimens and were in response (complete or partial) to their most recent platinum-based regimen. The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST, version 1.1. An additional efficacy outcome measure was OS.</paragraph> <paragraph>A total of 295 patients were randomized, 196 to Lynparza and 99 to placebo. The median age of patients treated with Lynparza was 56 years (range: 28 to 83) and 56 years (range: 39 to 78) among patients treated with placebo. The ECOG PS was 0 in 83% of patients receiving Lynparza and 78% of patients receiving placebo. Of all patients, 89% were White, 17% were enrolled in the U.S. or Canada, 47% were in complete response to their most recent platinum-based regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum regimen. Prior bevacizumab therapy was reported for 17% of those treated with Lynparza and 20% of those receiving placebo. Approximately 44% of patients on the Lynparza arm and 37% on placebo had received three or more lines of platinum-based treatment.</paragraph> <paragraph>All patients had a deleterious or suspected deleterious germline <content styleCode="italics">BRCA</content> mutation as detected either by a local test (n=236) or central Myriad CLIA test (n=59), subsequently confirmed by BRACAnalysis CDx^® (n=286).</paragraph> <paragraph>SOLO-2 demonstrated a statistically significant improvement in investigator-assessed PFS in patients randomized to Lynparza as compared with placebo. Results from a blinded independent review were consistent. The final analysis of OS did not reach statistical significance. Efficacy results are presented in Table 20 and Figures 3 and 4.</paragraph> <table cellpadding="0pt" width="100.86%"> <caption>Table 20 Efficacy Results - SOLO-2 (Investigator Assessment)</caption> <col width="39%"/> <col width="31%"/> <col width="31%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Lynparza tablets<br/>(n=196)</content> </th> <th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <content styleCode="bold">Placebo<br/>(n=99)</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>     Number of events (%)</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>107 (55%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>80 (81%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Median, months </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5.5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Hazard ratio<footnote ID="_Ref49141538">Hazard ratio from a Cox proportional hazards model including response to last platinum chemotherapy (complete response versus partial response) and time to disease progression in the penultimate platinum-based chemotherapy prior to enrollment (6-12 month versus &gt;12 months) as covariates.</footnote> (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.30 (0.22, 0.41)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>      p-value^† </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>&lt;0.0001</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Survival</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>116 (59)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>65 (66)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Median, months </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>51.7</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>38.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>     Hazard ratio<footnoteRef IDREF="_Ref49141538"/> (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.74 (0.54, 1.00)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>      p-value<footnote ID="_Ref49141662">The p-value is derived from a stratified log-rank test.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>p=0.0537</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 3 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival – SOLO-2</content> </paragraph> <renderMultiMedia ID="id494993279" referencedObject="ID_515ffc45-3fbd-45ff-b0f5-4986bfe31f41"/> <paragraph> <content styleCode="bold">Figure 4 Kaplan-Meier Curves of Overall Survival – SOLO-2</content> </paragraph> <renderMultiMedia ID="id267278461" referencedObject="ID_4463722c-4e9f-40ae-a5e6-dcb3b3cb8212"/> <paragraph> <content styleCode="underline">Study 19</content> </paragraph> <paragraph>The efficacy of Lynparza was evaluated in Study 19 (NCT00753545), a randomized (1:1) double-blind, placebo-controlled trial in patients with platinum-sensitive ovarian cancer who had received 2 or more previous platinum-containing regimens. Patients were randomized to Lynparza capsules 400 mg orally twice daily or placebo until unacceptable toxicity or progressive disease. Randomization was stratified by response to last platinum chemotherapy (complete response versus partial response), time to disease progression in the penultimate platinum-based chemotherapy (6-12 months versus &gt;12 months), and descent (Jewish versus non-Jewish). The major efficacy outcome measure was investigator-assessed PFS according to RECIST, version 1.0. </paragraph> <paragraph>A total of 265 patients were randomized, 136 to Lynparza and 129 to placebo. The median age of patients treated with Lynparza was 58 years (range: 21 to 89) and 59 years (range 33 to 84) among patients treated with placebo. ECOG PS was 0 in 81% of patients receiving Lynparza and 74% of patients receiving placebo. Of all patients, 97% were White, 19% were enrolled in the US or Canada, 45% were in complete response following their most recent platinum chemotherapy regimen, and 40% had a progression-free interval of 6-12 months since their penultimate platinum. Prior bevacizumab therapy was reported for 13% of patients receiving Lynparza and 16% of patients receiving placebo. </paragraph> <paragraph>A retrospective analysis for germline <content styleCode="italics">BRCA</content> mutation status, some performed using the Myriad test, indicated that 36% (n=96) of patients from the ITT population had deleterious g<content styleCode="italics">BRCA</content> mutation, including 39% (n=53) of patients on Lynparza and 33% (n=43) of patients on placebo.</paragraph> <paragraph>Efficacy results are presented in Table 21 and Figure 5. Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with Lynparza versus placebo.</paragraph> <table width="100%"> <caption>Table 21 Efficacy Results - Study 19 (Investigator Assessment)</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza capsules</content> </paragraph> <paragraph> <content styleCode="bold">(n=136)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">(n=129)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>60 (44%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>94 (73%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>8.4</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Hazard ratio<footnote ID="_Ref23953607">Hazard ratio from a Cox proportional hazards model including response to last platinum chemotherapy (complete response versus partial response), time to disease progression in the penultimate platinum-based chemotherapy (6-12 months versus &gt;12 months) and Jewish descent (yes versus no) as covariates.</footnote> (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.35 (0.25, 0.49)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     p-value<footnote ID="_Ref23953629">The p-value is derived from a Cox proportional hazards model.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>&lt;0.0001</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Survival</content> <footnote ID="_Ref23953638">Without adjusting for multiple analyses.</footnote> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>98 (72%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>112 (87%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>29.8</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>27.8</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Hazard ratio (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0.73 (0.55, 0.95)</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 5 Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival - Study 19</content> </paragraph> <renderMultiMedia ID="id357855580" referencedObject="ID_4cfbdcad-1315-40e9-b17b-b51170993682"/> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="ID_515ffc45-3fbd-45ff-b0f5-4986bfe31f41"> <text>Figure 3</text> <value mediaType="image/jpeg"> <reference value="image-02.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_4463722c-4e9f-40ae-a5e6-dcb3b3cb8212"> <text>Figure 4</text> <value mediaType="image/jpeg"> <reference value="image-07.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="ID_4cfbdcad-1315-40e9-b17b-b51170993682"> <text>Figure 4</text> <value mediaType="image/jpeg"> <reference value="image-03.jpg"/> </value> </observationMedia> </component> </section> </component> <component> <section ID="ID_9639caef-740b-4d6d-81fb-c72fa258af8d"> <id root="f2cc962b-f9b7-452c-bc81-ebe7bad98cb2"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.4 Advanced Germline <content styleCode="italics">BRCA</content>-mutated Ovarian Cancer Treated with 3 or More Prior Lines of Chemotherapy </title> <text> <paragraph>The efficacy of Lynparza was investigated in a single-arm study of patients with deleterious or suspected deleterious g<content styleCode="italics">BRCA</content>m advanced cancers. A total of 137 patients with measurable, advanced g<content styleCode="italics">BRCA</content>m ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Lynparza capsules 400 mg orally twice daily until disease progression or intolerable toxicity. The efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to RECIST, version 1.0.</paragraph> <paragraph>The median age of the patients was 58 years, the majority were White (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious g<content styleCode="italics">BRCA</content>m status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the BRACAnalysis CDx^TM. </paragraph> <paragraph>Efficacy results are summarized in Table 22.</paragraph> <table width="100%"> <caption>Table 22 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced Ovarian Cancer Who Received 3 or More Lines of Chemotherapy</caption> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza Capsules</content> </paragraph> <paragraph> <content styleCode="bold">n=137</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Objective Response Rate (95% CI)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>34% (26, 42)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Complete response</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Partial response</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>32%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Median DOR in months (95% CI)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>7.9 (5.6, 9.6)</paragraph> </td> </tr> </tbody> </table> </text> <effectiveTime value="20210610"/> </section> </component> <component> <section ID="ID_7eff5af5-ad29-4f8e-a7cc-19d136ee42ea"> <id root="dd997cd8-6cb6-48ca-9885-78ed5b14ee44"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.5 Treatment of Germline <content styleCode="italics">BRCA</content>-mutated HER2-negative Metastatic Breast Cancer </title> <text> <paragraph>The efficacy of Lynparza was evaluated in OlympiAD (NCT02000622), an open-label randomized (2:1) study in patients with g<content styleCode="italics">BRCA</content>m HER2-negative metastatic breast cancer. Patients were required to have received treatment with an anthracycline (unless contraindicated) and a taxane, in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor-positive disease must have progressed on at least 1 endocrine therapy (adjuvant or metastatic), or have disease that the treating healthcare provider believed to be inappropriate for endocrine therapy. Patients with prior platinum therapy were required to have no evidence of disease progress during platinum treatment. No prior treatment with a PARP inhibitor was permitted. Patients were randomized to Lynparza tablets 300 mg orally twice daily or healthcare provider’s choice of chemotherapy (capecitabine, eribulin, or vinorelbine, at standard doses) until progression or unacceptable toxicity. Randomization was stratified by prior use of chemotherapy for metastatic disease (yes vs no), hormone receptor status (hormone receptor positive vs triple negative), and previous use of platinum-based chemotherapy (yes vs no). The major efficacy outcome measure was PFS assessed by blinded independent central review (BICR) using RECIST version 1.1.</paragraph> <paragraph>A total of 302 patients were randomized, 205 to Lynparza and 97 to chemotherapy. Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76), 65% were White, 4% were males and all the patients had an ECOG PS of 0 or 1. Approximately 50% of patients had triple-negative tumors and 50% had estrogen receptor and/or progesterone receptor positive tumors and the proportions were balanced across treatment arms. Patients in each treatment arm had received a median of 1 prior chemotherapy regimen for metastatic disease; approximately 30% had not received a prior chemotherapy regimen for metastatic breast cancer. Twenty-one percent of patients in the Lynparza arm and 14% in the chemotherapy arm had received platinum therapy for metastatic disease. Seven percent of patients in each treatment arm had received platinum therapy for localized disease. </paragraph> <paragraph>Of the 302 patients randomized onto OlympiAD, 299 were tested with the BRACAnalysis CDx^®and 297 were confirmed to have deleterious or suspected deleterious g<content styleCode="italics">BRCA</content>m status; 202 were randomized to the Lynparza arm and 95 to the healthcare provider’s choice of chemotherapy arm.</paragraph> <paragraph>A statistically significant improvement in PFS was demonstrated for the Lynparza arm compared to the chemotherapy arm. Efficacy data for OlympiAD are displayed in Table 23 and Figure 6. Consistent results were observed across patient subgroups defined by study stratification factors. An exploratory analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results.</paragraph> <table width="100%"> <caption>Table 23 Efficacy Results - OlympiAD (BICR-assessed)</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">(n=205)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Chemotherapy</content> </paragraph> <paragraph> <content styleCode="bold">(n=97)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>163 (80%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>71 (73%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7.0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4.2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Hazard ratio (95% CI)<footnote ID="_Ref23956920">Hazard ratio is derived from a stratified log-rank test, stratified by ER, PgR negative versus ER and or PgR positive and prior chemotherapy (yes versus no).</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.58 (0.43, 0.80)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     p-value<footnote ID="_Ref23954797">For PFS, p-value (2-sided) was compared to 0.05.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.0009</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Patients with Measurable Disease</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=167</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=66</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Objective Response Rate (95% CI)<footnote ID="_Ref23954829">Response based on confirmed responses. The confirmed complete response rate was 7.8% for Lynparza compared to 1.5% for chemotherapy arm.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>52% (44, 60)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23% (13, 35)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Survival</content> </paragraph> </td> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>130 (63%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>62 (64%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>17.1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>     Hazard ratio (95% CI)<footnoteRef IDREF="_Ref23956920"/> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>0.90 (0.66, 1.23)</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 6 Kaplan-Meier Curves of Progression-Free Survival - OlympiAD </content> </paragraph> <renderMultiMedia ID="id-208341871" referencedObject="F30C5A1B-DDB5-46B5-BF94-575BFE5A2BB7"/> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="F30C5A1B-DDB5-46B5-BF94-575BFE5A2BB7"> <text>Figure 5</text> <value mediaType="image/jpeg"> <reference value="image-04.jpg"/> </value> </observationMedia> </component> </section> </component> <component> <section ID="ID_a1d1299e-3abe-4f12-a454-2eda60a57f56"> <id root="ff7b9657-b340-4793-a087-8e4235f1e22d"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.6 First-Line Maintenance Treatment of Germline <content styleCode="italics">BRCA</content>-mutated Metastatic Pancreatic Adenocarcinoma </title> <text> <paragraph>The efficacy of Lynparza was evaluated in POLO (NCT02184195), a randomized (3:2), double-blind placebo-controlled, multi-center trial. Patients were required to have metastatic pancreatic adenocarcinoma with a deleterious or suspected deleterious germline <content styleCode="italics">BRCA</content> mutation (g<content styleCode="italics">BRCA</content>m) and absence of disease progression after receipt of first-line platinum-based chemotherapy for at least 16 weeks. Patients were randomized to receive Lynparza tablets 300 mg orally twice daily or placebo until disease progression or unacceptable toxicity. The major efficacy outcome measure was PFS by BICR using RECIST, version 1.1 modified to assess patients with clinical complete response at entry who were assessed as having no evidence of disease unless they had progressed based on the appearance of new lesions. Additional efficacy outcome measures were OS and ORR.</paragraph> <paragraph>A total of 154 patients were randomized, 92 to Lynparza and 62 to placebo. The median age was 57 years (range 36 to 84); 54% were male; 92% were White, 4% were Asian, and 3% were Black; baseline ECOG PS was 0 (67%) or 1 (31%). The median time from initiation of first-line platinum-based chemotherapy to randomization was 5.8 months (range 3.4 to 33.4 months). Seventy-five percent (75%) of patients received FOLFIRINOX with a median of 9 cycles (range 4-61), 8% received FOLFOX or XELOX, 4% received GEMOX, and 3% received gemcitabine plus cisplatin; 49% achieved a complete or partial response to platinum-based chemotherapy.</paragraph> <paragraph>All patients had a deleterious or suspected deleterious germline <content styleCode="italics">BRCA</content>-mutation as detected by the Myriad BRAC<content styleCode="italics">Analysis</content> ^® or BRACAnalysis CDx^®at a central laboratory only (n=106), local <content styleCode="italics">BRCA</content> test only (n=4), or both local and central testing (n=44). Among the 150 patients with central test results, 30% had a mutation in <content styleCode="italics">BRCA1</content>; 69% had a mutation in <content styleCode="italics">BRCA2</content>; and 1 patient (1%) had mutations in both <content styleCode="italics">BRCA1</content> and <content styleCode="italics">BRCA2</content>.</paragraph> <paragraph>Efficacy results of POLO are provided in Table 24 and Figure 7.</paragraph> <table width="100%"> <caption>Table 24 Efficacy Results - POLO (BICR-assessed)</caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets</content> </paragraph> <paragraph> <content styleCode="bold">(n=92)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">(n=62)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Progression-Free Survival</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)<footnote ID="_Ref40345384">Number of events: Progression - Lynparza 55, placebo 44; death before BICR-documented progression - Lynparza 5, placebo 0</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>60 (65%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>44 (71%)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median, months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>7.4 (4.1, 11.0)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3.8 (3.5, 4.9)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Hazard ratio<footnote ID="_Ref40345516">Hazard ratio, 95% CI, and p-value calculated from a log-rank test. A hazard ratio &lt;1 favors Lynparza.</footnote> (95% CI)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.53 (0.35, 0.81)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     p-value</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.0035</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Patients with Measurable Disease</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=78</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=52</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Objective Response Rate (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>23% (14, 34)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12% (4, 23)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Complete response (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2 (2.6)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Partial response (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>16 (21)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>6 (12)</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Duration of Response (DOR)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median time in months (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>25 (15, NC)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4 (2, NC)</paragraph> </td> </tr> <tr> <td colspan="3" valign="top"> <paragraph>NC Not calculable</paragraph> </td> </tr> </tbody> </table> <paragraph>The result of an OS interim analysis conducted based on 67% information fraction did not show a statistically significant improvement in OS for Lynparza compared to placebo.</paragraph> <paragraph> <content styleCode="bold">Figure 7 Kaplan-Meier Curves of BICR-Assessed Progression-Free Survival – POLO</content> </paragraph> <renderMultiMedia ID="id1055663807" referencedObject="ID_4a472364-bc35-45a8-92ab-021ccffb22d7"/> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="ID_4a472364-bc35-45a8-92ab-021ccffb22d7"> <text>Figure 6</text> <value mediaType="image/jpeg"> <reference value="image-05.jpg"/> </value> </observationMedia> </component> </section> </component> <component> <section ID="ID_d17760ea-331e-411a-8649-1791b3994867"> <id root="4931ab98-3cd8-4b4c-b11a-ed809dd3deb6"/> <code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/> <title>14.7 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer </title> <text> <paragraph>The efficacy of Lynparza was evaluated in PROfound (NCT02987543), randomized, open-label, multi-center trial that evaluated the efficacy of Lynparza 300 mg twice daily versus a comparator arm of investigator’s choice of enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer (mCRPC). All patients received a GnRH analog or had prior bilateral orchiectomy. Patients needed to have progressed on prior enzalutamide or abiraterone for the treatment of metastatic prostate cancer and/or CRPC and have a tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. </paragraph> <paragraph>Patients were divided into two cohorts based on HRR gene mutation status. Patients with mutations in either <content styleCode="italics">BRCA1</content>, <content styleCode="italics">BRCA2</content>, or <content styleCode="italics">ATM</content> were randomized in Cohort A; patients with mutations among 12 other genes involved in the HRR pathway (<content styleCode="italics">BARD1</content>, <content styleCode="italics">BRIP1</content>, <content styleCode="italics">CDK12</content>, <content styleCode="italics">CHEK1</content>, <content styleCode="italics">CHEK2</content>, <content styleCode="italics">FANCL</content>, <content styleCode="italics">PALB2</content>, <content styleCode="italics">PPP2R2A</content>, <content styleCode="italics">RAD51B</content>, <content styleCode="italics">RAD51C</content>, <content styleCode="italics">RAD51D</content>, or <content styleCode="italics">RAD54L</content>) were randomized in Cohort B; patients with co-mutations (<content styleCode="italics">BRCA1</content>, <content styleCode="italics">BRCA2</content>, or <content styleCode="italics">ATM</content> plus a Cohort B gene) were assigned to Cohort A. Although patients with <content styleCode="italics">PPP2R2A</content> gene mutations were enrolled in the trial, Lynparza is not indicated for the treatment of patients with this gene mutation due to unfavorable risk-benefit. Patients were randomized (2:1), 256 to Lynparza arm and 131 to enzalutamide or abiraterone acetate arm; in Cohort A there were 245 (162 Lynparza arm and 83 in enzalutamide or abiraterone acetate arm) and in Cohort B there were 142 patients (94 in Lynparza arm and 48 in enzalutamide or abiraterone acetate arm). Randomization was stratified by prior receipt of taxane chemotherapy and presence of measurable disease by RECIST 1.1. Treatment was continued until objective radiological disease progression determined by BICR. Upon radiological progression confirmed by BICR, patients randomized to enzalutamide or abiraterone acetate were given the option to switch to olaparib. Patients with HRR gene mutations were identified by tissue-based testing using the Foundation Medicine FoundationOne^® clinical trial HRR assay performed at a central laboratory.</paragraph> <paragraph>Determination of deleterious or suspected deleterious somatic or germline HRR mutation status in line with the FDA approved mutation classification and testing criteria for the Foundation Medicine F1CDx tissue-based assay and assessment of the germline-<content styleCode="italics">BRCA</content> status using the Myriad BRACAnalysis CDx blood-based assay was performed retrospectively. Representation of individual gene mutations by cohort is provided in Table 25. No patients were enrolled who had mutations in two of the 15 pre-specified HRR genes: <content styleCode="italics">FANCL</content> and <content styleCode="italics">RAD51C</content>.</paragraph> <table width="100%"> <caption>Table 25 Frequency of Patients with HRR Mutations Enrolled in PROfound</caption> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">HRR Mutation</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Cohort A</content> </paragraph> <paragraph> <content styleCode="bold">N=245</content> </paragraph> <paragraph> <content styleCode="bold">n (%)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Cohort B</content> <footnote ID="_Ref40330486">Three patients with single <content styleCode="italics">BRCA2</content> or <content styleCode="italics">ATM</content> gene mutations and 1 patient with co-occurring <content styleCode="italics">BRCA2+CDK12</content> gene mutations were incorrectly assigned to Cohort B.</footnote> </paragraph> <paragraph> <content styleCode="bold">N=142</content> </paragraph> <paragraph> <content styleCode="bold">n (%)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Single mutation</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>224 (91)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>135 (95)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    BRCA2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>127 (52)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1 (&lt;1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    ATM</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>84 (34)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2 (1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    BRCA1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>13 (5)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    CDK12</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>89 (63)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    CHEK2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>12 (8)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    PPP2R2A</content> <footnote ID="_Ref40257048">Lynparza is not indicated for patients with <content styleCode="italics">PPP2R2A</content> mutations.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>10 (7)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    RAD51B</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5 (4)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    RAD54L</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5 (4)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    PALB2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>4 (3)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    BRIP1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3 (2)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    CHEK1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>2 (1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    BARD1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1 (&lt;1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">    RAD51D</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1 (&lt;1)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Co-occurring mutation<footnote ID="_Ref40257066">Patients with co-occurring mutations (<content styleCode="italics">BRCA1, BRCA2,</content> or <content styleCode="italics">ATM</content> plus a Cohort B gene) were assigned to Cohort A.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>21 (9)</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>7 (5)</paragraph> </td> </tr> </tbody> </table> <paragraph>In Cohort A+B, the median age was 69 years (range: 47 to 91 years) in both arms; 69% were White, 29% were Asian, and 1% were Black. The ECOG performance score was 0 or 1 in most patients (95%) in both arms. In patients treated with Lynparza, the proportion of patients with RECIST 1.1 measurable disease at baseline was 58%, including 17% with lung and 10% with liver metastases, respectively. At randomization, 66% of patients had received prior taxane chemotherapy, 40% had received enzalutamide, 38% had received abiraterone acetate, and 20% had received both enzalutamide and abiraterone acetate. Patient characteristics were well-balanced between arms.</paragraph> <paragraph>The major efficacy outcome of the study was radiological progression free survival (rPFS) (Cohort A) as determined by BICR using RECIST version 1.1 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (bone) criteria. Additional efficacy outcomes included confirmed objective response rate (ORR) (Cohort A), rPFS (combined Cohorts A+B) as assessed by BICR, and overall survival (OS) (Cohort A). </paragraph> <paragraph>PROfound demonstrated a statistically significant improvement in BICR-assessed rPFS for Lynparza compared to investigator’s choice of enzalutamide or abiraterone acetate in Cohort A and Cohort A+B. In an exploratory analysis for patients in Cohort B, the median rPFS was 4.8 months for Lynparza vs 3.3 months for comparator with a HR of 0.88 (95% CI 0.58, 1.36). The major efficacy outcome was supported by a statistically significant improvement in ORR by BICR for patients with measurable disease at baseline in Cohort A. In Cohort B, ORR by BICR was 3.7% (95% CI 0.5, 12.7) in Lynparza treated patients and 8.3% (95% CI 1.0, 27.0) in patients treated with enzalutamide or abiraterone acetate.</paragraph> <paragraph>The final analysis of overall survival (OS) demonstrated a statistically significant improvement in OS in patients randomized to Lynparza compared to patients in the enzalutamide or abiraterone acetate arm in Cohort A.</paragraph> <paragraph>Efficacy results of PROfound are provided in Tables 26 and 27 and Figures 8 and 9.</paragraph> <table width="100%"> <caption>Table 26 Efficacy Results - PROfound (BICR-assessed)</caption> <col width="39%"/> <col width="16%"/> <col width="17%"/> <col width="13%"/> <col width="15%"/> <tbody> <tr> <td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Cohort A</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Cohort A+B</content> <footnote ID="_Ref40330690">Although 10 patients with PPP2R2A mutation were included in all analyses of Cohort A+B, Lynparza is not indicated for this population due to unfavorable risk-benefit.</footnote> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets<br/>(n=162)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Enzalutamide or Abiraterone acetate<br/>(n=83)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Lynparza tablets<br/>(n=256)</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">Enzalutamide or Abiraterone acetate<br/>(n=131)</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Radiological Progression-Free Survival (rPFS)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>106 (65)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>68 (82)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>180 (70)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>99 (76)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Median (95% CI), in months </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>7.4 (6.2, 9.3)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>3.6 (1.9, 3.7)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>5.8 (5.5, 7.4)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>3.5 (2.2, 3.7)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     Hazard ratio (95% CI)<footnote ID="_Ref40257538">The HR and CI were calculated using a Cox proportional hazards model adjusted for prior taxane use and measurable disease. An HR &lt;1 favors Lynparza 300 mg bd.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>0.34 (0.25, 0.47)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.49 (0.38, 0.63)</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>     p-value<footnote ID="_Ref40258438">The analysis was performed using the log-rank test stratified by prior taxane use and measurable disease.</footnote> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>&lt;0.0001</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>&lt;0.0001</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Confirmed ORR </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Patients with measurable disease at baseline</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=84</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=43</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    ORR, n (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>28 (33)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>1 (2)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    (95% CI)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>(23, 45)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>(0, 12)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    p-value </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>&lt;0.0001</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Overall Survival </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=162</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>n=83</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Number of events (%)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>91 (56)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>57 (69)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Median (95% CI), in months</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>19.1 (17.4, 23.4)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>14.7 (11.9, 18.8)</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    Hazard ratio (95% CI)<footnoteRef IDREF="_Ref40257538"/> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.69 (0.50, 0.97)</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>    p-value<footnoteRef IDREF="_Ref40258438"/> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>0.0175</paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph>-</paragraph> </td> </tr> <tr> <td colspan="5" valign="top"> <paragraph>CI Confidence interval</paragraph> </td> </tr> </tbody> </table> <paragraph> <content styleCode="bold">Figure 8 Kaplan-Meier Curves of BICR-Assessed Radiological Progression-Free Survival – PROfound – Cohort A</content> </paragraph> <renderMultiMedia ID="id-1544595824" referencedObject="A43F4CC9-6AAF-471A-924B-2D80D62C911D"/> <paragraph>Consistent results were observed in exploratory analyses of rPFS for patients who received or did not receive prior taxane therapy and for those with germline-<content styleCode="italics">BRCA</content> mutations identified using the Myriad BRACAnalysis CDx assay compared with those with <content styleCode="italics">BRCA</content> mutations identified using the Foundation Medicine F1CDx assay.</paragraph> <paragraph> <content styleCode="bold">Figure 9 Kaplan-Meier Curves of Overall Survival – PROfound – Cohort A</content> </paragraph> <renderMultiMedia ID="id1921214827" referencedObject="C78144DE-8ED3-4E7B-844A-D15D432470BA"/> <paragraph>Response data by HRR mutations for patients in the Lynparza arm are presented in Table 27. In the comparator arm of Cohorts A and B, a total of three patients achieved a partial response, including one patient with an <content styleCode="italics">ATM</content> mutation alone and 2 patients with co-occurring mutations (one with <content styleCode="italics">PALB2</content>+<content styleCode="italics">PPP2R2A</content> and one with <content styleCode="italics">CDK12</content>+<content styleCode="italics">PALB2</content>).</paragraph> <table width="100%"> <caption>Table 27 Response Rate and Duration of Response by HRR Mutation in Patients with Measurable Disease at Baseline on the Lynparza Arm – PROfound (BICR-assessed)</caption> <col width="37%"/> <col width="21%"/> <col width="23%"/> <col width="19%"/> <tbody> <tr> <td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">HRR mutation</content> <footnote ID="_Ref40260349">No patients with <content styleCode="italics">FANCL</content> or <content styleCode="italics">RAD51C</content> enrolled. Three patients with <content styleCode="italics">PPP2R2A</content> mutations had measurable disease, however, Lynparza is not indicated for patients with <content styleCode="italics">PPP2R2A</content> mutation.</footnote> </paragraph> </td> <td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Patients</content> </item> <item> <caption> </caption> <content styleCode="bold">(N=138)</content> </item> </list> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">Confirmed ORR</content> <footnote ID="_Ref40260406">In patients with a single <content styleCode="italics">BRCA2</content> mutation the median duration of response in the Lynparza arm (n=24) was 5.6 months (95% C.I: 5.5, 9.2). In the 3 responders with a single <content styleCode="italics">ATM</content> mutation in the Lynparza arm, the duration of response ranged from 5.8+ to 9.0 months. In the 2 responders with a single <content styleCode="italics">CDK12</content> mutation in the Lynparza arm, the duration of response was 3.7 and 7.2 months. + denotes ongoing response.</footnote> </item> </list> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">n (%)</content> </item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption> <content styleCode="bold">95% CI</content> </item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Single mutation</content> </paragraph> </td> <td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2 </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>43</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>24 (56)</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>(40, 71)</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">ATM </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>30</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>3 (10)</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>(2, 27)</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">CDK12 </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>34</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>2 (6)</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>(1, 20)</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA1 </content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>6</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD, PD (4), NE</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">CHEK2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>4</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD (2), PD (2)</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRIP1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>2</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD, PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">PALB2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>2</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD, PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">CHEK1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">RAD51B</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">RAD51D</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">RAD54L</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Co-occurring mutations</content> </paragraph> </td> <td align="center" colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2/CDK12</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>2</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>PR, SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2/ATM</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>2</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD, SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2/BARD1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2/CHEK2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">CDK12/CHEK1</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">CDK12/PALB2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2/CDK12/CHEK2</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>PD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="italics">BRCA2/CHEK2/RAD51D</content> </paragraph> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>1</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>SD</item> </list> </td> <td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <list listType="ordered"> <item> <caption> </caption>NA</item> </list> </td> </tr> <tr> <td colspan="4" valign="top"> <list listType="ordered"> <item> <caption> </caption>PR Partial response; SD Stable disease; PD Progressive disease; NE Not evaluable; NA Not applicable due to small numbers or lack of response.</item> </list> </td> </tr> </tbody> </table> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="A43F4CC9-6AAF-471A-924B-2D80D62C911D"> <text>figure_7</text> <value mediaType="image/jpeg"> <reference value="figure_7.jpg"/> </value> </observationMedia> </component> <component> <observationMedia ID="C78144DE-8ED3-4E7B-844A-D15D432470BA"> <text>figure_8</text> <value mediaType="image/jpeg"> <reference value="figure_8.jpg"/> </value> </observationMedia> </component> </section> </component> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_c6edcbe7-9e46-48ba-977e-8d77e1ca1dc5"> <id root="7360270d-8346-4e70-bb6f-49b5f330a9f0"/> <code code="34069-5" codeSystem="2.16.840.1.113883.6.1" displayName="HOW SUPPLIED SECTION"/> <title>16 HOW SUPPLIED/STORAGE AND HANDLING </title> <text> <paragraph>Lynparza is available as 150 mg and 100 mg tablets.</paragraph> <list listType="unordered"> <item> <caption>•</caption>150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with debossment ‘OP150’ on one side and plain on the reverse, are available in:<list listType="unordered"> <item> <caption>∘</caption>Bottles of 60 tablets (NDC 0310-0679-60) and </item> <item> <caption>∘</caption>Bottles of 120 tablets (NDC 0310-0679-12).</item> </list> </item> <item> <caption>•</caption>100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, with debossment ‘OP100’ on one side and plain on the reverse, are available in:<list listType="unordered"> <item> <caption>∘</caption>Bottles of 60 tablets (NDC 0310-0668-60) and </item> <item> <caption>∘</caption>Bottles of 120 tablets (NDC 0310-0668-12).</item> </list> </item> </list> <paragraph>Store at 20ºC to 25ºC (68ºF to 77ºF), excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Store in original bottle to protect from moisture.</paragraph> </text> <effectiveTime value="20210610"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_26fddca3-6678-4a32-a760-14cae682d598"> <id root="7cd8704d-3a81-43e8-a73d-b07214b521ee"/> <code code="34076-0" codeSystem="2.16.840.1.113883.6.1" displayName="INFORMATION FOR PATIENTS SECTION"/> <title>17 PATIENT COUNSELING INFORMATION</title> <text> <paragraph>Advise the patient to read the FDA-approved patient labeling (Medication Guide).</paragraph> <paragraph> <content styleCode="underline">MDS/AML</content> </paragraph> <paragraph>Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza <content styleCode="italics">[see <linkHtml href="#ID_ddb21fce-152b-4f6c-8c2a-e181418a068c">Warnings and Precautions (5.1)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Pneumonitis</content> </paragraph> <paragraph>Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing <content styleCode="italics">[see <linkHtml href="#ID_77122f3a-5030-4c60-a986-fa38152f1aa7">Warnings and Precautions (5.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Embryo-Fetal Toxicity</content> </paragraph> <paragraph>Inform pregnant women of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of known or suspected pregnancy <content styleCode="italics">[see <linkHtml href="#ID_929586ba-127d-4cc0-bd5a-dfdea42c2b87">Use in Specific Populations (8.1)</linkHtml>]</content>. </paragraph> <paragraph>Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months after the last dose <content styleCode="italics">[see <linkHtml href="#ID_aefb7be1-5ba8-4334-8dcc-19abb24c2cad">Use in Specific Populations (8.3)</linkHtml>]</content>. </paragraph> <paragraph>Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months after receiving the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza <content styleCode="italics">[see <linkHtml href="#ID_a784e1ea-98c0-4c96-8486-32353c47e4c5">Warnings and Precautions (5.3)</linkHtml> and </content> <content styleCode="italics"> <linkHtml href="#ID_aefb7be1-5ba8-4334-8dcc-19abb24c2cad">Use in Specific Populations (8.3)</linkHtml> </content> <content styleCode="italics">].</content> </paragraph> <paragraph> <content styleCode="underline">Venous Thromboembolic Events</content> </paragraph> <paragraph>Advise patients with metastatic castration-resistant prostate cancer to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia <content styleCode="italics">[see <linkHtml href="#ID_9d7c095f-cd4c-4495-bd4a-2ca07305f94f">Warnings and Precautions (5.4)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Lactation</content> </paragraph> <paragraph>Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose <content styleCode="italics">[see <linkHtml href="#ID_36d256f0-3f04-4f55-9999-1d9af2481676">Use in Specific Populations (8.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Drug Interactions</content> </paragraph> <paragraph>Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza <content styleCode="italics">[see <linkHtml href="#ID_234fa3d4-b847-4ab5-a73b-8b5807c75f9e">Drug Interactions (7.2)</linkHtml>]</content>.</paragraph> <paragraph> <content styleCode="underline">Nausea/Vomiting</content> </paragraph> <paragraph>Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options <content styleCode="italics">[see <linkHtml href="#ID_45e158de-cdf6-4826-8ae8-946e0ee65930">Adverse Reactions (6.1)</linkHtml>]</content>.</paragraph> <paragraph>Distributed by:</paragraph> <paragraph>AstraZeneca Pharmaceuticals LP</paragraph> <paragraph>Wilmington, DE 19850</paragraph> <paragraph>© AstraZeneca 2021</paragraph> </text> <effectiveTime value="20210610"/> </section>

<?xml version="1.0" encoding="UTF-8"?><section ID="ID_7a0cde27-f156-4bde-a9be-729324666d43"> <id root="e8d69e91-3bb9-45b4-bf46-a1bb8df0f931"/> <code code="42231-1" codeSystem="2.16.840.1.113883.6.1" displayName="SPL MEDGUIDE SECTION"/> <text> <table width="100%"> <col width="50%"/> <col width="50%"/> <tbody> <tr> <td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Medication Guide</content> </paragraph> <paragraph> <content styleCode="bold">Lynparza^® (Lin-par-zah)</content> </paragraph> <paragraph> <content styleCode="bold">(olaparib)</content> </paragraph> <paragraph> <content styleCode="bold">tablets</content> </paragraph> <paragraph> <content styleCode="bold"> </content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">What is the most important information I should know about Lynparza?</content> </paragraph> <paragraph> <content styleCode="bold">Lynparza may cause serious side effects, including:</content> </paragraph> <paragraph> <content styleCode="bold">Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML).</content> Some people who have ovarian cancer or breast cancer and who have received previous treatment with chemotherapy, radiotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with Lynparza. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with Lynparza. </paragraph> <paragraph>Symptoms of low blood cell counts are common during treatment with Lynparza, but can be a sign of serious bone marrow problems, including MDS or AML. Symptoms may include:</paragraph> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>weakness</item> <item> <caption>•</caption>weight loss</item> <item> <caption>•</caption>fever</item> <item> <caption>•</caption>frequent infections</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>blood in urine or stool</item> <item> <caption>•</caption>shortness of breath</item> <item> <caption>•</caption>feeling very tired</item> <item> <caption>•</caption>bruising or bleeding more easily</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Your healthcare provider will do blood tests to check your blood cell counts:</paragraph> <list listType="unordered"> <item> <caption>•</caption>before treatment with Lynparza</item> <item> <caption>•</caption>every month during treatment with Lynparza</item> <item> <caption>•</caption>weekly if you have low blood cell counts that last a long time. Your healthcare provider may stop treatment with Lynparza until your blood cell counts improve.</item> </list> <paragraph> <content styleCode="bold">Lung problems (pneumonitis).</content> Tell your healthcare provider if you have any new or worsening symptoms of lung problems, including shortness of breath, fever, cough, or wheezing. Your healthcare provider may do a chest x-ray if you have any of these symptoms. Your healthcare provider may temporarily or completely stop treatment if you develop pneumonitis. Pneumonitis may lead to death.</paragraph> <paragraph> <content styleCode="bold">Blood clots (Venous Thromboembolic Events).</content> Some people with prostate cancer who take Lynparza along with gonadotropin-releasing hormone (GnRH) analog therapy may develop a blood clot in a deep vein, usually in the leg (venous thrombosis) or a clot in the lung (pulmonary embolism). Tell your healthcare provider if you have any symptoms such as pain or swelling in an extremity, shortness of breath, chest pain, breathing that is more rapid than normal (tachypnea), or heart beats faster than normal (tachycardia). Your healthcare provider will monitor you for these symptoms and may prescribe blood thinner medicine.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <paragraph> <content styleCode="bold">What is Lynparza?</content> </paragraph> <paragraph>Lynparza is a prescription medicine used to treat adults who have: </paragraph> <list listType="unordered"> <item> <caption>•</caption>advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with a certain type of inherited (germline) or acquired (somatic) abnormal <content styleCode="italics">BRCA</content> gene. Lynparza is used alone as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.</item> <item> <caption>•</caption>advanced ovarian cancer, fallopian tube cancer or primary peritoneal cancer with a certain type of abnormal BRCA gene or a positive laboratory tumor test for genomic instability called HRD. Lynparza is used in combination with another anti-cancer medicine, bevacizumab, as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.</item> <item> <caption>•</caption>ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy. </item> <item> <caption>•</caption>advanced ovarian cancer with a certain type of abnormal inherited <content styleCode="italics">BRCA</content> gene, <content styleCode="bold">and</content> have received treatment with 3 or more prior types of chemotherapy medicines. Your healthcare provider will perform a test to make sure that Lynparza is right for you.</item> <item> <caption>•</caption>a certain type of abnormal inherited <content styleCode="italics">BRCA</content> gene, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.</item> <item> <caption>•</caption>metastatic pancreatic cancer with a certain type of abnormal inherited <content styleCode="italics">BRCA</content> gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.</item> <item> <caption>•</caption>prostate cancer with certain inherited or acquired abnormal genes called homologous recombination repair (HRR genes). Lynparza is used when the cancer has spread to other parts of the body (metastatic), and no longer responds to a medical or surgical treatment that lowers testosterone, and has progressed after treatment with enzalutamide or abiraterone. Your healthcare provider will perform a test to make sure Lynparza is right for you.</item> </list> <paragraph>It is not known if Lynparza is safe and effective in children.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Before taking Lynparza, tell your healthcare provider about all of your medical conditions, including if you: </content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>have lung or breathing problems</item> <item> <caption>•</caption>have kidney problems </item> <item> <caption>•</caption>are pregnant, become pregnant, or plan to become pregnant. Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage). <list listType="unordered"> <item> <caption>∘</caption>If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with Lynparza.</item> <item> <caption>∘</caption> <content styleCode="bold">Females</content> who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 6 months after the last dose of Lynparza. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think you might be pregnant following treatment with Lynparza.</item> <item> <caption>∘</caption> <content styleCode="bold">Males</content> with female partners who are pregnant or able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 3 months after the last dose of Lynparza.</item> <item> <caption>∘</caption>Do not donate sperm during treatment with Lynparza and for 3 months after your final dose.</item> </list> </item> <item> <caption>•</caption>are breastfeeding or plan to breastfeed. It is not known if Lynparza passes into your breast milk. Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time.</item> </list> <paragraph> </paragraph> <paragraph> <content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Lynparza and certain other medicines may affect how Lynparza works and may cause side effects.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I take Lynparza?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Take Lynparza tablets exactly as your healthcare provider tells you.</item> <item> <caption>•</caption>Do not change your dose or stop taking Lynparza unless your healthcare provider tells you to. Your healthcare provider may temporarily stop treatment with Lynparza or change your dose of Lynparza if you experience side effects.</item> <item> <caption>•</caption>Your healthcare provider will decide how long you stay on treatment.</item> <item> <caption>•</caption> <content styleCode="bold">Do not</content> take more than 4 Lynparza tablets in 1 day. If you have any questions about Lynparza, please talk to your healthcare provider or pharmacist.</item> <item> <caption>•</caption>Take Lynparza by mouth 2 times a day. </item> <item> <caption>•</caption>Each dose should be taken about 12 hours apart.</item> <item> <caption>•</caption>Swallow Lynparza tablets whole. Do not chew, crush, dissolve, or divide the tablets.</item> <item> <caption>•</caption>Take Lynparza with or without food.</item> <item> <caption>•</caption>If you are taking Lynparza for prostate cancer and you are receiving gonadotropin-releasing hormone (GnRH) analog therapy, you should continue with this treatment during your treatment with Lynparza unless you have had a surgery to lower the amount of testosterone in your body (surgical castration).</item> <item> <caption>•</caption>If you miss a dose of Lynparza, take your next dose at your usual scheduled time. Do not take an extra dose to make up for a missed dose.</item> <item> <caption>•</caption>If you take too much Lynparza, call your healthcare provider or go to the nearest hospital emergency room right away.</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What should I avoid while taking Lynparza?</content> </paragraph> <paragraph>Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during treatment with Lynparza since they may increase the level of Lynparza in your blood.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <paragraph> <content styleCode="bold">What are the possible side effects of Lynparza? </content> </paragraph> <paragraph> <content styleCode="bold">Lynparza may cause serious side effects. </content> </paragraph> <paragraph> <content styleCode="bold">See “What is the most important information I should know about Lynparza?”</content> </paragraph> <paragraph> <content styleCode="bold">The most common side effects of Lynparza are:</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.</item> </list> </td> </tr> <tr> <td styleCode="Lrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>tiredness or weakness</item> <item> <caption>•</caption>low red blood cell counts</item> <item> <caption>•</caption>diarrhea</item> <item> <caption>•</caption>loss of appetite</item> <item> <caption>•</caption>headache</item> <item> <caption>•</caption>changes in the way food tastes</item> </list> </td> <td styleCode="Rrule " valign="top"> <list listType="unordered"> <item> <caption>•</caption>cough</item> <item> <caption>•</caption>low white blood cell counts</item> <item> <caption>•</caption>shortness of breath</item> <item> <caption>•</caption>dizziness</item> <item> <caption>•</caption>indigestion or heartburn</item> <item> <caption>•</caption>low platelet counts</item> </list> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>These are not all of the possible side effects of Lynparza. </paragraph> <paragraph>Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">How should I store Lynparza?</content> </paragraph> <list listType="unordered"> <item> <caption>•</caption>Store Lynparza at room temperature, between 68°F to 77°F (20°C to 25°C).</item> <item> <caption>•</caption>Store Lynparza in the original bottle to protect it from moisture.</item> </list> <paragraph> <content styleCode="bold">Keep Lynparza and all medicines out of reach of children.</content> </paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General information about the safe and effective use of Lynparza.</content> </paragraph> <paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lynparza for a condition for which it was not prescribed. Do not give Lynparza to other people, even if they have the same symptoms you have. It may <content styleCode="bold">harm</content> them. </paragraph> <paragraph>You can ask your healthcare provider or pharmacist for information about Lynparza that is written for health professionals.</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">What are the ingredients in Lynparza?</content> </paragraph> <paragraph> <content styleCode="bold">Active ingredient:</content> olaparib</paragraph> <paragraph> <content styleCode="bold">Inactive ingredients:</content> </paragraph> <paragraph>Tablet contains: copovidone, mannitol, colloidal silicon dioxide and sodium stearyl fumarate </paragraph> <paragraph>Tablet coating contains: hypromellose, polyethylene glycol 400, titanium dioxide, ferric oxide yellow and ferrosoferric oxide (150 mg tablet only)</paragraph> </td> </tr> <tr> <td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Lynparza is a registered trademark of the AstraZeneca group of companies.</paragraph> <paragraph>© AstraZeneca 2021</paragraph> <paragraph>Distributed by:</paragraph> <paragraph>AstraZeneca Pharmaceuticals LP</paragraph> <paragraph>Wilmington, DE 19850</paragraph> <paragraph>For more information, call 1-800-236-9933 or go to <linkHtml href="http://www.Lynparza.com">www.Lynparza.com</linkHtml>. </paragraph> </td> </tr> </tbody> </table> <paragraph>This Medication Guide has been approved by the U.S. Food and Drug Administration.                          Revised: 3/2021</paragraph> </text> <effectiveTime value="20210610"/> </section>

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<?xml version="1.0" encoding="UTF-8"?><section ID="ID_6f6c31e1-902a-4895-8318-ea841c456833"> <id root="ea13e8aa-e52a-4fd4-9d38-a3b25eb5dfe2"/> <code code="51945-4" codeSystem="2.16.840.1.113883.6.1" displayName="PACKAGE LABEL.PRINCIPAL DISPLAY PANEL"/> <title>PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 150 mg </title> <text> <paragraph>NDC 0310-0679-12</paragraph> <paragraph>Lynparza^® </paragraph> <paragraph>(olaparib) tablets</paragraph> <paragraph>150 mg </paragraph> <paragraph>Dispense accompanying </paragraph> <paragraph>Medication Guide to each patient.</paragraph> <paragraph>120 Tablets</paragraph> <paragraph>Rx only</paragraph> <paragraph>AstraZeneca</paragraph> <renderMultiMedia ID="id1262575781" referencedObject="ID_4e5288fd-34b5-4d92-839d-88d44150a1b6"/> </text> <effectiveTime value="20210610"/> <component> <observationMedia ID="ID_4e5288fd-34b5-4d92-839d-88d44150a1b6"> <text>lynparza_150mg_120_tablet_bottle_label</text> <value mediaType="image/jpeg"> <reference value="lynparza_150mg_120tablet_bottle.jpg"/> </value> </observationMedia> </component> </section>