Optimizing clinical monitoring and management guidelines for capivasertib in patients with HR+/HER2- advanced breast cancer: expert opinion

Capivasertib inhibits AKT, the master switch of the PI3K/AKT/PTEN pathway,
1, 2

1. TRUQAP. Prescribing information.

2. Uhlenbrock N, Smith S, Weisner J, et al. Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt. Chem Sci. 2019;10(12):3573-3585. doi:10.1039/c8sc05212c.

restricting the flow of amplified oncogenic signaling — driven by PIK3CA and AKT1 activating mutations, or PTEN alterations — before those signals can have further downstream effects that drive tumor growth.
3-6

3. Skolariki A, D’Costa J, Little M, et al. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. Explor Target Antitumor Ther. 2022;3(2):172-199. doi:10.37349/etat.2022.00078.

4. Andrikopoulou A, Chatzinikolaou S, Panourgias E, et al. “The emerging role of capivasertib in breast cancer”. Breast. 2022;63:157-167. doi:10.1016/j.breast.2022.03.018.

5. Martorana F, Motta G, Pavone G, et al. AKT Inhibitors: New Weapons in the Fight Against Breast Cancer? Front Pharmacol. 2021;12:662232. doi:10.3389/fphar.2021.662232.

6. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131.

However, as capivasertib inhibits physiologic PI3K/AKT/PTEN pathway signaling, it may lead to several on-target, off-tumor toxicities.
7

7. Nunnery SE, Mayer IA. Management of toxicity to isoform α-specific PI3K inhibitors. Ann Oncol. 2019;30:x21-x26. doi:10.1093/annonc/mdz440.

These include diarrhea, rash, and hyperglycemia, which require effective management strategies to support patient care.
This resource outlines expert recommendations for monitoring and managing common capivasertib-associated AEs, specifically diarrhea, rash, and hyperglycemia. Informed by the prescribing information for safe and effective use, as well as clinical trial data and real-world experience, these structured recommendations for toxicity management aim to support patient care.
8

8. Iyengar NM, O'Shaughnessy JA, Moore HN, et al. Optimizing clinical monitoring and management guidelines for capivasertib in HR-positive/HER2-negative advanced breast cancer: expert opinion. npj Breast Cancer. 2025;12(1):16. doi:10.1038/s41523-025-00864-2.

Diarrhea
Common presentations: 
  • Increased stool frequency and urgency
  • Abdominal cramping
  • Signs of dehydration
View clinical guidance View etiology

Rash
Common presentations: 
  • Areas of redness
  • Itching and bumps
  • Blistering and peeling
View clinical guidance View etiology

Hyperglycemia
Common presentations: 
  • Excessive thirst
  • Frequent urination
  • Blurred vision
View clinical guidance View etiology

Diarrhea – etiology

  • AKT inhibitor-associated diarrhea may be caused by decreased AKT/mTOR-dependent activation of Na+/H+ exchanger 3
    9
  • This is a sodium-hydrogen exchanger that facilitates intestinal sodium absorption and water homeostasis
    9
9. Yang J, Zhao X, Patel A, et al. Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea. Gastroenterology. 2015;149(1):151-62. doi:10.1053/j.gastro.2015.03.046.

Rash – etiology

  • The PI3K/AKT/PTEN pathway plays a key role in skin homeostasis, supporting the epidermal barrier, hair follicle regeneration, wound healing, and skin senescence
    8
  • The exact etiology of rash associated with PI3K/AKT inhibitors is not fully understood, but it is considered an ‘on-target off-tumor’ effect of pathway inhibition.
    8
8. Iyengar NM, O'Shaughnessy JA, Moore HN, et al. Optimizing clinical monitoring and management guidelines for capivasertib in HR-positive/HER2-negative advanced breast cancer: expert opinion. npj Breast Cancer. 2025;12(1):16. doi:10.1038/s41523-025-00864-2.

Hyperglycemia – etiology

  • Insulin signals via the PI3K/AKT/PTEN pathway to promote glucose uptake, suppress gluconeogenesis, and increase glycogenesis
    10
  • AKT acts on GLUT4-containing vesicles in the cytosol to facilitate their fusion with the cell membrane, elevating glucose uptake
    11
  • Hyperglycemia is thought to occur due to the effect of AKT inhibition on decreasing glucose uptake and increasing gluconeogenesis and its potential to induce insulin deficiency
    11, 12
10. Liu D, Weintraub MA, Garcia C, et al. Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment. Cancer Med. 2022;11(8):1796-1804. doi:10.1002/cam4.4579.
11. Wang W, Shi B, Cong R, et al. RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism. Cell Death Discov. 2022;8(1):372. doi:10.1038/s41420-022-01162-7.
12. Fowler M. Hyperglycemic Crisis in Adults: Pathophysiology, Presentation, Pitfalls, and Prevention. Clin Diabetes. 2009;27(1):19–23. doi:10.2337/diaclin.27.1.19.

Important Safety Information

TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components.
 
Hyperglycemia
 
TRUQAP can cause severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes.
 
Increased fasting glucose (FG) from baseline occurred in 37% of patients treated with TRUQAP, including 11% of patients with Grade 2 (FG >160 to 250 mg/dL), 2% with Grade 3 (FG >250 to 500 mg/dL), and 1.1% with Grade 4 (FG >500 mg/dL) events. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367). Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. Diabetic metabolic decompensation occurred in 0.6% of patients, including diabetic ketoacidosis in 0.3%.
 
In CAPItello-291, 12% (43/355) of patients who received TRUQAP had an anti-hyperglycemic medication either initiated or changed during the study, including treatment with insulin in 4.8% (17/355) of patients.
The safety of TRUQAP has not been established in patients with Type 1 diabetes or Type 2 diabetes that is uncontrolled or requiring insulin at baseline as these patients were excluded from clinical studies. Before initiating treatment with TRUQAP, test fasting glucose levels (fasting plasma glucose or fasting blood glucose), hemoglobin A1C (HbA1C) levels, and optimize fasting glucose. After initiating treatment with TRUQAP, monitor or self-monitor FG levels on Day 3 or 4 of the dosing week during weeks 1, 2, 4, 6, and 8; then monthly while on treatment with TRUQAP; and as clinically indicated. Monitor HbA1C levels every 3 months during treatment with TRUQAP and as clinically indicated. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of FG levels.
For patients who experience hyperglycemia during treatment with TRUQAP, monitor FG at least twice weekly, on days on and off TRUQAP, until FG decreases to baseline levels. During treatment with anti-diabetic medications, monitor FG at least once a week for 2 months, followed by once every 2 weeks, or as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and initiation of FG monitoring at home for patients who have risk factors for hyperglycemia or who experience hyperglycemia. Advise patients on the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes.
Withhold TRUQAP immediately when ketoacidosis is suspected. If ketoacidosis is confirmed, permanently discontinue TRUQAP. Withhold TRUQAP in clinical situations known to increase the risk of severe hyperglycemia or ketoacidosis (eg, suspected serious infection or acute illness). Based on the severity of hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP.
Diarrhea
TRUQAP can cause severe diarrhea associated with dehydration.
Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea occurred in 9% of patients. The median time to first occurrence was 8 days (range: 1 to 519). In the 257 patients with diarrhea, 59% required antidiarrheal medications to manage symptoms. Dose reductions were required in 8% of patients and 2% of patients permanently discontinued TRUQAP due to diarrhea. In patients with Grade ≥2 diarrhea (n=93) with at least 1 grade improvement (n=89), median time to improvement from the first event was 4 days (range: 1 to 154).
Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start antidiarrheal treatment at the first sign of diarrhea while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity.
Cutaneous Adverse Reactions
TRUQAP can cause cutaneous adverse reactions, which can be severe, including erythema multiforme (EM), palmar-plantar erythrodysesthesia (PPE), and drug reaction with eosinophilia and systemic symptoms (DRESS).
Cutaneous adverse reactions occurred in 58% of patients. Grade 3 or 4 cutaneous adverse reactions occurred in 17% of patients receiving TRUQAP. EM occurred in 1.7% of patients and DRESS occurred in 0.3% of patients. Dose reduction was required in 7% of patients and 7% of patients permanently discontinued TRUQAP due to cutaneous adverse reactions.
Monitor patients for signs and symptoms of cutaneous adverse reactions. Early consultation with a dermatologist is recommended. Withhold, dose reduce, or permanently discontinue TRUQAP based on severity.
Embryo-Fetal Toxicity
Based on findings from animals and mechanism of action, TRUQAP can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRUQAP and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRUQAP and for 4 months after the last dose.
TRUQAP is used in combination with fulvestrant. Refer to the full Prescribing Information of fulvestrant for pregnancy and contraception information.
Among the 355 patients who received TRUQAP in CAPItello-291, the most common (≥20%) adverse reactions, including laboratory abnormalities, were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%).
 
In the 155 patients with PIK3CA/AKT1/PTEN alterations treated with TRUQAP + fulvestrant, dose reductions due to adverse reactions were reported in 21% of patients. Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients. Dose interruptions of TRUQAP occurred in 39% of patients.
Strong CYP3A Inhibitors: Avoid concomitant use with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the dose of TRUQAP and monitor patients for adverse reactions.
 
Moderate CYP3A Inhibitors: When concomitantly used with a moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor patients for adverse reactions.
 
Strong or Moderate CYP3A Inducers: Avoid concomitant use of TRUQAP with strong or moderate CYP3A inducers.
TRUQAP in combination with fulvestrant is indicated for the treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alteration as detected by an FDA-authorized test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.
 
Please see full Prescribing Information, including Patient Information for TRUQAP.
 
You may report side effects related to AstraZeneca products

ADLactivities of daily living
AEadverse event
AKT1/2/3serine/threonine protein kinase 1/2/3
BIDtwice daily
BMIbody mass index
BSAbody surface area
CYP3Acytochrome P450, family 3, subfamily A
DKAdiabetic ketoacidosis
DRESSdrug reaction with eosinophilia and systemic symptoms
eGFRestimated glomerular filtration rate
EMerythema multiforme
ETendocrine therapy
FDAUS Food and Drug Administration
FGfasting glucose
GIgastrointestinal

GLP-1Rglucagon-like peptide-1 receptor
HbA1chemoglobin A1C
HCPhealthcare professional
IVintravenous
mBCmetastatic breast cancer
PI3Kphosphoinositide 3-kinase
PIK3CAphosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PTENphosphatase and tensin homolog
QDonce daily
SGLT2isodium-glucose co-transporter-2 inhibitor
sppspecies
T2Dtype 2 diabetes
TIDthree times daily
TZDthiazolidinedione
ULNupper limit of normal

1. TRUQAP. Prescribing information.

2. Uhlenbrock N, Smith S, Weisner J, et al. Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt. Chem Sci. 2019;10(12):3573-3585. doi:10.1039/c8sc05212c.

3. Skolariki A, D’Costa J, Little M, et al. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. Explor Target Antitumor Ther. 2022;3(2):172-199. doi:10.37349/etat.2022.00078.

4. Andrikopoulou A, Chatzinikolaou S, Panourgias E, et al. “The emerging role of capivasertib in breast cancer”. Breast. 2022;63:157-167. doi:10.1016/j.breast.2022.03.018.

5. Martorana F, Motta G, Pavone G, et al. AKT Inhibitors: New Weapons in the Fight Against Breast Cancer? Front Pharmacol. 2021;12:662232. doi:10.3389/fphar.2021.662232.

6. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131.

7. Nunnery SE, Mayer IA. Management of toxicity to isoform α-specific PI3K inhibitors. Ann Oncol. 2019;30:x21-x26. doi:10.1093/annonc/mdz440.

8. Iyengar NM, O'Shaughnessy JA, Moore HN, et al. Optimizing clinical monitoring and management guidelines for capivasertib in HR-positive/HER2-negative advanced breast cancer: expert opinion. npj Breast Cancer. 2025;12(1):16. doi:10.1038/s41523-025-00864-2.

9. Yang J, Zhao X, Patel A, et al. Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea. Gastroenterology. 2015;149(1):151-62. doi:10.1053/j.gastro.2015.03.046.

10. Liu D, Weintraub MA, Garcia C, et al. Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment. Cancer Med. 2022;11(8):1796-1804. doi:10.1002/cam4.4579.

11. Wang W, Shi B, Cong R, et al. RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism. Cell Death Discov. 2022;8(1):372. doi:10.1038/s41420-022-01162-7.

12. Fowler M. Hyperglycemic Crisis in Adults: Pathophysiology, Presentation, Pitfalls, and Prevention. Clin Diabetes. 2009;27(1):19–23. doi:10.2337/diaclin.27.1.19.