Pharmacist's Application to Practice: Capivasertib

FDA approves capivasertib with fulvestrant for breast cancer

What is the potential role of capivasertib in the treatment of advanced breast cancer?

• Capivasertib (Truqap) is approved for use in combination with fulvestrant for HR-positive, HER2-negative locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alteration and previous progression on endocrine therapy in the metastatic setting or recurrence < 12 months of completing adjuvant therapy.1
• Capivasertib is an oral medication that inhibits several isoforms of serine/threonine kinases (AKT) including AKT1, AKT2, and AKT3.1
• AKT plays an important role in the PI3K-AKT-PTEN signal transduction pathway, which is upstream of activated AKT in tumors.2
• Alterations of PI3K pathways including PIK3CA, PTEN, and AKT1 can be acquired or present at time of recurrence and are common alterations seen among HR-positive, HER2-negative breast cancers.2
• The CAPItello-291 trial was an international, multicenter, placebo-controlled, double-blind, phase 3 clinical trial that included 708 patients randomized 1:1 to receive capivasertib-fulvestrant or placebo-fulvestrant.2
• Population: Premenopausal, perimenopausal and postmenopausal women or men with HR-positive, HER2-negative advanced or metastatic breast cancer who had disease progression on endocrine therapy with an aromatase inhibitor with or without a CDK4/6 inhibitor. Of participants randomized, 40.8% had AKT-pathway alterations present in their tumors.
• Intervention: Capivasertib 400 mg by mouth BID x 4 days, then 3 days off plus fulvestrant 500 mg IM days 1, 15, 29 and then every 28 days thereafter vs placebo-fulvestrant. Additionally, women who were pre- or peri-menopausal received a luteinizing hormone-releasing hormone agonist.
• Randomization was stratified based on past use of CDK4/6 inhibitor, presence of liver metastases, and geographic region.
• Primary Outcome: progression-free survival in overall patient population and within patient population with AKT-pathway alteration, which includes activating mutations in PIK3CA or AKT1 or inactivating alterations in PTEN. Results:
• Median progression free survival in the overall population was 7.2 months in the capivasertib-fulvestrant group vs 3.6 months in placebo-fulvestrant group (HR 0.60; 95% CI 0.51 to 0.71; p<0.001).  Median progression free survival in the patient population with AKT-pathway alteration was 7.3 months in the capivasertib-fulvestrant group vs 3.1 months in placebo-fulvestrant group (HR 0.50; 95% CI 0.38 to 0.65; p<0.001). Additionally, this effect was consistent in an exploratory analysis of patients without AKT-pathway alterations or unknown status.
• Overall survival at 18 months: in overall population, 73.9% in capivasertib-fulvestrant group vs 65% in placebo-fulvestrant group and in the patient population with AKT-pathway alteration, 73.2% vs 62.9%.
• Safety: in the intervention group the most common adverse effects of all grades were diarrhea (72.4%), rash (38%), and nausea (36.4%).  Other common adverse effects of any grade > 20% included vomiting and  fatigue, and >10% included stomatitis, decreased appetite, and hyperglycemia.
• The FDA approved capivasertib in November 2023 for the use in HR-positive, HER2-negative advanced or metastatic breast cancer that progressed on previous endocrine therapy and displays at least one alteration in the AKT/PIK3CA/PTEN pathway. The FDA also provides guidance on approved tests to assess for alterations including FoundationOne®CDx assay.3
• Capivasertib is a category 1 recommendation from the National Comprehensive Cancer Network (NCCN) as a preferred second or subsequent-line therapy in patients with HR-positive, HER2-negative recurrent unresectable or metastatic breast cancer with a PIK3CA or AKT1 activating mutations or PTEN alterations.4
• For patients that harbor a PIK3CA alteration, apelisib is another oral treatment option. There is no comparative efficacy to compare the use of capivasertib vs apelisib. Assessment of the risks, benefits, and incidence of adverse effects of each treatment should guide therapeutic selection.6

What role can the pharmacist play in the management of patients on capivasertib?

• Pharmacists can play a role in the management of patients on capivasertib by ensuring appropriate dosing and dose reductions, management of side effects, and accessibility.
• Dosing and Administration5
• The standard starting dose of capivasertib is 400 mg by mouth twice daily (12 hours apart) for 4 days, then 3 days off in combination with fulvestrant. This medication should be continued until disease progression or unacceptable toxicities.
• There are no dose adjustments required for renal or hepatic impairment. However, those with moderate impairment (Bilirubin >1.5 to 3 times ULN and any AST) may have increased exposure of capivasertib and should be monitored for adverse reactions.
• Capivasertib is available as a 200 mg and 160 mg tablet. Therefore, standard dosing will require 200 mg tablets with instructions to take 2 tablets twice daily.
• For administration, capivasertib can be given without regard to food and should not be chewed, crushed, or split.1
• If a patient misses a dose by more than 4 hours, advise the patient to skip the dose.1
• Baseline Monitoring1,5
• Genetic testing to assess for alterations in PIK3CA, AKT1, and PTEN.
• Hepatic function.
• Blood glucose levels including fasting blood glucose (FBG) levels and glycated hemoglobin test (HbA1c).
• Regular Monitoring1,5
• Blood glucose levels – HbA1c every 3 months, and FBG every 2 weeks for the first month, then once per month. Check FBG more frequently in patients with a history of diabetes, those at risk of hyperglycemia, or those who experience hyperglycemia after initiation of capivasertib.
• Dose Adjustments1,5
• First dose reduction: 320 mg BID for 4 days, then 3 days off.
• Second dose reduction: 200 mg BID for 4 days, then 3 days off.
• Capivasertib is a substrate of CYP3A4 and UGT2B7 and is mainly metabolized by the liver. Avoid concomitant use of strong or moderate CYP3A4 inhibitors as this will increase exposure of capivasertib and risk of side effects. If use cannot be avoided, reduce the dose of capivasertib. Avoid use of strong or moderate CYP3A inducers as this will decrease the effectiveness of capivasertib.
• Management of Side Effects1,5
• If a patient’s FBG is elevated up to 160 mg/dL or HbA1c is >7%, consider initiation or intensification of anti-diabetic treatment.
• If a patient’s FBG is elevated from 161 mg/dL to 250 mg/dL, hold capivasertib until FBG < 160 mg/dL. When resuming capivasertib, if FBG recovers within 28 days, resume the same dose or if FBG recovers >28 days, resume capivasertib at first dose reduction.
• If a patient’s FBG is elevated from 251 mg/dL to 500 mg/dL, hold capivasertib until FBG < 160 mg/dL. When resuming capivasertib, if FBG recovers within 28 days, resume capivasertib at first dose reduction or if FBG recovers >28 days, do not resume capivasertib.
• For diarrhea Grade 2 or 3 that recovers within 28 days, resume capivasertib at same dose or first dose reduction. For diarrhea Grade 2 that does not recover within 28 days, resume capivasertib at first dose reduction. For diarrhea Grade 3 that does not recover within 28 days and diarrhea Grade 4 regardless of recovery time, discontinue capivasertib.
• For cutaneous adverse reactions, hold capivasertib until recovery to < grade 1. Prolonged recovery >28 days or recurrent reactions may require dose reduction of capivasertib.

Clinical Pearls

• The CAPItello-291 trial did not include patients with type 1 diabetes mellitus or those utilizing insulin. Capivasertib increases the risk of hyperglycemia, including severe hyperglycemia associated with ketoacidosis. Thus, clinicians should carefully consider the risks and benefits associated with use of capivasertib in patients utilizing insulin and should counsel on the signs and symptoms of ketoacidosis.2,5
• In older adults, the CAPItello-291 trial showed no difference in efficacy of capivasertib. However, patients 65 or older experienced a higher incidence of grade 3, 4 and 5 adverse reactions requiring dose modifications. As a result, these patients should be closely monitored for assessment of adverse reactions and appropriate dose reductions.2,5
• In patients who experience cutaneous reactions, early consultation with a dermatologist is recommended. Of those who experienced cutaneous reactions in the CAPItello-291 trial, some were treated with topical or oral corticosteroids.1,5
• Capivasertib tablets should be stored in the original container.1
• AstraZeneca provides a program called “Access 360” to assist with insurance coverage including prior authorization, claims and appeals process. Additionally, AstraZeneca provides a patient savings program for commercially insured patients.7

References

1. Capivasertib (Truqap) [package insert]. AstraZeneca Pharmaceuticals LP: Wilmington, DE. 2023.
2. 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
3. U.S. Food and Drug Administration. FDA approves capivasertib with fulvestrant for breast cancer.  November 2023. Accessed February 25, 2024.
4. National Comprehensive Cancer Network. Invasive Breast Cancer (Version 1.2024). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed February 27, 2024.
5. Lexicomp Online, Waltham, MA:UpToDate, Inc; February 24, 2024. https://online.lexi.com. Accessed February 25, 2024.
6. American Society of Clinical Oncology. Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer Guideline and Rapid Update. February 6, 2024. Accessed February 25, 2024.
7. TRUQAP (capivasertib). AstraZeneca. December 2023. Accessed February 25, 2024.