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Capivasertib Plus Fulvestrant Approved for Breast Cancer

Breast cancer cell.

The FDA has approved capivasertib (Truqap™, AstraZeneca Pharmaceuticals) in combination with fulvestrant for adult patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer. This indication is for patients with one or more PIK3CA/AKT1/PTEN alterations, as detected by an FDA-approved 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. Capivasertib is a first-in-class pan-AKT inhibitor. This is the first approval of capivasertib.

In addition, the FDA has approved the companion diagnostic device FoundationOne®CDx assay to identify patients with breast cancer who are eligible for treatment with capivasertib plus fulvestrant. 

Why it matters: "AKT pathway activation is implicated in endocrine-therapy resistance," wrote Nicholas Turner, MD, a Consultant Medical Oncologist at The Royal Marsden, National Health Service (NHS) Foundation Trust, in the United Kingdom, and colleagues, in their published results of the CAPItello-291 trial (NCT04305496), on which approval was based.

What they studied: Efficacy was studied in the phase 3, multicenter, double-blind, placebo-controlled trial that enrolled 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer, of which 289 patients had tumors with a PIK3CA/AKT1/PTEN alteration. Patients were randomized 1:1 to receive either 400 mg of capivasertib or placebo orally, twice daily, for four days, followed by three days off treatment each week over a 28-day treatment cycle. In addition, 500 mg of fulvestrant was administered intramuscularly to both the capivasertib and placebo arms on Cycle 1, Days 1 and 15, and then every 28 days thereafter. Treatment was continued until disease progression or unacceptable toxicity.

Inclusionary criteria for those enrolled included the requirement for all patients to have progressed on aromatase inhibitor–based treatment. Patients could have received up to two prior lines of endocrine therapy and up to one line of chemotherapy for locally advanced or metastatic disease.

The primary end point measured was progression-free survival in the overall population and in the PIK3CA/AKT1/PTEN alteration population, as assessed by investigators per RECIST v1.1.

What they found: Progression-free survival saw a statistically meaningful improvement in both the overall population as well as the 289 patients with PIK3CA/AKT1/PTEN alterations. Of those with PIK3CA/AKT1/PTEN-altered tumors, the median progression-free survival for those receiving capivasertib/fulvestrant was 7.3 months compared with those receiving placebo/fulvestrant at 3.1 months.

In an exploratory analysis of progression-free survival in the 313 patients without a PIK3CA/AKT1/PTEN alteration, the hazard ratio was 0.79, indicating that the difference in the overall population was primarily attributable to the results seen among patients with PIK3CA/AKT1/PTEN-altered tumors.

Adverse events: The most common adverse events seen in ≥20% of patients, including laboratory abnormities, were diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting, and stomatitis.

Conclusion: "Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with HR-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor," concluded Dr. Turner and colleagues.

Future Directions: The FDA review of capivasertib was conducted under Project Orbis, an international project allowing concurrent review of oncology products among multiple regulatory bodies worldwide. Capvasertib is currently undergoing regulatory review under the Australian Therapeutic Goods Administration (TGA), Health Canada, Israel's Ministry of Health (IMoH), Singapore's Health Sciences Authority (HSA), Switzerland's Swissmedic, and the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), along with ongoing reviews with other international regulatory bodies.

Instructions: The recommended dosage of capivasertib is 400 mg orally, twice daily—approximately 12 hours apart—with or without food, for four days followed by three off days. Treatment should continue until disease progression or unacceptable toxicity.

For More Information

Truqap™ (capivasertib) prescribing information will be made available here.

Turner NC, Oliveira M, Howell SJ, et al (2023). Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med; 388(22):2058-2070. DOI:10.1056/NEJMoa2214131 (2023). Capivasertib+fulvestrant vs placebo+fulvestrant as treatment for locally advanced (inoperable) or metastatic HR+/HER2- breast cancer (CAPItello-291). NLM identifier: NCT04305496.

US Food and Drug Administration (2023). FDA approves capivasertib with fulvestrant for breast cancer. Available at:

Image credit: National Cancer Institute. Licensed under Public Domain.

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