On November 16, 2023, the U.S. Food and Drug Administration (FDA) approved capivasertib (Truqap) with fulvestrant for adult patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations, as detected by an FDA-approved test, following disease progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.
The FDA also approved the FoundationOne CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with capivasertib with fulvestrant.
CAPItello-291 Trial
The efficacy of this therapy was evaluated in CAPItello-291 (ClinicalTrials.gov identifier NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial in 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer, of which 289 had tumors with PIK3CA/AKT1/PTEN alterations. All patients were required to have had disease progression 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.
Patients were randomly assigned (1:1) to either capivasertib at 400 mg or placebo administered orally twice daily for 4 days, followed by 3 days off treatment each week over a 28-day treatment cycle. Both investigational and control arm patients received fulvestrant at 500 mg intramuscularly on cycle 1, days 1 and 15, and then every 28 days thereafter. Patients received therapy until disease progression or unacceptable toxicity.
Key Findings
The major efficacy outcome measure was investigator-assessed progression-free survival in the overall population and in the population of patients whose tumors had PIK3CA/AKT1/PTEN alterations evaluated according to Response Evaluation Criteria in Solid Tumors, version 1.1. A statistically significant difference in progression-free survival was observed in the overall population and in the population of patients whose tumors have PIK3CA/AKT1/PTEN alterations.
In the 289 patients with PIK3CA/AKT1/PTEN altered tumors, the median progression-free survival was 7.3 months (95% confidence interval [CI] = 5.5–9.0) in the capivasertib/fulvestrant group and 3.1 months (95% CI = 2.0–3.7) in the placebo/fulvestrant group (hazard ratio = 0.50, 95% CI = 0.38–0.65, P < .0001).
An exploratory analysis of progression-free survival in the 313 patients (44%) whose tumors did not have a PIK3CA/AKT1/PTEN alteration showed a hazard ratio of 0.79 (95% CI = 0.61–1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumors have PIK3CA/AKT1/PTEN alterations.
The most common adverse reactions (reported 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.
The recommended capivasertib dose is 400 mg orally twice daily (approximately 12 hours apart), with or without food, for 4 days followed by 3 days off until disease progression or unacceptable toxicity.
Additional Study Details
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Israel’s Ministry of Health, Singapore’s Health Sciences Authority, Switzerland's Swissmedic, and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 2 weeks ahead of the FDA goal date. The application was granted Priority Review.
