On November 16, 2023, the Food and Drug Administration approved capivasertib with fulvestrant for 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-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.

FDA also approved the FoundationOne®CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with capivasertib with fulvestrant.

Efficacy was evaluated in CAPItello-291 (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 patients had tumours with PIK3CA/AKT1/PTEN-alterations. All patients were required to have progression on aromatase inhibitor-based treatment. Patients could have received up to two prior lines of endocrine therapy and up to 1 line of chemotherapy for locally advanced or metastatic disease.

Patients were randomized (1:1) to either capivasertib 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 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.

The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) in the overall population and in the population of patients whose tumours had PIK3CA/AKT1/PTEN-alterations evaluated according to RECIST, version 1.1. A statistically significant difference in PFS was observed in the overall population and in the population of patients whose tumours have PIK3CA/AKT1/PTEN-alteration(s).

In the 289 patients with PIK3CA/AKT1/PTEN-altered tumours, the median PFS was 7.3 months (95% 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 [HR] 0.50 [95% CI: 0.38, 0.65] p-value< 0.0001).

An exploratory analysis of PFS in the 313 (44%) patients whose tumours did not have a PIK3CA/AKT1/PTEN-alteration showed a HR 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 tumours have PIK3CA/AKT1/PTEN-alteration.

The most common adverse reactions (reported in ≥20% of patients), including laboratory abnormalities, were diarrhoea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased haemoglobin, 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 off days until disease progression or unacceptable toxicity.

The full prescribing information for capivasertib is here.

Source: FDA