Capivasertib with fulvestrant is approved by the USFDA for breast cancer treatment

Capivasertib (Truqap, AstraZeneca Pharmaceuticals) in combination with fulvestrant was approved by the Food and Drug Administration on November 16, 2023, for adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. This approval is specifically for patients with one or more PIK3CA/AKT1/PTEN-alterations, as identified by an FDA-approved test, who have experienced disease progression after at least one endocrine-based treatment in the metastatic setting or recurrence within 12 months of completing adjuvant therapy.

The FDA authorized the FoundationOne®CDx test as a companion diagnostic device for identifying breast cancer patients eligible for therapy with capivasertib and fulvestrant.

llo-291 (NCT04305496) was a randomized, double-blind, placebo-controlled, multicenter trial involving 708 patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer. Among them, 289 patients had tumors with PIK3CA/AKT1/PTEN-alterations. All patients needed to show progression while on aromatase inhibitor-based treatment. Patients may have undergone a maximum of two previous rounds of endocrine therapy and one round of chemotherapy for locally advanced or metastatic illness.

Patients were randomly assigned in a 1:1 ratio to receive either capivasertib 400 mg or a placebo orally twice daily for 4 days, with 3 days off therapy each week, across a 28-day treatment cycle. Both patients in the investigational and control groups were administered Fulvestrant 500 mg intramuscularly on cycle 1 days 1 and 15, and subsequently every 28 days. Patients were treated until disease progression or unacceptable toxicity occurred.

The primary effectiveness endpoint was investigator-assessed progression-free survival (PFS) in the entire study population and in the subgroup of patients with PIK3CA/AKT1/PTEN changes assessed using RECIST version 1.1. Statistically significant differences in progression-free survival (PFS) were found in both the total population and in patients with tumors that contain PIK3CA/AKT1/PTEN alterations.

Among the 289 patients with PIK3CA/AKT1/PTEN-altered tumors, those in the capivasertib-fulvestrant group had a median progression-free survival (PFS) of 7.3 months (95% CI: 5.5, 9.0), while those in the placebo-fulvestrant group had a median PFS of 3.1 months (95% CI: 2.0, 3.7). The Hazard Ratio (HR) was 0.50 (95% CI: 0.38, 0.65) with a p-value of less than 0.0001.

An exploratory analysis of progression-free survival (PFS) in 313 patients (44%) without PIK3CA/AKT1/PTEN-alterations showed a hazard ratio (HR) of 0.79 (95% CI: 0.61, 1.02). This suggests that the observed difference in the overall population was mainly driven by the outcomes in patients with PIK3CA/AKT1/PTEN-alterations.

The most frequent adverse reactions (reported in ≥20% of patients), including laboratory abnormalities, 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 suggested capivasertib dosage is 400 mg taken orally twice a day, about 12 hours apart, with or without food, for 4 consecutive days, followed by 3 days off, until disease progression or unacceptable toxicity.