Data from the phase 3 CAPItello-291 trial of capivasertib plus fulvestrant in HR-positive, HER2-negative locally advanced or metastatic breast cancer have led the FDA to grant priority review to the new drug application for the combination.
The FDA has accepted and granted priority review to the new drug application for the combination of capivasertib and fulvestrant (Faslodex) for patients with hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence or progression on or after endocrine-based therapy, according to AstraZeneca.1
This decision is supported by data from the phase 3 CAPItello-291 trial (NCT04305496), in which the combination reduced the risk of disease progression or death by 40% vs fulvestrant plus placebo in this patient population. The median progression-free survival (PFS) was 7.2 months (95% CI, 5.5-7.4) with the combination vs 3.6 months (95% CI, 2.8-3.7) with fulvestrant alone (HR, 0.60; 95% CI, 0.51-0.71. P < .001), and the safety profile of the combination was similar with what has been observed in previous trials. Although overall survival (OS) data were immature at the time of the analysis, the trial continues to assess OS as a secondary end point.
The FDA has set a Prescription Drug User Fee Act decision date for the fourth quarter of 2023.
“The results of the trial showed that progression-free survival was significantly improved in patients who received capivasertib with their fulvestrant, whether it was the intent-to-treat population or the sub population of patients, and about 40%, who had an alteration in the AKT pathway,” Hope S. Rugo, MD, FASCO, director of Breast Oncology and Clinical Trials Education and professor of medicine in the Division of Hematology and Oncology at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, told Targeted OncologyTM.
Previously in January 2023, capivasertib was granted a fast track designation from the FDA as a treatment option for this patient population, also based on the CAPItello-291 trial.
In the phase 3, double-blind, randomized trial, 708 adult patients with histologically confirmed, locally advanced or metastatic HR-positive, HER2-low or negative breast cancer following disease recurrence or progression during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, who received up to 1 line of chemotherapy for advanced disease were enrolled.2 Patients were randomly assigned 1:1 in the overall population to receive either the capivasertib plus fulvestrant (n = 355) or placebo plus fulvestrant (n = 353).
Investigators assessed the coprimary end points of PFS in the overall patient population and in the population of patients whose tumors had PIK3CA, AKT1 or PTEN alterations in the AKT pathway (combination, n = 155 vs placebo, n = 134), and the secondary end points of overall survival (OS), objective response rate, and safety. Patient-reported end points were also studied, including responses from the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
Additional results from the study showed that median PFS was 7.3 months (95% CI, 5.5-9.0) in the combination arm vs 3.1 months (95% CI, 2.0-3.7) in the fulvestrant alone arm, among patients with AKT pathway alterations (HR, 0.50; 95% CI, 0.38-0.65; P < .001).
Although the OS data were immature at the time of the analysis, early data were encouraging with estimated 18-month survival rates of 73.9% (95% CI, 68.3%-78.7%) in the combination arm and 65.0% (95% CI, 58.7%-70.6%) in the fulvestrant alone arm in the overall population (HR, 0.74; 95% CI, 0.56-0.98). For patients in the AKT pathway–altered population, the estimated 18-month OS rates were 73.2% (95% CI, 64.8%-80.0%) and 62.9% (95% CI, 53.1%-71.2%), respectively (HR, 0.69; 95% CI, 0.45-1.05).
Regarding safety, grade 3 or higher adverse events (AEs) that were most common among patients receiving capivasertib vs placebo included diarrhea (9.3% vs 0.3%), rash that was maculopapular (6.2% vs 0%), rash (5.4% vs 0.6%), hyperglycemia (2.3% vs 0.3%), and stomatitis (2.0% vs 0%), respectively. Additionally, AEs leading to treatment discontinuation occurred in 2.3% of patients in both the capivasertib and placebo arms.
“This priority review decision underscores the potential of capivasertib to extend the effectiveness of endocrine-based treatment approaches for patients with hormone receptor–positive breast cancer who experience tumor progression on, or resistance to these widely used therapies. We look forward to working with the FDA to bring this potential first-in-class AKT inhibitor to patients as quickly as possible,” said Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, in a press release.1