Alpelisib Plus Fulvestrant in PIK3CA-Mutated HR-Positive, HER2-Negative Advanced Breast Cancer
Key Clinical Takeaways
- Design/Population: This double-blind, placebo-controlled phase 3 trial randomized 188 patients with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer who had progressed on prior CDK4/6 inhibitor plus aromatase inhibitor therapy. Patients received alpelisib plus fulvestrant or placebo plus fulvestrant, with PFS by blinded independent review as the primary end point.
- Key Outcomes: Alpelisib plus fulvestrant significantly prolonged PFS compared with placebo plus fulvestrant (7.4 vs 2.8 months; HR, 0.52). Objective response rate and clinical benefit rate were higher with alpelisib, and final OS analysis demonstrated a statistically significant improvement.
- Clinical Relevance: Findings from EPIK-B5 support alpelisib plus fulvestrant as an effective option for patients with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer after progression on CDK4/6 inhibitor therapy. No new safety signals were observed, although discontinuations due to adverse events were more frequent with alpelisib.
According to updated results from the phase 3 EPIK-B5 trial, alpelisib plus fulvestrant demonstrated clinical activity among patients with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with CDK4/6 inhibitor and aromatase inhibitor therapy.
These findings were presented by Michelino De Laurentiis, MD, PhD, National Cancer Institute, Naples, Italy, at the 2025 San Antonio Breast Cancer Symposium in San Antonio, Texas.
In this double-blind, placebo-controlled study, 188 patients were randomized 1:1 to receive alpelisib plus fulvestrant (n = 94) or placebo plus fulvestrant (n = 94). The primary end point was progression-free survival (PFS) assessed by blinded independent review. Key secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate, and safety.
At a median follow-up of 17.7 months, median PFS was 7.4 months in the alpelisib plus fulvestrant arm and 2.8 months in the placebo plus fulvestrant arm (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.37 to 0.72; P <.0001). Median OS was not reached in the alpelisib plus fulvestrant arm and was 22.6 months in the placebo plus fulvestrant arm. Among patients with measurable disease, the ORR was 24.7% with alpelisib plus fulvestrant versus 4.4% with placebo plus fulvestrant, and the clinical benefit rate was 47.1% and 22.2%, respectively. At the preplanned final PFS analysis (median follow-up, 23.5 months), median OS was 29.5 months in the alpelisib arm and 23.8 months in the placebo arm (HR, 0.64; 95% CI, 0.41 to 0.99; P = .021).
The most common adverse events included hyperglycemia (72.8%), diarrhea (51.1%), nausea (44.6%), decreased appetite (30.4%), and rash (30.4%). Grade ≥3 adverse events occurred in 72.8% of patients receiving alpelisib plus fulvestrant and 11.7% of those receiving placebo. Adverse events led to treatment discontinuation in 27.2% and 2.1% of patients, respectively. There were 5 on-treatment deaths in the alpelisib plus fulvestrant arm and 6 in the placebo arm.
“EPIK-B5 met its primary objective with [alpelisib plus fulvestrant] showing a statistically significant and clinically meaningful improvement in PFS in patients with [HR-positive, HER2-negative advanced breast cancer] harboring a PIK3CA-[mutation] after CDK4/6 [inhibition],” concluded Dr De Laurentiis.
Source:
De Laurentiis M, Ferreira AM, Gligorov J, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer after a CDK4/6 inhibitor (EPIK-B5): Phase III, randomized, double-blind, placebo-controlled, multicenter study. Presented at SABCS 2025. December 9 - 12, 2025. San Antonio, Texas. Abstract RF7-02
