Abstract Background: Alpelisib (ALP), an α-specific PI3K inhibitor, plus fulvestrant (FUL) improved disease control with a manageable safety in patients (pts) with HR+, HER2− advanced breast cancer (ABC) harboring a PIK3CA-m in SOLAR-1 and in BYLieve Cohort A trials. We report primary results from the EPIK-B5 study, comparing ALP+FUL vs placebo (PBO)+FUL in men/postmenopausal women with PIK3CA-m HR+, HER2− ABC who had progressed on cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)+aromatase inhibitor (AI). Methods: EPIK-B5 was a phase 3, double-blind, PBO-controlled study. Pts (n=188) were randomised 1:1 to ALP+FUL (arm 1) or PBO+FUL (arm 2). The primary endpoint was progression-free survival (PFS) by Blinded Independent Review Committee BIRC. Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), time to response (TTR), PFS by PIK3CA-m in baseline ctDNA, adverse events (AEs), time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status, change in global health status and symptom scale scores of the EORTC QLQ-C30, and time to progression on next line treatment or death (PFS2) by investigator assessment. Results: Baseline characteristics are shown in the Table. At primary analysis (data cutoff Oct 2024), median follow-up duration was 17.7 (1.4-33.1) months (mo). The median PFS (BIRC) was 7.4 and 2.8 mo in arm 1 and 2, respectively, (HR: 0.52, 95% CI: 0.37,0.72, log-rank p0.0001). Median OS was not reached for arm 1 and was 22.6 mo for arm 2 (HR:0.60, 95% CI: 0.36,1.01). In pts with measurable disease, (n= 85 vs 90 in arm 1 vs 2) ORR was 24.7% vs 4.4% and CBR was 47.1% vs 22.2% in arm 1 vs 2, respectively. Dose reductions (45.7% vs 0%) and interruptions (68.5 vs 13.8%) were more frequent for ALP+FUL. Most common AEs (all grades; ≥30%) in arm 1 and 2 were hyperglycemia (72.8% vs 11.7%), diarrhea (51.1% vs 11.7%), nausea (44.6% vs 13.8%), decreased appetite and rash (30.4% each in both arms). Discontinuations in arm 1 and 2 due to AEs (all grades) were 27.2% vs 2.1% respectively. On-treatment deaths were comparable (5.4% vs. 6.4%). At the pre-planned final PFS analysis (cut-off May 2025; median duration 23.5 mo), the median OS was 29.5 and 23.8 months in arms 1 and 2, respectively (HR:0.64, 95% CI: 0.41-0.99, p=0.021). Conclusion: EPIK-B5 met its primary objective with ALP+FUL showing a statistically significant and clinically meaningful improvement in PFS in patients with HR+, HER2− ABC harboring a PIK3CA-m after CDK4/6i. There was a positive trend for a prolonged OS in favor of ALP+FUL over PBO with about 5.7 mo improvement in the median OS. There were no new safety signals. Citation Format: M. De Laurentiis, A. M. Ferreira, J. Gligorov, E. Dobi, L. Costa, M. Vidal, A. S. Knop, T. Bachelot, E. Senkus, M. Colleoni, P. Schmid, A. Santoro, G. Zhbantov, J. Foglietta, M. Miller, P. Serra, A. Heniquez, P. Chaudhary, R. Haidinger, S. Kuemmel. 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 abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF7-02.
Laurentiis et al. (Tue,) studied this question.