Abstract RF7-02: 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 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 p<0.0001). 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.