Abstract RF7-03: Updated results and an exploratory analysis of ESR1m circulating tumor DNA (ctDNA) dynamics from SERENA-6, a phase 3 trial of camizestrant (CAMI) + CDK4/6 inhibitor (CDK4/6i) for emergent ESR1 mutations (ESR1m) during first-line (1L) endocrine-based therapy and ahead of disease progression in patients (pts) with HR+/HER2- advanced breast cancer (ABC)

Abstract Background: At SERENA-6 interim analysis, switching to CAMI, with continued CDK4/6i, at ESR1m emergence during 1L aromatase inhibitor (AI) + CDK4/6i significantly improved PFS, extending time on first-line therapy, and delayed time to deterioration (TTD) in global health status and quality of life (GHS/QOL) (DCO: Nov 28, 2024). We report the prespecified final PFS analysis and an exploratory analysis of ESR1m ctDNA dynamics. Methods: SERENA-6, a randomized, double-blind, phase 3 trial, enrolled pts with HR+/HER2- ABC who had received ≥6 months of 1L AI (anastrozole/letrozole) + CDK4/6i (palbociclib/ribociclib/abemaciclib). Pts had ctDNA tested for ESR1m every 2-3 months, coinciding with routine clinical assessments. At ESR1m detection, pts without evidence of disease progression were randomized 1:1 to switch to CAMI (75 mg) with continued CDK4/6i (type and dose) + placebo for AI vs continuing AI + CDK4/6i + placebo for CAMI. The primary endpoint was PFS (per RECIST v1.1). Key secondary endpoints were PFS2 and OS. Chemotherapy-free survival was a secondary endpoint; TTD in GHS/QOL was an exploratory endpoint. ctDNA was analyzed by next-generation sequencing of plasma samples at baseline and Cycle 3 Day 1 (C3D1). This final PFS analysis was planned after ∼195 PFS events. DCO2: June 30, 2025. Results: 315 pts were randomized to switch to CAMI (n=157) or continue AI (n=158) with continued CDK4/6i. At DCO, median follow-up was 18.7 months. Updated results are shown in the Table and were consistent with primary analyses. PFS benefit was consistent across pt subgroups. At C3D1 (8 weeks) ESR1m allele frequency (AF) was profoundly reduced in the CAMI + CDK4/6i arm (median change from baseline, −100% [IQR: −100 to −100]) and increased in the AI + CDK4/6i arm (median change from baseline, +66.7% [IQR: −67.9 to +465.0], Wilcoxon P<0.00001). In the AI + CDK4/6i arm, ESR1m AF increased >500% from baseline in 24.4% pts vs 0.8% in the CAMI + CDK4/6i arm. OS results remained immature (22%). Updated safety data were consistent with previous results. Rates of treatment discontinuation due to AEs were 1.3% for CAMI and 2.6% for AI. Conclusions: Consistent with the primary results, CAMI + CDK4/6i significantly prolongs PFS in pts with HR+/HER2- ABC and ESR1m emergence during 1L AI + CDK4/6i and ahead of disease progression. CAMI + CDK4/6i profoundly reduced ESR1m AF within 8 weeks, whereas it increased for many pts continuing AI + CDK4/6i. PFS2 and chemotherapy or antibody drug-conjugate-free survival hazard ratios favor the CAMI + CDK4/6i arm. No new safety signals were observed. These results further support an early switch to CAMI + CDK4/6i during 1L therapy to delay disease progression. Citation Format: F. Bidard, E. L. Mayer, Y. Park, W. Janni, C. Ma, M. Cristofanilli, G. Bianchini, K. Kalinsky, H. Iwata, S. Chia, A. Brufsky, P. Fasching, Z. Nowecki, J. Pascual, E. Gal-Yam, W. Chung, S. Im, A. Zambelli, F. Dalenc, M. Oliveira, S. Fox, M. Selvi Miralles, C. Morrow, C. Huang Bartlett, N. C. Turner. Updated results and an exploratory analysis of ESR1m circulating tumor DNA (ctDNA) dynamics from SERENA-6, a phase 3 trial of camizestrant (CAMI) + CDK4/6 inhibitor (CDK4/6i) for emergent ESR1 mutations (ESR1m) during first-line (1L) endocrine-based therapy and ahead of disease progression in patients (pts) with HR+/HER2- advanced breast cancer (ABC) [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 RF7-03.