First-line (1L) camizestrant (CAMI) for emergent <i>ESR1</i> mutations ( <i>ESR1</i> m) in advanced breast cancer (ABC): Final progression-free survival 2 (PFS2) from the phase III SERENA-6 trial.

Abstract

LBA1007 Background: CAMI is a next-generation SERD and complete ER antagonist. SERENA-6 enrolled patients (pts) with HR+/HER2− ABC receiving 1L aromatase inhibitor (AI) + CDK4/6i and without disease progression. Switching to CAMI, with continued CDK4/6i, at ESR1 m emergence during 1L AI + CDK4/6i significantly improved PFS (HR: 0.44 [95% CI: 0.31–0.60]; p&lt;0.0001; median follow-up: 12.6 mo). Here, we report the final PFS2 results. Methods: SERENA-6 was powered for PFS (primary endpoint) and the key secondary endpoint of investigator-assessed PFS2 (time from randomization to the earliest of disease progression after first subsequent therapy or death). Pts had scans to assess PFS2 every 8–12 weeks after first progression. PFS2 analysis was planned after ~158 PFS2 events (77% power to detect HR of 0.65) and analyzed using an adjusted log-rank test and a 2-sided significance level of ~5%. Chemotherapy/ADC-free survival was a secondary endpoint. Results: 157 pts were randomized to CAMI + CDK4/6i and 158 pts to AI + CDK4/6i. After 23.5 mo median follow-up (data cutoff: Jan 3, 2026), median PFS2 was 25.7 mo with CAMI + CDK4/6i vs 19.1 mo with AI + CDK4/6i; statistically significant improvement, HR: 0.63 (95% CI: 0.46–0.86); p=0.00373 (Table). Endocrine-based therapy was the most common first subsequent treatment (CAMI + CDK4/6i arm, 55.2%; AI + CDK4/6i arm, 66.7%). CAMI + CDK4/6i prolonged chemotherapy/ADC-free survival (HR: 0.64 [95% CI: 0.47–0.87]; nominal p=0.00375; Table) and TTD in GHS/QoL (0.48 [0.31–0.76]); nominal p&lt;0.001). PFS benefit with CAMI + CDK4/6i was maintained with longer follow-up (Table); 30-mo PFS rate was 30.4% vs 2.7% with continued AI + CDK4/6i. PFS benefit was not impacted by common co-mutations ( PIK3CA in 41.3% of pts, HR: 0.44 [95% CI: 0.28–0.68]; TP53 in 25.4% of pts, 0.49 [0.30–0.82]). At 30% maturity, OS HR was 0.87 (0.57–1.30). Safety was consistent with previous results. Conclusions: Switching to CAMI + CDK4/6i at ESR1 m emergence continued to result in PFS benefit, with approximately a third of pts still progression-free at 30 mo. PFS benefit was maintained beyond first progression; PFS2 was significantly improved and the clinically meaningful endpoint of chemotherapy/ADC-free survival was prolonged vs continuing AI + CDK4/6i. These results continue to support a switch to CAMI + CDK4/6i for pts with ESR1 m during 1L therapy to delay disease progression and deteriorations in QoL. Clinical trial information: NCT04964934 . DCO3 CAMI + CDK4/6i (n=157) AI + CDK4/6i (n=158) HR (95% CI) PFS Events, n (%)Median, mo24-mo rate, %30-mo rate, % 99 (63.1)16.834.930.4 124 (78.5)9.214.22.7 0.45 (0.34–0.59); p&lt;0.00001 PFS2 Events, n (%)Median, mo24-mo rate, %30-mo rate, % 80 (51.0)25.750.841.5 90 (57.0)19.136.329.7 0.63 (0.46–0.86); p=0.00373 Chemotherapy/ADC-free survival Events, n (%)Median, mo 85 (54.1)22.6 98 (62.0)18.7 0.64 (0.47–0.87); nominal p=0.00375