107 Updated Results and an Exploratory Analysis of ESR1 Mutations (ESR1m) Circulating Tumor DNA (ctDNA) Dynamics From SERENA-6, a Phase III Trial of Camizestrant + CDK4/6 Inhibitor (CDK4/6i) for Emergent ESR1m During First-Line (1L) Endocrine-Based Therapy and Ahead of Disease Progression in Patients With HR+/HER2– Advanced Breast Cancer (ABC)

Background

At SERENA-6 interim analysis, switching to camizestrant, with continued CDK4/6 inhibitor (CDK4/6 i), at ESR1 mutationemergence during first-line aromatase inhibitor plus CDK4/6i significantly improved progression-free survival (PFS), extended time on first-line therapy, and delayed time to deterioration (TTD) in global health status/quality of life (GHS/QOL) (data cutoff [DCO]: November 28, 2024). We report prespecified final PFS analysis and an exploratory analysis of ESR1 mutation ctDNA dynamics.

Methods

SERENA-6 (NCT04964934), a randomized, double-blind, phase III trial, enrolled patients with hormone receptor–positive (HR+)/HER2-negative (HER2–) advanced breast cancer who had received 6 months or more of first-line aromatase inhibitor (anastrozole/letrozole) plus CDK4/6i (palbociclib/ribociclib/abemaciclib). Patients had ctDNA tested for ESR1 mutation every 2 to 3 months, coinciding with routine clinical assessments. At ESR1 mutation detection, patients without evidence of disease progression were randomly assigned 1:1 to switch to camizestrant (75 mg) with continued CDK4/6i (type and dose) plus placebo for aromatase inhibitor vs continuing AI plus CDK4/6i plus placebo for camizestrant. The primary end point was PFS (per RECIST v1.1). Key secondary end points were PFS2 and overall survival (OS). Chemotherapy-free survival was a secondary end point; TTD in GHS/QOL was an exploratory end point. 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 approximately 195 PFS events. DCO2: June 30, 2025.

Results

A total of 315 patients were randomized to switch to camizestrant (n = 157) or continue aromatase inhibitor (n = 158) with continued CDK4/6i. At DCO, median follow-up was 18.7 months. Updated results are shown (Table) and were consistent with primary analyses. At C3D1 (8 weeks), ESR1 mutation allele frequency (AF) was profoundly reduced in the camizestrant plus CDK4/6i arm (median change from baseline, –100% [IQR: –100, –100]) and increased in the aromatase inhibitor plus CDK4/6i arm (median change from baseline, +66.7% [IQR: –67.9, +465.0], Wilcoxon P <.00001). In the AI + CDK4/6i arm, ESR1m AF increased >500% from baseline in 24.4% of patients versus 0.8% in the camizestrant plus CDK4/6i arm. OS results remained immature (22%). Updated safety data were consistent with previous results. Rates of treatment discontinuation due to adverse events were 1.3% for camizestrant and 2.6% for aromatase inhibitors.

Conclusions

Consistent with the primary results, camizestrant plus CDK4/6i significantly prolonged PFS in patients with HR+/HER2– advanced breast cancer and ESR1 mutation emergence during first-line aromatase inhibitor plusCDK4/6i and ahead of disease progression. Camizestrant plus CDK4/6i profoundly reduced ESR1 mutation AF within 8 weeks, whereas AF increased for many patients continuing aromatase inhibitor plus CDK4/6i. PFS2 and chemotherapy or antibody–drug conjugate (ADC)-free survival hazard ratios favor the camizestrant plus CDK4/6i arm. No new safety signals were observed. These results further support an early switch to camizestrant plus CDK4/6i during first-line therapy to delay disease progression.