Early Switch to Camizestrant at ESR1 Mutation Emergence Improves Outcomes in HR-Positive, HER2-Negative Advanced Breast Cancer
Key Clinical Takeaways
- Design/Population: The phase 3 SERENA-6 trial enrolled 315 patients with HR-positive, HER2-negative advanced breast cancer receiving first-line aromatase inhibitor plus CDK4/6 inhibitor therapy. Patients underwent serial ctDNA monitoring every 2 to 3 months, and those with newly emergent ESR1 mutations without radiographic progression were randomized to switch to camizestrant or continue aromatase inhibitor therapy, both with ongoing CDK4/6 inhibition.
- Key Outcomes: Switching to camizestrant significantly improved PFS (16.6 vs 9.2 months; HR, 0.46; P <.00001) and also prolonged PFS2, chemotherapy/ADC-free survival, and time to deterioration in global health status or quality of life. ctDNA analysis showed a −100% median change in ESR1 allele frequency at 8 weeks with camizestrant versus a +66.7% increase with continued aromatase inhibitor therapy.
- Clinical Relevance: Findings support an early-switch strategy at the onset of ESR1 mutation emergence, offering meaningful disease control and favorable molecular response with a manageable safety profile. These results underscore the potential for ctDNA-guided treatment adaptation in HR-positive, HER2-negative advanced breast cancer.
Updated results from the phase 3 SERENA-6 trial indicate that switching to camizestrant at the time of ESR1 mutation emergence may offer clinical benefit for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.
These findings were presented by François-Clément Bidard, MD, PhD, Institut Curie, Paris, France, at the 2025 San Antonio Breast Cancer Symposium in San Antonio, Texas.
In this double-blind study, 315 patients who had received ≥6 months of first-line aromatase inhibitor therapy (anastrozole or letrozole) plus a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) underwent circulating tumor DNA (ctDNA) testing every 2 to 3 months to detect ESR1 mutations. Patients with newly emergent ESR1 mutations and no evidence of disease progression were randomized 1:1 to switch to 75 mg of daily camizestrant with continued CDK4/6 inhibitor therapy plus placebo (acting as the aromatase inhibitor; n = 157) or to continue aromatase inhibitor plus CDK4/6 inhibitor therapy with placebo (acting as camizestrant; n = 158).
The primary end point was progression-free survival (PFS). Key secondary end points included PFS2, overall survival (OS), and chemotherapy- or antibody-drug conjugate (ADC)-free survival. Exploratory end points included time to deterioration in global health status or quality of life and ctDNA analysis at cycle 3 day 1.
At a median follow-up of 18.7 months, median PFS was 16.6 months in the camizestrant arm and 9.2 months in the placebo arm (hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P <.00001). Median PFS2 was 25.7 months and 19.4 months, respectively (P = .00153). OS remained immature at the time of analysis. Median chemotherapy- or ADC-free survival was 22.7 months in the camizestrant arm and 18.7 months in the placebo arm. Median time to deterioration was 23 months and 8.3 months, respectively. Safety findings were consistent with prior data, and treatment-related adverse events led to discontinuation in 1.3% of patients in the camizestrant arm and 2.6% in the placebo arm.
At ctDNA analysis, the median change in 8-week ESR1 allele frequency was −100% in the camizestrant arm and +66.7% in the placebo arm (P <.00001). Increases greater than 500% occurred in 24.4% of patients in the placebo arm and in 0.8% of those in the camizestrant arm.
“Consistent with the primary results, [camizestrant plus] CDK4/6i significantly prolongs PFS in [patients] with [HR-positive, HER2-negative advanced breast cancer] and ESR1m emergence during [first-line aromatase inhibitor plus] CDK4/6i and ahead of disease progression,” concluded Dr Bidard. “These results further support an early switch to [camizestrant plus] CDK4/6i during [first-line] therapy to delay disease progression.”
Source:
Bidard F, Mayer EL, Park Y, et al. 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). Presented at SABCS 2025. December 9 - 12, 2025. San Antonio, Texas. Abstract RF7-03
