Switching to camizestrant after ESR1 mutation detection prolongs progression free survival in advanced breast cancer

1. In patients with ER-positive, HER2-negative advanced breast cancer who developed an ESR1 mutation during first-line aromatase inhibitor plus CDK4/6 inhibitor therapy, those who switched to camizestrant while continuing the CDK4/6 inhibitor had longer progression-free survival (PFS) compared to those who continued the aromatase inhibitor.

2. The switch to camizestrant was also associated with a longer time to deterioration in patient-reported global health status and quality of life, with a low discontinuation rate due to adverse events.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Advanced ER-positive, HER2-negative breast cancer is commonly treated with endocrine therapy plus a CDK4/6 inhibitor, but resistance often develops through ESR1 mutations, prompting investigation of alternative hormonal strategies such as camizestrant. This trial evaluated whether an early switch to camizestrant, guided by ctDNA detection of ESR1 mutations, could improve outcomes for patients with advanced ER-positive, HER2-negative breast cancer receiving first-line endocrine therapy. Participants with an emerging ESR1 mutation but no clinical or radiologic progression were randomized to replace their aromatase inhibitor with camizestrant or to continue the aromatase inhibitor, with both arms maintaining the same CDK4/6 inhibitor. The camizestrant group experienced a longer median progression-free survival and delayed deterioration in quality of life compared to the control group. Adverse events were consistent with known effects of CDK4/6 inhibitors, and discontinuations due to toxicity were rare. These findings suggest that integrating serial ctDNA ESR1 testing into first-line care and adapting treatment before clinical progression may extend disease control and preserve quality of life.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This was a randomized controlled trial (SERENA-6) of ER-positive, HER2-negative advanced breast cancer patients who developed an ESR1 mutation during first-line aromatase inhibitor plus CDK4/6 inhibitor therapy, comparing continued therapy to switching to camizestrant while continuing the CDK4/6 inhibitor. Between June 2021 and June 2024, 3,256 patients at 264 sites in 23 countries were screened with serial ctDNA testing for ESR1 mutations while on first-line aromatase inhibitor plus CDK4/6 inhibitor therapy. A total of 548 patients developed an ESR1 mutation; 315 without radiologic progression were randomized 1:1 to camizestrant (75 mg daily) plus the same CDK4/6 inhibitor (n=157) or to continue their aromatase inhibitor plus the same CDK4/6 inhibitor (n=158). Median follow-up was 12.6 months. Investigator-assessed median progression-free survival (PFS) was 16.0 months (95% CI, 12.7–18.2) with camizestrant vs 9.2 months (95% CI, 7.2–9.5) with aromatase inhibitor, hazard ratio (HR) for progression or death 0.44 (95% CI, 0.31–0.60; p<0.0001). At 24 months, 29.7% of camizestrant patients were progression-free vs 5.4% in the control group. Blinded central review confirmed findings (median PFS 19.3 vs 11.5 months; HR 0.43, 95% CI, 0.29–0.63). Median time to deterioration in global health status/quality of life was 21.0 months with camizestrant vs 6.4 months with aromatase inhibitor (HR 0.54, 95% CI, 0.34–0.84). Grade ≥3 adverse events occurred in 60.0% of camizestrant patients and 45.8% of controls, primarily neutropenia (45.2% vs 34.2%). Photopsia was more frequent with camizestrant (20.0% vs 7.7%), generally grade 1 and non-disabling. Discontinuations due to adverse events were rare (1.3% vs 1.9%). These results support ctDNA-guided switching to camizestrant in this setting to prolong PFS, delay symptomatic decline, and maintain treatment tolerability.

Image: PD

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