Research Summary

Can Switching to Camizestrant Delay Progression in ESR1-Mutated Advanced Breast Cancer?

Key Highlights

  • Switching to camizestrant plus a CDK4/6 inhibitor significantly prolonged progression-free survival vs continuing an aromatase inhibitor.
  • Median progression-free survival: 16.0 months with camizestrant vs 9.2 months with an aromatase inhibitor.
  • Quality-of-life deterioration occurred later with camizestrant (21.0 vs 6.4 months).
  • Safety profile was consistent with prior data, with mostly low-grade adverse events and rare discontinuations.

In the SERENA-6 trial, patients with ER-positive, HER2-negative advanced breast cancer who developed an ESR1 mutation during first-line therapy experienced significantly longer progression-free survival when switched to camizestrant plus a CDK4/6 inhibitor compared with those who continued aromatase-inhibitor therapy.

Median progression-free survival was 16.0 months in the camizestrant group and 9.2 months in the aromatase-inhibitor group (HR 0.44; 95% CI, 0.31-0.60; P < .0001). At 24 months, 30% of patients receiving camizestrant were alive without disease progression versus only 5% in the comparator arm. Quality-of-life deterioration occurred later with camizestrant (median, 21.0 months vs 6.4 months), further underscoring clinical benefit.

Mutations in ESR1 are the most common mechanism of acquired resistance to aromatase inhibitors combined with CDK4/6 inhibitors, the current standard of care for this patient population. Because these mutations confer resistance to estrogen suppression but not necessarily to estrogen receptor degradation, selective estrogen receptor degraders (SERDs) such as camizestrant may provide therapeutic benefit. Earlier trials demonstrated that camizestrant had activity against both wild-type and mutant ESR1, supporting its evaluation as an adaptive switch strategy before overt progression.

In this phase 3, randomized, double-blind trial, Bidard and colleagues enrolled patients with advanced ER-positive, HER2-negative disease who had received at least 6 months of an aromatase inhibitor plus a CDK4/6 inhibitor without progression. Surveillance circulating tumor DNA testing was performed every 2 to 3 months. Patients with an ESR1 mutation detected in the absence of radiographic progression were randomized to continue aromatase inhibition or switch to camizestrant (75 mg once daily) while maintaining their CDK4/6 inhibitor. The primary endpoint was investigator-assessed progression-free survival.

Beyond the primary results, central blinded review confirmed the progression-free survival benefit with camizestrant (19.3 vs 11.5 months; HR 0.43). Secondary analyses showed consistent findings across subgroups and a prolonged time to deterioration in global health status and quality of life with camizestrant (HR 0.54). Safety results were consistent with prior reports: grade ≥3 adverse events occurred more often with camizestrant, mainly hematologic, but discontinuation rates were low (1.3%). Photopsia was more common in the camizestrant group but was generally mild and non-limiting.

The authors noted several study limitations including immature overall survival data, limited racial diversity, and a trial design requiring continuation of the same CDK4/6 inhibitor, which may not reflect broader clinical practice.

“In patients with ER-positive, HER2-negative advanced breast cancer with an ESR1 mutation that emerged during treatment, those who were switched to camizestrant with continuation of a CDK4/6 inhibitor during first-line therapy had significantly longer progression-free survival than those who maintained the aromatase-inhibitor combination,” the authors concluded.

Reference
Bidard F-C, Mayer EL, Park YH, et al; SERENA-6 Study Group. First-line camizestrant for emerging esr1-mutated advanced breast cancer. N Engl J Med. 2025;393(6):569-580. doi:10.1056/NEJMoa2502929