Camizestrant (oral SERD) + CDK4/6i doubles PFS when ctDNA ESR1 mutations emerge on 1L AI

Camizestrant (AZD9833) is an oral selective estrogen receptor degrader (SERD) designed to antagonize and degrade ER, including mutant ER, and in SERENA-6 (Phase 3, double-blind) it was used as an early “molecular switch” from aromatase inhibitor (AI) at ctDNA-detected ESR1 mutation emergence while continuing the same CDK4/6 inhibitor. Among patients with ER+/HER2− locally advanced/metastatic breast cancer on 1L AI+CDK4/6i for ≥6 months who developed ctDNA ESR1 mutations without radiographic progression (n=315 randomized; 157 camizestrant+CDK4/6i vs 158 AI+CDK4/6i), median PFS was 16.8 vs 9.2 months (HR 0.45; nominal p<0.0001; data cutoff Jan 2, 2026) and median second PFS was 25.7 vs 19.1 months (HR 0.63; p=0.0037; NCT04964934). Grade 3-4 neutropenia was higher with camizestrant+CDK4/6i (27% vs 17%), serious AEs were similar (15% vs 19%), and there were 3 investigator-attributed “possibly treatment-related” deaths (1 vs 2); benchmark-wise, upfront AI+CDK4/6i typically yields ~24–28 months mPFS in unselected 1L ER+/HER2− disease, so SERENA-6 isn’t trying to beat 1L mPFS overall—it’s showing that after ESR1-mutant ctDNA escape, staying on an AI looks like a ~9-month mPFS strategy whereas switching endocrine backbone restores a more meaningful disease-control window.