Updated results and exploratory analysis of ESR1 mutations (ESR1m) circulating tumor DNA (ctDNA) dynamics from SERENA-6, a phase 3 trial of camizestrant+CDK4/6 inhibitor (CDK4/6i) for emergent ESR1 mutations (ESR1m) during first-line (1L) endocrine-based therapy and ahead of disease progression in patients with HR+/HER2- advanced breast cancer (aBC)

Background: ESR 1m constitutively activate the estrogen receptor (ER) and represent the prevalent resistance mechanism to AI plus CDK4/6i. ctDNA monitoring detects emerging ESR1 m during 1L AI+CDK4/6i in aBC. Camizestrant, a next-generation SERD and complete ER antagonist, demonstrates antitumour activity irrespective of ESR1 m. SERENA-6 is the first global Phase III trial evaluating ctDNA-guided ESR1m detection to enable early switch. Methods: HR+/HER2–aBC patients on 1L AI (anastrozole/letrozole)+CDK4/6i (abemaciclib/palbociclib/ribociclib) for≥6 months underwent ctDNA testing every 2–3 months. On ESR1m detection without progression, patients were randomised 1:1 to switch to camizestrant+CDK4/6i (same type/dose)+placebo for AI, or continue AI+CDK4/6i+placebo for camizestrant. The primary endpoint was investigator-assessed PFS (RECISTv1.1). Key secondary endpoints were PFS2 and chemotherapy-free survival. ctDNA was analysed by NGS of plasma at baseline and Cycle 3 Day 1 (C3D1). Result: 315 ESR1 m patients were randomised (camizestrant n=157, AI n=158), maintaining the same CDK4/6i. Updated results were consistent with primary analyses. At C3D1 (8 weeks), ESR1 m allele frequency (AF) was markedly reduced with camizestrant+CDK4/6i (median change−100% [IQR−100 to−100]) and increased with AI+CDK4/6i (median change+66.7% [IQR−67.9 to+465.0]; Wilcoxon P<0.00001). PFS2 and chemo/ADC-free survival favoured camizestrant+CDK4/6i, with HR of 0.56 (p=0.00153) and 0.69, respectively. Camizestrant+CDK4/6i was well tolerated (AE-related discontinuation 1.3% vs 2.9%). Conclusion: Camizestrant+CDK4/6i significantly prolonged PFS in HR+/HER2−aBC with emergent ESR1 m during 1L AI+CDK4/6i, prior to progression. ESR1 m AF decreased on camizestrant+CDK4/6i but increased on AI+CDK4/6i. PFS2 and chemo/ADC-free survival favoured camizestrant+CDK4/6i. No new safety signals, supporting an early switch. Clinical trial: NCT04964934. Publication History Article published online: 19 May 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany