Abstract GS3-02: GS3-02 Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial

Abstract

Abstract Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) in the Phase 1 SERENA-1 study1,2 with a dose-dependent safety profile. The Phase 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) in post-menopausal women with ER+ HER2˗ BC with disease recurrence or progression after ≤1 endocrine therapy (ET) in the advanced setting. Methods SERENA-2 evaluated efficacy and safety of C 75, 150 or 300 mg monotherapy QD vs F (per label). Eligible patients were randomized 1:1:1:1. The Primary objective was to determine clinical efficacy of C vs F by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate, response duration, clinical benefit rate at 24 weeks, overall survival and safety. Patients had no prior F or oral SERD and ≤1 ET and ≤1 chemotherapy (CTX) in the advanced setting. To assess the impact of prior CDK4/6 inhibitor (CDK4/6i) treatment, randomization was stratified so that 50% of patients had prior CDK4/6i. Planned enrolment of 288 patients began in April 2020. The C 300 arm was closed after 20 patients were enrolled, changing target enrolment to 236. By August 2021, 240 patients had been randomized. Primary analysis was triggered when 108 progression events (75% maturity) had occurred in the best performing pair (C vs F) in August 2022. Efficacy analyses compared C 75 and 150 mg doses with F, with no formal analyses of C 300 vs F. 108 events for pairwise comparison vs F gave 86% power at the 2-sided 10% significance level. Primary analyses used a Cox proportional hazards model to compare PFS, adjusting for prior CDK4/6i and lung/liver metastases. ESR1 mutations (ESR1m) were detected in plasma samples using next-generation sequencing. Results 119/240 (49.6%) patients had had prior CDK4/6i therapy. At baseline, 88 (36.7%) patients had detectable ESR1m and 140 (58.3%) had lung/liver metastases. Prior CTX or ET rates in the advanced setting were 19.2 and 65.4%. Treatment-emergent adverse events (AEs) (grade ≥3) occurred in 77.0 (12.2), 90.4 (21.9) and 68.5 (13.7) % of patients in the C 75, C 150 and F arms. AEs leading to treatment discontinuation occurred in 2.7, 0 and 0% of patients in the C 75, C 150 and F arms. The most common AEs considered by the investigator to be causally related to study drug were photopsia (18.4%) and (sinus) bradycardia (13.6%) – all were grade 1 or 2. Hot flush (2.7%) and myalgia (2.7%) were the most common AEs related to F. Conclusions SERENA-2 is the first Phase 2 trial investigating multiple dose levels of an ngSERD vs F in post-menopausal women with advanced ER+ HER2˗ BC with disease recurrence or progression after ≤1 ET in the advanced setting. C at both 75 and 150 mg dose levels showed a statistically significant and clinically meaningful benefit in PFS vs F in the overall study population, and was well tolerated. The results of SERENA-2 support the further development of C in ER+ HER2- BC. Acknowledgements AstraZeneca sponsored this trial and funded medical writing support from Helen Heffron (InterComm International).