Oral selective estrogen receptor degraders in hormone receptor-positive, HER2-negative advanced breast cancer: a systematic review and meta-analysis.

Abstract

The development of endocrine resistance is frequent in hormone receptor-positive, HER2-negative advanced breast cancer (HR + /HER2-ABC), particularly after CDK4/6 inhibitor exposure. Next-generation oral selective estrogen receptor degraders (SERDs) have been developed to improve estrogen receptor blockade; however, randomized trials have yielded heterogeneous results with uncertain clinical benefit. A PRISMA 2020 compliant systematic review and meta-analysis with PROSPERO registration was conducted. PubMed, Embase, and Cochrane CENTRAL were searched through October 2025 for phase II-III randomized trials comparing oral SERDs with standard endocrine therapy (ET) in HR + /HER2-ABC after prior ET. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and treatment-related adverse events (TRAEs). Treatment effects were pooled using random effects models with prespecified subgroup analyses by ESR1 mutation status and key clinical characteristics. Six randomized trials, including 2808 patients, were analyzed. Oral SERDs improved PFS versus standard ET in the overall population (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.70 to 0.89). ORR was higher with oral SERDs (odds ratio [OR] 1.67; 95% CI 1.23 to 2.28), corresponding to absolute response rates of approximately 21% versus 14%. An OS improvement was observed (HR 0.72; 95% CI 0.57 to 0.90), although follow-up was limited. Benefit was concentrated in ESR1-mutated tumors (PFS, HR 0.57; 95% CI 0.48 to 0.67) with no significant PFS advantage in ESR1 wild-type disease. Gastrointestinal adverse events were more frequent with oral SERDs compared with the control ET. Pooled randomized evidence supports a clinically meaningful benefit of oral SERDs over standard ET after endocrine progression in HR + /HER2-ABC, with the strongest and most consistent efficacy observed in ESR1-mutated disease.