Systematic review and meta-analysis of oral SERDs in HR-positive, HER2-negative advanced breast cancer

The development of endocrine resistence is frequent in HR-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 systematic review and meta-analysis of phase 2 or 3 randomized trials published through October 2025 compared oral SERDs with standard endocrine therapy (ET) in HER+/HER2- aBC after prior ET. Six trials, including 2808 patients, were analyzed. Oral SERDs improved progression-free survival versus standard ET (HR 0.79; 95% CI 0.70-0.89); an overall survival improvement was observed too (0.72; 0.57-0.90), although follow-up was limited. Objective response rate was higher with oral SERDs (OR 1.67; 95% CI 1.23-2.28), corresponding to absolute response rates of approximately 21% versus 14%. Benefit was concentrated in ESR1-mutated tumors (PFS-HR 0.57; 95% CI 0.48-0.67) with no significant advantage in ESR1 wild-type disease. Gastrointestinal adverse events were more frequent with oral SERDs compared with control ET. The authors conclude that this analysis demonstrates a clinically meaningful benefit of oral SERDs over standard ET after endocrine progression in HR+/HER2- aBC, with the strongest efficacy observed in ESR1-mutated disease.