Clinical benefit of oral selective estrogen receptor degraders in <i>ESR1</i> -mutant, HR-positive, HER2-negative advanced breast cancer: A systematic review and meta-analysis.

Abstract

e13058 Background: ESR1 mutations are a key mechanism of acquired endocrine resistance in hormone receptor-positive, HER2-negative advanced breast cancer (ABC). Next-generation oral selective estrogen receptor degraders (SERDs) were developed to suppress mutant estrogen receptor signaling more effectively. Individual randomized trials have yielded heterogeneous results. We conducted a systematic review and meta-analysis to quantify the clinical benefits of oral SERDs, with a particular emphasis on the ESR1-mutant population. Methods: Phase II–III randomized trials comparing oral SERD monotherapy versus standard endocrine therapy (ET) in HR-positive, HER2-negative ABC after prior endocrine therapy were identified through systematic searches of PubMed, Embase, and CENTRAL through October 2025. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), grade ≥3 treatment-related adverse events, and overall survival (OS). Random-effects models with Hartung-Knapp adjustment were used. Results: Six randomized trials including 2,808 patients were analyzed. In the overall population, oral SERDs improved PFS versus standard ET (HR 0.82; 95% CI 0.72–0.93; I² 9.5%). In patients with ESR1-mutant tumors, oral SERDs demonstrated a pronounced PFS benefit (HR 0.58; 95% CI 0.39–0.87; I² 50%) and a significant OS improvement (HR 0.57; 95% CI 0.36–0.89; I² 0%). In contrast, no PFS benefit was observed in ESR1 wild-type disease (HR 0.93; 95% CI 0.77–1.13). Among ESR1-mutant patients, consistent PFS benefit was observed across clinically high-risk subgroups, including visceral metastases (HR 0.70; 95% CI 0.51–0.96), liver metastases (HR 0.55; 95% CI 0.34–0.88), prior fulvestrant exposure (HR 0.66; 95% CI 0.56–0.79), and ≥2 prior lines of therapy (HR 0.70; 95% CI 0.51–0.96). ORR was higher with oral SERDs in the overall population (OR 1.67; 95% CI 1.23–2.28). Oral SERDs increased rates of low-grade gastrointestinal adverse events, including diarrhea and nausea, without excess grade ≥3 toxicity. Conclusions: Oral SERDs provide clinically meaningful improvements in PFS and OS predominantly in patients with ESR1-mutant HR-positive, HER2-negative ABC, supporting ESR1 mutation status as a predictive biomarker for therapeutic selection. These findings reinforce a biomarker-driven approach to post-endocrine treatment sequencing.