Oral selective estrogen receptor degraders in HR+/HER2- advanced breast cancer and impact of ESR1 mutation status: A systematic review and meta-analysis.

Abstract

1081 Background: Oral selective estrogen receptor degraders (SERDs) are a promising therapeutic class for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Several randomized controlled trials (RCTs) have evaluated oral SERDs, but results have varied across agents and populations. Methods: We searched MEDLINE, EMBASE, CENTRAL, and conference proceedings until December 31 st 2025 and identified RCTs comparing oral SERDs with standard endocrine therapy in adults with HR+/HER2- advanced breast cancer. Two reviewers independently screened studies, extracted data, and assessed risk of bias using Cochrane RoB 2. Random effects meta-analysis was performed using generic inverse variance for hazard ratios for progression-free survival (PFS). Odds ratios for safety outcomes were pooled using Mantel-Haenszel (fixed effect). Results: A total of 9 trials comprising 4,258 participants were included. Overall, oral SERDs demonstrated a statistically significant improvement in PFS compared with standard endocrine therapy (HR 0.76, 95% CI 0.60 to 0.97; p=0.03). In the estrogen receptor 1 gene mutated (ESR1m) subgroup (7 trials, n=1,273), oral SERDs showed a more pronounced PFS benefit (HR 0.53, 95% CI 0.39 to 0.70; I²=53.4%; p=0.002). In contrast, patients with ESR1 wild-type tumors (6 trials, n=1,212) derived no significant benefit (HR 0.95, 95% CI 0.81 to 1.12; I²=0%). The interaction between ESR1m and treatment was statistically significant (p<0.001). Grade ≥3 adverse events were similar between groups (RR 1.09, 95% CI 0.87 to 1.38). Treatment discontinuation due to adverse events was significantly higher with oral SERDs (RR 1.65, 95% CI 1.02 to 2.65). Conclusions: Oral SERDs lead to a statistically significant improvement in PFS over standard endocrine treatments albeit with the effect seemingly limited to patients with ESR1m. These results support the use of biomarkers to determine which patients are most likely to receive clinical benefits from oral SERD therapy and underscore the importance of ESR1 testing in order to tailor treatment optimally. ESR1 mutation status subgroup analysis. Subgroup Trials Participants HR 95% CI P-value ESR1 Mutant 7 1,273 0.53 0.39 – 0.70 0.0015 ESR1 Wild-Type 6 1,212 0.95 0.81 – 1.12 0.4684