Oral selective estrogen receptor degrader monotherapy versus standard endocrine therapy in estrogen receptor-positive, HER2-negative advanced breast cancer with ESR1 mutations: A meta-analysis of randomized trials.

Abstract

e13061 Background: Resistance to endocrine therapy remains a major clinical challenge in estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer. Oral selective estrogen receptor degraders (SERDs) have been developed to overcome limitations of intramuscular fulvestrant and resistance associated with ESR1 mutations. However, the comparative efficacy and safety of oral SERD monotherapy versus standard endocrine therapy or physician’s choice endocrine therapy (SOC/PCET) remain incompletely defined. Methods: meta-analysis of randomized controlled trials was performed comparing oral SERD monotherapy with SOC/PCET in patients with ER+/HER2– advanced breast cancer. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety endpoints. Prespecified subgroup analyses were conducted in patients with ESR1-mutant tumors. Hazard ratios (HRs) were pooled for time-to-event outcomes and risk ratios (RRs) for binary outcomes using fixed- or random-effects models based on statistical heterogeneity. Results: Three randomized trials comprising more than 1,400 patients were included. Oral SERD monotherapy significantly improved PFS compared with SOC/PCET in the overall population (HR 0.80, 95% CI 0.70–0.91; P = 0.001), with low heterogeneity (I² = 2%). A statistically significant OS benefit was also observed (HR 0.72, 95% CI 0.57–0.91; P = 0.005). ORR was higher with oral SERDs (RR 1.64, 95% CI 1.12–2.39; P = 0.01), while improvement in CBR did not reach statistical significance (RR 1.22, 95% CI 0.95–1.56; P = 0.11). In patients with ESR1-mutant disease, oral SERD monotherapy was associated with a pronounced PFS benefit (HR 0.65, 95% CI 0.51–0.82; P = 0.0003), with no heterogeneity detected. Although ORR and CBR numerically favored SERDs in this subgroup, these differences were not statistically significant. Safety analyses showed no significant differences between oral SERDs and SOC/PCET in grade ≥3 adverse events (RR 1.13, 95% CI 0.79–1.62), treatment discontinuation due to adverse events (RR 1.72, 95% CI 0.80–3.69), grade ≥3 nausea, or grade ≥3 alanine aminotransferase elevation. Conclusions: Oral SERD monotherapy provides significant improvements in progression-free and overall survival compared with SOC/PCET in ER+/HER2– advanced breast cancer, with the greatest benefit observed in patients with ESR1-mutant tumors. These efficacy gains are achieved without a meaningful increase in serious toxicity, supporting oral SERDs as an effective and well-tolerated endocrine treatment option in this setting.