Oral estrogen receptor (ER) degraders compared to standard endocrine therapy (ET) in ER-positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC): A systematic review and meta-analysis.

1087 Background: Treatment with ER-positive HER2-negative (ER+HER2-) MBC has evolved during the past decade. Several novel oral ER degraders have shown to modestly improve progression free survival (PFS) compared to standard ET, with significant results specifically in patients carrying activating ESR1 mutations. However, whether overall survival (OS) is also improved is unknown. Methods: This was a PRISMA guided meta-analysis. We identified all randomized controlled trials (RCTs) comparing ER degraders to standard ET in patients with ER+HER2- MBC. Efficacy outcomes included PFS and OS for the intention to treat (ITT) population, as well as for patients with ESR1 mutation, and for patients with wildtype ESR1 . Hazard ratios (HRs) and 95% confidence intervals (CI) for PFS and OS were extracted, and pooled into meta-analysis using RevMan Version 9.18.0. Statistical tests were two-sided, and statistical significance was defined as p<0.05. Subgroup analyses comparing outcomes based on ESR1 mutation were also performed. In trials with multiple investigational arms, the monotherapy ER degrader arm (EMBER-3) and the dose selected for further development (SERENA-2) were include. Results: Seven RCTs comprising 3926 patients were analyzed. Compared to standard ET, ER degraders were associated with statistically significant improvement in OS in the ITT population, HR 0.74, 95% CI 0.62-0.89, p=0.001. Analysis by ESR1 status demonstrated that ER degraders were associated with significant improvement in OS for patients with ESR1 mutation (HR 0.60, 95% CI 0.47-0.77, p<0.001), but not for patients with ESR1 wild type (HR 0.87, 95% CI 0.66-1.15, p=0.33), p=0.05 for the subgroup difference. ER degraders were associated with significant improvement in PFS in the ITT population, HR 0.80, 95% CI 0.66-0.98, p=0.03. Analysis based on ESR1 status demonstrated significant improvement is PFS for patients with ESR1 mutation (HR 0.54, 95% CI 0.43-0.68, p<0.0001), but not for patients with ESR1 wild type (HR 0.95, 95% CI 0.82-1.09, p=0.46), p=0.001 for the subgroup difference. Conclusions: Compared to standard ET, ER degraders were associated with statistically significant improvement of OS and PFS. While this impact was notable in the ITT population, subgroups analyses confirmed the statistically significant benefit is limited to patients with ESR1 mutations.