Oral Estrogen Receptor Degraders Compared to Standard Endocrine Therapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Several novel oral estrogen receptor (ER) degraders have been shown to modestly improve progression-free survival (PFS) compared to standard endocrine therapy (ET) in patients carrying ESR1 mutations. However, whether overall survival (OS) is also improved is unknown. Methods: All randomized controlled trials (RCTs) comparing ER degraders to standard ET in patients with ER+HER2-metastatic breast cancer were identified. The efficacy outcomes included PFS and OS for the intention-to-treat (ITT) population and were stratified according to ESR1 status (mutated versus wildtype). Hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS were extracted and pooled into a meta-analysis. Results: Eight RCTs comprising 4230 patients were analyzed. Compared to standard ET, ER degraders were associated with statistically significant improvement in OS in the ITT population, with HR 0.81, 95% CI 0.69-0.95, p = 0.01. Analysis by ESR1 status demonstrated that ER degraders were associated with significant improvement in the OSs for patients with an ESR1 mutation (HR = 0.70, 95% CI 0.56-0.88, p = 0.002), but not for patients with ESR1 wildtype (HR = 0.88, 95% CI 0.68-1.13, p = 0.32). ER degraders were associated with a significant improvement in PFS in the ITT population, with HR 0.81, 95% CI 0.68-0.96, p = 0.02. Significant improvement in PFS was found for patients with an ESR1 mutation (HR 0.55, 95% CI 0.45-0.68, p < 0.0001), but not for patients with the ESR1 wildtype (HR 0.97, 95% CI 0.86-1.09, p = 0.61. Conclusions: Compared to standard ET, ER degraders were associated with statistically significant improvement in OS and PFS. Subgroup analyses confirmed that the benefit is limited to patients with ESR1 mutations.