Impact of oral SERDs, including giredestrant, on survival in HR+ HER2− metastatic breast cancer: A meta-analysis.

1084 Background: Oral selective estrogen receptor degraders (SERDs) are designed to overcome endocrine resistance in HR+ HER2- breast cancer due to ESR1 mutations. Several SERDs have been evaluated in recent trials. We performed a meta-analysis evaluating oral SERDs in previously treated patients with HR+ HER2- metastatic breast cancer (MBC). Methods: Randomized controlled trials comparing oral SERDs to standard endocrine therapy in previously treated HR+, HER2- MBC, reporting progression-free survival (PFS) or overall survival (OS) and adverse events (AEs), were identified via a systematic PubMed search. To incorporate the latest SERDs data, results from the recently presented giradestrant trial were included. Meta-analysis was performed for the overall intention-to-treat (ITT) population and the ESR1-mutant (ESR1m) subgroups. Leave-one-out analyses excluding giradestrant were conducted to highlight its specific impact. Rates of serious adverse events (grade ≥3) and treatment discontinuation were also analyzed. Results: A total of 2324 patients from six phase III trials were included in this analysis. Oral SERDs improved PFS compared with standard endocrine therapy in the ITT population (HR 0.734, CI 0.620-0.869, p<0.001) with greater benefit observed in the ESR1m subgroup (HR 0.538, CI 0.430-0.673, p<0.001). Excluding giradestrant data from the evERA trial led to modest reduction in PFS benefit in both the ITT (HR 0.755, CI 0.661-0.908, p<0.05) and the ESR1m (HR 0.582, CI 0.471-0.718, p<0.05) subsets, though overall PFS benefit remained. Additionally, SERDs were associated with an OS advantage in pooled analyses for the ITT population (HR 0.743, CI 0.621-0.889, p<0.05) and ESR1m population (HR 0.584, CI 0.433-0.768, p<0.001). Excluding giradestrant did not result in significant changes in OS estimates. Grade ≥3 AEs were more frequent with SERDs (OR 1.53, CI 1.20-1.95, p<0.001) while discontinuation rates were similar between groups (OR 1.53, CI 0.99-2.37, p=0.06). Conclusions: Oral SERDs significantly improve PFS in previously treated HR+ HER2- MBC with the greatest benefit in patients with ESR1 mutations. Pooled analysis suggests an OS advantage favoring SERDs. Giradestrant contributes to the observed PFS class effect without altering OS outcomes. SERDs are associated with increased toxicity. Although a trend towards higher discontinuation rates was noted, it did not reach statistical significance, and discontinuation rates remain comparable to standard endocrine therapy. These findings support the use of oral SERDs in the second- and third-line treatment of HR+ HER2- MBC, particularly in ESR1-mutant disease.