Oral selective estrogen receptor degraders in ER+/HER2- breast cancer: a systematic review with pooled analysis of metastatic randomized trials and narrative synthesis of adjuvant evidence.

BACKGROUND: Oral selective estrogen receptor degraders (SERDs) have become a key therapeutic option for hormone receptor-positive, HER2-negative advanced breast cancer. The recent presentation of lidERA-the first positive adjuvant Phase III trial of any oral SERD-necessitates a comprehensive evidence synthesis spanning both early and advanced disease settings, beyond the scope of existing meta-analyses confined to metastatic disease. METHODS: This review was prospectively registered (PROSPERO CRD420261358420). We searched PubMed, Cochrane CENTRAL, and conference abstract archives (SABCS, ESMO, ASCO; 2020-2026) for Phase II/III randomized controlled trials comparing oral SERDs (giredestrant, imlunestrant, elacestrant, camizestrant, vepdegestrant, amcenestrant) with standard endocrine therapy in ER-positive, HER2-negative breast cancer. Progression-free survival hazard ratios in the metastatic setting were pooled using random-effects models. Prespecified sensitivity analyses included Bayesian re-analysis. RESULTS: Ten randomized controlled trials met inclusion criteria (one adjuvant, n = 4,170; nine metastatic). Giredestrant significantly improved invasive disease-free survival in the adjuvant lidERA trial (HR 0.70; 95% CI 0.57-0.87; P = 0.0014). In the metastatic setting, pooled analysis of six oral degrader monotherapy trials (n = 2,502) showed a progression-free survival benefit (HR 0.815; 95% CI 0.718-0.924; P = 0.0014) with moderate heterogeneity (I² = 35.2%). The ESR1-mutated subgroup revealed a particularly robust and consistent effect (HR 0.617; 95% CI 0.527-0.723; P < 0.0001) with zero heterogeneity across five independent trials (I² = 0%). These findings were unchanged across all sensitivity analyses: restriction to Phase III trials only (HR 0.811; I² = 5.8%), exclusion of the PROTAC agent (HR 0.807), leave-one-out iteration (range 0.790-0.843), and Bayesian re-analysis (posterior median HR 0.814; 95% credible interval 0.678-0.969). Egger's test did not detect significant funnel plot asymmetry (P = 0.40), though power was limited (k = 6). CONCLUSIONS: Oral SERDs confer a consistent progression-free survival benefit in advanced breast cancer, with the most robust and consistent effect in ESR1-mutated tumors. Giredestrant is the first oral SERD to achieve significantly improved invasive disease-free survival in the adjuvant setting, marking a potential new standard of care. This evidence synthesis across the full breast cancer continuum offers a framework for clinical decision-making as oral SERDs expand from advanced to early-stage disease. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php, identifier CRD420261358420.