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.

Authors

Bing Guan, Sijia Zhang, Rong Zhou, Yawen Chen, Lulu Li, Ping He

Published in

Frontiers in oncology. Volume 16. Pages 1896847. Epub Sep 03, 2026.

Abstract

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.
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.
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).
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.
https://www.crd.york.ac.uk/prospero/display_record.php, identifier CRD420261358420.

PMID:
42755923
Bibliographic data and abstract were imported from PubMed on 18 Sep 2026.

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