Efficacy and safety of antibody-drug conjugates in HR+/HER2− advanced breast cancer: A systematic review and meta-analysis of phase III randomized trials.

Abstract

e13038 Background: Hormone receptor–positive (HR+)/HER2- advanced breast cancer is characterized by disease progression after initial endocrine and targeted therapies, with modest benefit from conventional chemotherapy. Antibody–drug conjugates (ADCs) are a promising therapeutic class in this setting following initial approval for HER2+ disease. We performed a systematic review and meta-analysis of Phase III ADC efficacy and safety in HR+/HER2- (including HER2-low) breast cancer. Methods: PubMed, Cochrane CENTRAL, ESMO, and major conference proceedings through December 2025 were systematically searched. Phase III randomized controlled trials of ADCs versus standard-of-care (SOC) therapy in HR+/HER2- unresectable/metastatic breast cancer were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and Grade ≥3 treatment-related adverse events (TRAEs). Pooled hazard ratios (HRs) were estimated using inverse-variance random-effects models; risk ratios (RR) were synthesized for binary endpoints. Heterogeneity was assessed with sensitivity analyses performed. Results: Five Phase III RCTs with nearly 3000 total patients were assessed. Median PFS and OS across ADC-treated populations were 6.9 months (range: 4.3–13.2) and 19.8 months (range: 14.5–23.9), respectively. ADCs significantly improved PFS compared with SOC (pooled HR 0.58, 95% CI 0.47–0.72) and showed an OS benefit (pooled HR 0.69, 95% CI 0.49–0.98). Significantly higher ORR (pooled RR 1.81, 95% CI 1.43–2.29; RD +17.5%, 95% CI +6.7%-+28.4%) with favorable DCR (pooled RR 1.21, RD +11.5%) and DOR (median 8.1 vs. 5.7 months; pooled RoM 1.44 [95% CI 1.23–1.68]) trends were seen with ADC treatment. Grade ≥3 TRAEs showed a higher trial-level median rate with ADCs (61.0% vs 55.4%) but were comparable overall versus SOC (pooled RR 0.97, 95% CI 0.73–1.29). Despite heterogeneity in effect magnitude (I² 81-92% for PFS/OS), between-study variance was modest for PFS (τ²≈0.05) and moderate for OS (τ²≈0.15), reflective of inter-trial differences in follow-up maturity and post-progression therapy. Conclusions: Collectively, ADCs demonstrated a consistent clinically meaningful improvement in PFS with an OS benefit as compared with SOC despite trial-level variability. ADC efficacy measures showed earlier and more sustained anti-tumor activity with improved overall disease control, supportive of more rapid symptom relief and as well as time to subsequent-line therapy. The observed toxicity profile highlights regimen-dependent effects and the importance of patient selection and monitoring. These findings support the use of ADCs as a more efficacious alternative to chemotherapy in pre-treated HR+/HER2- advanced breast cancer.