Efficacy and Safety of Antibody Drug Conjugates in Previously Treated Hormone Receptor Positive HER2 Negative (or Low) Metastatic Breast Cancer–A Systematic Review and Meta-Analysis

OBJECTIVES: Antibody-drug conjugates (ADCs) have improved outcomes for metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative or low breast cancer; however, direct efficacy comparisons are limited. We compared trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) in chemotherapy-pretreated HR+/HER2-negative or low metastatic breast cancers. METHODS: This meta-analysis conducted a comprehensive search of the Embase and Ovid Medline databases up to July 2025. Efficacy endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Hazard and odds ratios were calculated for the relevant outcomes. Safety was assessed using grade ≥3 treatment-related adverse events (TRAEs). RESULTS: Four randomized controlled trials were included. All 3 ADCs significantly improved PFS ( P <0.00001) and ORR ( P =0.008) compared with chemotherapy. Both T-DXd and SG demonstrated significant OS benefits ( P =0.002), whereas Dato-DXd did not ( P =0.94). For SG, OS benefit was observed primarily in later (≥3) lines ( P =0.03). Among them, T-DXd demonstrated the most favorable outcomes across PFS, OS, and ORR, particularly in earlier lines. Grade ≥3 treatment-related adverse events (TRAEs) were most frequent with SG (60.2%), followed by T-DXd (52.6%) and Dato-DXd (20.8%). Neutropenia was the most common grade ≥3 TRAE with SG and T-DXd, while stomatitis was most common with Dato-DXd. CONCLUSIONS: T-DXd demonstrated better efficacy in pretreated HR+/HER2-low metastatic breast cancer (MBC), especially in earlier lines. SG showed significant OS benefit primarily in later lines. Dato-DXd showed no OS benefit but had the most favorable safety profile.