This narrative review synthesizes clinical trial evidence for four ADCs—trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), datopotamab deruxtecan (Dato-DXd), and sacituzumab tirumotecan (sac-TMT)—in HR+/HER2-negative and triple-negative metastatic breast cancer, covering mechanisms, efficacy, toxicity management, biomarkers, and sequencing strategies.
All four ADCs improved PFS vs chemotherapy in their pivotal phase 3 trials. Key highlights include: T-DXd vs chemo in chemotherapy-naïve HR+/HER2-low mBC (PFS 13.2 vs 8.1 months; HR 0.62); SG vs chemo in pretreated HR+ mBC (OS 14.4 vs 11.2 months; HR 0.79); Dato-DXd vs chemo in first-line TNBC (OS 23.7 vs 18.7 months; HR 0.79); sac-TMT vs chemo in pretreated HR+ mBC (PFS 8.3 vs 4.1 months; HR 0.35). SG plus pembrolizumab improved PFS over chemo plus pembrolizumab in first-line PD-L1–positive TNBC (11.2 vs 7.8 months; HR 0.65).
- All cross-ADC comparisons are indirect; no head-to-head randomized trials exist between ADCs. - Sac-TMT data derive exclusively from East Asian populations, limiting generalizability to Western patients. - Most sequencing and biomarker data (including post-ADC outcomes) come from retrospective analyses with small samples and selection bias.
For HR+/HER2-low or ultralow mBC after CDK4/6 inhibitor progression, T-DXd is preferred when ADC therapy is indicated, especially with symptomatic or rapidly progressing disease; SG or Dato-DXd are alternatives for HER2-null tumors. In first-line TNBC, SG plus pembrolizumab is the preferred option for PD-L1–positive disease, while Dato-DXd monotherapy is an emerging option for PD-L1–negative or immunotherapy-ineligible patients—clinicians should individualize ADC choice based on HER2 status, toxicity profile (ILD risk with T-DXd, neutropenia/diarrhea with SG, stomatitis with Dato-DXd/sac-TMT), and infusion logistics.
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