FDA Approval Summary: Datopotamab deruxtecan-dlnk for treatment of patients with unresectable or metastatic, HR-positive, HER2-negative breast cancer

On January 17, 2025, the FDA approved datopotamab deruxtecan-dlnk (DATROWAY, Dato-DXd), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for the treatment of adults with unresectable or metastatic, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Approval was based on results from TROPION-Breast01 (TB01), a multicenter, randomized, open-label trial comparing Dato-DXd to investigator's choice of chemotherapy (ICC). The trial was designed with dual primary endpoints: progression-free survival (PFS) assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and overall survival (OS). TB01 demonstrated a 2-month improvement in median PFS for Dato-DXd compared to ICC (6.9 months vs. 4.9 months, respectively; stratified hazard ratio (HR) 0.63 (95% CI: 0.52, 0.76; p<0.0001). The OS endpoint was not met; at the final analysis (FA) of OS, the median OS was 18.6 months in the Dato-DXd arm and 18.3 months in the ICC arm (HR: 1.01, 95% CI: 0.83, 1.22). Although there was no OS improvement, Dato-DXd was also not associated with a clear trend toward potential detriment compared to ICC. The most commonly reported adverse reactions (≥20%) with Dato-DXd were stomatitis, nausea, fatigue, alopecia, constipation, dry eye, keratitis, and vomiting. Overall, the favorable benefit-risk profile for Dato-DXd supported its approval for the intended indication.