The FDA approved datopotamab deruxtecan (Datroway/Dato-DXd) for adults with unresectable or metastatic triple-negative breast cancer who are not candidates for PD-1/PD-L1 inhibitor therapy. The decision is based on the phase 3 TROPION-Breast02 trial (NCT05374512), where the antibody-drug conjugate improved overall survival and progression-free survival versus investigator’s-choice chemotherapy. Across the pivotal data set, Dato-DXd achieved a median OS of 23.7 months versus 18.7 months with chemotherapy (HR 0.79; P=0.0290). The trial also showed a 43% reduction in risk of progression or death (HR 0.57) and higher objective response rates (64% vs 30%). The approval expands TROP2-directed treatment options in a difficult-to-treat setting. Separately, the FDA granted a key approval for Datroway as a first-line option for triple-negative breast cancer, marking another regulatory milestone for the program and reinforcing its positioning relative to competing ADC strategies. Together, these approvals may influence sequencing decisions for frontline TNBC therapies in patients ineligible for immunotherapy.