Real-world outcomes of datopotamab deruxtecan after trastuzumab deruxtecan in hormone receptor-positive, HER2-negative metastatic breast cancer.

BACKGROUND: Optimal sequencing of antibody-drug conjugates (ADCs) is an important clinical issue in metastatic breast cancer. However, data on datopotamab deruxtecan (Dato-DXd) following trastuzumab deruxtecan (T-DXd) have not been reported. This study evaluated real-world outcomes of Dato-DXd in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, focusing on prior T-DXd exposure. METHODS: This single-center retrospective study included patients who received at least one dose of Dato-DXd by December 2025. Outcomes were evaluated overall and by prior T-DXd exposure. Endpoints included disease control rate (DCR), objective response rate (ORR), time to treatment failure (TTF), and progression-free survival (PFS). Among patients who received prior T-DXd, TTF with T-DXd and subsequent Dato-DXd was compared. RESULTS: A total of 45 patients were analyzed: 19 had prior T-DXd exposure and 26 were T-DXd-naïve. The cohort was heavily pretreated with a median of six prior treatment lines and three prior chemotherapy regimens for metastatic disease. Overall, the DCR and ORR were 57.8% and 24.4%, respectively; the corresponding rates were 52.6% and 10.5% in the prior T-DXd group and 61.5% and 34.6% in the T-DXd-naïve group. The median TTF and PFS were 4.2 and 4.1 months in the overall cohort, and 3.4 and 3.0 months in the prior T-DXd group, respectively. Among 16 patients evaluable for TTF with both agents, five (31.3%) had a longer TTF with Dato-DXd than with prior T-DXd. CONCLUSIONS: Dato-DXd showed limited but clinically relevant activity, including after prior T-DXd. Further studies are needed to optimize ADC sequencing.