Efficacy of datopotamab deruxtecan after trastuzumab deruxtecan in metastatic hormone receptor–positive HER2-negative breast cancer: A real-world study.

e13040 Background: Datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd) are antibody–drug conjugates used in metastatic hormone receptor–positive HER2-negative breast cancer that target different antigens but share an identical topoisomerase I inhibitor payload. However, the activity of Dato-DXd in patients previously treated with T-DXd has not been reported. We compared the efficacy of Dato-DXd between patients with and without prior T-DXd exposure in real-world setting. Methods: This single-center retrospective study included patients who initiated Dato-DXd between March and September 2025 (data cutoff, January 2, 2026). Patients were classified as T-DXd–pretreated if they had received at least one prior dose of T-DXd and as T-DXd–naïve otherwise. The primary endpoint was disease control rate (DCR); progression-free survival (PFS) was evaluated as a secondary endpoint. DCR was defined as the proportion achieving complete response, partial response, or stable disease. PFS was defined as time from Dato-DXd initiation to progression or death. PFS was estimated using Kaplan–Meier methods, with group comparisons by log-rank test. Results: Thirty-seven patients were included; median age was 59 years (range, 41–76). At Dato-DXd initiation, ECOG performance status was 0 in 40.5%, 1 in 48.6%, and 2 in 10.8%. Fifteen patients had prior T-DXd exposure, of whom 14 received T-DXd for HER2-low disease and 1 for HER2-ultralow disease; among pretreated patients, 5 received Dato-DXd immediately after T-DXd and 10 after receiving other systemic therapies. The median proceeding number of treatment for metastatic disease was 7 (range, 4–11) in the T-DXd-pretreated group and 5.5 (range, 2-10) in the T-DXd–naïve group. DCR was 60.0% (9/15) in the T-DXd–pretreated group and 63.6% (14/22) in the T-DXd–naïve group. At a median follow-up of 6.5 months, median PFS was 4.5 months (95% CI, 1.9–7.1) overall, 4.1 months (95% CI, 2.2–6.0) in T-DXd–pretreated patients, and 8.7 months (95% CI, not evaluable) in T-DXd–naïve patients (log-rank p = 0.457). Conclusions: Dato-DXd showed clinically meaningful activity in heavily pretreated metastatic breast cancer irrespective of prior T-DXd exposure, supporting its use as a subsequent-line option and the feasibility of sequencing payload-sharing ADCs. Longer follow-up and accumulation of cases are warranted to further characterize PFS outcomes in clinical practice.