More effective therapies are required for advanced breast cancer. We report results from 58 women with locally advanced unresectable or metastatic hormone-receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-low breast cancer enrolled in arm 6 of the multicenter, open-label phase 1b/2 BEGONIA platform trial, who received durvalumab (1,120 mg) plus trastuzumab deruxtecan (T-DXd; 5.4 mg kg-1) intravenously every 3 weeks as first-line treatment. Objective response rate (ORR) and safety were primary endpoints; duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Median follow-up was 20.6 months (range: 1-37). ORR was 62.1% (95% confidence interval (CI): 48.4-74.5), which did not meet the protocol-specified objective of 38/57 (66.6%) responses. Median DoR was 15.2 months (95% CI: 8.44-not calculable), PFS was 12.6 months (95% CI: 8.4-16.3) and OS was 30.3 months (95% CI: 18.8-not calculable). The safety profile of the combination treatment was consistent with those of the individual therapies. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 20.7% of participants (grades 1 and 2, 19.0%; grade 5, 1.7%). Durvalumab plus T-DXd demonstrated clinically relevant efficacy for first-line treatment of metastatic HR-negative, HER2-low breast cancer, with no unexpected toxicities observed. ClinicalTrials.gov identifier: NCT03742102 .