Background: BEGONIA (NCT03742102) is a phase Ib/II, Simon’s 2-stage, open-label, platform study evaluating the safety and efficacy of durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, combined with novel therapies, as first-line treatment for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC). Arms 7 and 8 of BEGONIA assessed the combination of datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, with durvalumab. Patients and methods: Arm 7 included patients regardless of tumor PD-L1 expression level. Arm 8 then enrolled patients with PD-L1-high tumors, as determined by local immunohistochemistry-based testing. In Arms 7 and 8, patients received Dato-DXd 6 mg/kg intravenously plus durvalumab 1120 mg intravenously every 3 weeks. Primary endpoints were safety and tolerability, and investigator-assessed confirmed objective response rate (cORR). Secondary endpoints included cORR (Part 1), duration of response (DoR), progression-free survival (PFS) per RECIST 1.1 and overall survival (OS). Results: Overall, 62 and 33 patients had received Dato-DXd and durvalumab in Arms 7 and 8, respectively. At data cutoff (29 November 2024), median study follow-up was 35.0 and 10.7 months in Arms 7 and 8, respectively. In Arm 7, cORR was 79.0% [95% confidence interval (CI) 66.8-88.3], median DoR was 17.6 months (95% CI 10.5-27.3), median PFS was 14.0 months (11.0-21.1) and median OS was not reached. In Arm 8, cORR was 81.8% (95% CI 64.5-93.0). The median DoR and median PFS for Arm 8 were immature given the short median follow-up (8.3 months in censored patients). The safety profile of the combination was manageable, with no new safety signals versus prior studies. Conclusions: First-line Dato-DXd plus durvalumab demonstrated substantial and durable antitumor activity in locally advanced unresectable or metastatic TNBC, regardless of PD-L1 status.