Background: Patients (pts) with mTNBC have limited treatment options and poor prognosis. The combination of immune checkpoint inhibitors with chemotherapy shows promise, but only a subset of pts with mTNBC derive benefit, highlighting the need for new combinations. BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of D, an anti–PD-L1 monoclonal antibody, with or without P, in combination with novel oncology therapies as first-line treatment for mTNBC (NCT03742102). Dato-DXd is an antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody, a stable tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. Dato-DXd displayed encouraging clinical activity with a manageable safety profile in heavily pretreated pts with metastatic NSCLC in the phase 1 TROPION-PanTumor01 (NCT03401385) study. TROP2 is highly expressed on breast and other epithelial tumors, and a TROP2 ADC showed activity in heavily pretreated pts with mTNBC (Bardia, NEJM 2019). Methods: Eligible female pts are aged ≥18 years with untreated unresectable, locally advanced or mTNBC, ≥12 months since prior taxane therapy, ECOG PS 0/1, adequate organ function, and ≥1 nonirradiated measurable lesion. For Arm 7, pts are excluded if they have clinically significant corneal disease, history of interstitial lung disease/pneumonitis, underlying pulmonary disorder, or prior treatment with an ADC containing a topoisomerase I inhibitor. Arm 7 will evaluate D (1120 mg) + Dato-DXd (6 mg/kg) given intravenously every 3 weeks until disease progression or unacceptable toxicity. Part 1 of each arm includes a total of 30 pts with a safety run-in (n=6) to observe dose-limiting toxicities, identify the recommended phase 2 dose (RP2D), and detect an efficacy signal for part 1 expansion. The primary endpoint of part 1 is safety and tolerability. Secondary endpoints include investigator-assessed objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Once the RP2D has been established for part 1, a futility analysis will be performed with an option to expand the cohort to an additional 27 pts if expansion criteria are met. The primary endpoint for part 1 is ORR. Tumors will be assessed every 6 weeks per RECIST v1.1. Kaplan-Meier analysis will be used for PFS and OS. PD-L1 and TROP2 expression will be assessed by immunohistochemistry. Enrollment is ongoing. Clinical trial information: NCT03742102.