Background: Treatment options are limited for pts with LA unresectable or mUC who progress after prior PLT-based and CPI therapies. SG is an antibody-drug conjugate (ADC) composed of an anti-trophopblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In the phase 2 registrational study TROPHY-U-01 (NCT03547973), SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.9 months in pts with mUC who progressed after prior PLT-based and CPI therapies (n = 113; median, 3 prior lines of therapy; 84% with ≥1 Bellmunt risk factors; Tagawa et al, J Clin Oncol. 2021). These results compared favorably with historic data for single-agent chemotherapy (ORR, ̃18%; OS, 9 months; Powles et al. J Clin Oncol. 2021) and led to accelerated approval of SG by the US Food and Drug Administration for pts with LA or mUC who previously received a PLT-containing chemotherapy and CPI. The phase 3 TROPiCS-04 trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in pts with LA unresectable or mUC who progressed after prior PLT-based and CPI therapies. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0-1; no prior CPI or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; and adequate hematologic, hepatic, and renal function. Pts will be randomly assigned 1:1 to receive SG 10 mg/kg intravenously (IV) on days 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m², docetaxel 75 mg/m², or vinflunine 320 mg/m² IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in pts deemed to be receiving clinical benefit per investigator assessment. Approximately 600 pts will be enrolled across ̃280 sites in 3 regions (North America, Europe, and Asia-Pacific) to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and investigator assessment), safety, and quality of life. Study enrollment started in January 2021 and is ongoing with pts currently enrolled at 30 sites across all 3 regions. Clinical trial information: NCT04527991.