Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 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 patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled 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 v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991