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Trial Design: Approximately 990 pts with histologically or cytologically confirmed unresectable/metastatic urothelial carcinoma will be randomly assigned 1:1:1 to pembrolizumab 200 mg every 3 weeks (Q3W), pembrolizumab + chemotherapy (investigator’s choice of cisplatin [70 mg/m2 Q3W] plus gemcitabine [1000 mg/m2 on days 1 and 8 Q3W] OR carboplatin [area under the concentration-time curve 5 Q3W] plus gemcitabine if cisplatin ineligible), or chemotherapy alone. Chemotherapy choice must be selected before randomization. Pts must have measurable disease per investigator review (RECIST v1.1), an Eastern Cooperative Oncology Group performance status 0-2, received no prior systemic chemotherapy for advanced urothelial cancer, and provided a tumor biopsy for biomarker analyses. Treatment allocation will be stratified by chemotherapy (cisplatin or carboplatin) and PD-L1 expression (+ or –). Response will be assessed Q9W for the first year and Q12W thereafter. Patients will be treated for 35 cycles of pembrolizumab (pembrolizumab arms only), or until progressive disease or unacceptable adverse events. The primary end points are progression-free survival (RECIST v1.1 per blinded independent central review) and overall survival, assessed in all patients and PD-L1+ patients. Secondary end points are objective response rate and safety. Efficacy will be compared for pembrolizumab versus chemotherapy and pembrolizumab + chemotherapy versus chemotherapy. Patient accrual is ongoing; 1 interim efficacy analysis is planned.