This open-label, international, phase 3 trial evaluated the efficacy and safety of pembrolizumab (a PD-1 inhibitor) compared to investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in patients with advanced urothelial carcinoma that progressed after platinum-based chemotherapy. The primary endpoints were overall survival and progression-free survival, assessed in the total population and in patients with a tumor PD-L1 combined positive score of 10% or more. The median overall survival was 10.3 months in the pembrolizumab group versus 7.4 months in the chemotherapy group (hazard ratio, 0.73; P=0.002). The median overall survival was 8.0 months in the pembrolizumab group versus 5.2 months in the chemotherapy group among patients with a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.57; P=0.005). Pembrolizumab also showed a higher objective response rate (21.1% vs. 11.4%) and a longer duration of response compared to chemotherapy. The safety profile of pembrolizumab was better, with fewer treatment-related adverse events and discontinuations. The results suggest that pembrolizumab is a more effective and safer option for second-line therapy in patients with advanced urothelial carcinoma that progressed after platinum-based chemotherapy.This open-label, international, phase 3 trial evaluated the efficacy and safety of pembrolizumab (a PD-1 inhibitor) compared to investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in patients with advanced urothelial carcinoma that progressed after platinum-based chemotherapy. The primary endpoints were overall survival and progression-free survival, assessed in the total population and in patients with a tumor PD-L1 combined positive score of 10% or more. The median overall survival was 10.3 months in the pembrolizumab group versus 7.4 months in the chemotherapy group (hazard ratio, 0.73; P=0.002). The median overall survival was 8.0 months in the pembrolizumab group versus 5.2 months in the chemotherapy group among patients with a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.57; P=0.005). Pembrolizumab also showed a higher objective response rate (21.1% vs. 11.4%) and a longer duration of response compared to chemotherapy. The safety profile of pembrolizumab was better, with fewer treatment-related adverse events and discontinuations. The results suggest that pembrolizumab is a more effective and safer option for second-line therapy in patients with advanced urothelial carcinoma that progressed after platinum-based chemotherapy.