Pembrolizumab, a PD-1 inhibitor, showed significant improvements in overall survival and reduced adverse events compared to chemotherapy in patients with advanced urothelial carcinoma that progressed after platinum-based therapy. In the phase 3 KEYNOTE-045 trial, 542 patients were randomly assigned to receive pembrolizumab (200 mg every 3 weeks) or investigator-selected chemotherapy (paclitaxel, docetaxel, or vinflunine). The median overall survival was 10.3 months in the pembrolizumab group versus 7.4 months in the chemotherapy group (hazard ratio 0.73; 95% CI 0.59–0.91; P=0.002). Among patients with a PD-L1 combined positive score of 10% or more, pembrolizumab improved survival to 8.0 months versus 5.2 months (hazard ratio 0.57; 95% CI 0.37–0.88; P=0.005). Progression-free survival was similar between groups. Pembrolizumab was associated with fewer treatment-related adverse events (60.9% vs. 90.2%) and fewer severe events (15.0% vs. 49.4%). Pembrolizumab also showed a higher objective response rate (21.1% vs. 11.4%) and longer duration of response. The safety profile of pembrolizumab was better than chemotherapy, with fewer severe adverse events and deaths. The study supports pembrolizumab as a preferred second-line therapy for platinum-refractory advanced urothelial carcinoma, regardless of PD-L1 expression status. The results highlight the potential of PD-1 inhibitors in this patient population.Pembrolizumab, a PD-1 inhibitor, showed significant improvements in overall survival and reduced adverse events compared to chemotherapy in patients with advanced urothelial carcinoma that progressed after platinum-based therapy. In the phase 3 KEYNOTE-045 trial, 542 patients were randomly assigned to receive pembrolizumab (200 mg every 3 weeks) or investigator-selected chemotherapy (paclitaxel, docetaxel, or vinflunine). The median overall survival was 10.3 months in the pembrolizumab group versus 7.4 months in the chemotherapy group (hazard ratio 0.73; 95% CI 0.59–0.91; P=0.002). Among patients with a PD-L1 combined positive score of 10% or more, pembrolizumab improved survival to 8.0 months versus 5.2 months (hazard ratio 0.57; 95% CI 0.37–0.88; P=0.005). Progression-free survival was similar between groups. Pembrolizumab was associated with fewer treatment-related adverse events (60.9% vs. 90.2%) and fewer severe events (15.0% vs. 49.4%). Pembrolizumab also showed a higher objective response rate (21.1% vs. 11.4%) and longer duration of response. The safety profile of pembrolizumab was better than chemotherapy, with fewer severe adverse events and deaths. The study supports pembrolizumab as a preferred second-line therapy for platinum-refractory advanced urothelial carcinoma, regardless of PD-L1 expression status. The results highlight the potential of PD-1 inhibitors in this patient population.