A dual-agent regimen combining the antibody-drug conjugate enfortumab vedotin with the PD-1 inhibitor pembrolizumab demonstrates clinical activity when administered before and after surgical removal of muscle-invasive bladder cancer. This perioperative approach targets cancer cells through complementary mechanisms: enfortumab vedotin delivers cytotoxic payload directly to tumor cells expressing nectin-4, while pembrolizumab unleashes immune system recognition by blocking PD-1 checkpoints. The combination represents a significant evolution in bladder cancer treatment, which has historically relied on cisplatin-based chemotherapy with limited efficacy and substantial toxicity. Perioperative immunotherapy strategies are gaining traction across multiple cancer types, as they theoretically maximize immune priming when tumor antigen load is highest. For the estimated 80,000 Americans diagnosed with bladder cancer annually, effective systemic therapy options remain constrained by patient frailty and cisplatin ineligibility. However, this early-stage evidence requires validation through larger randomized trials to establish definitive survival benefits, optimal timing sequences, and patient selection criteria. The approach may prove most valuable for cisplatin-ineligible patients or those with high-risk pathologic features, though long-term safety data for this intensive regimen remains limited.