The combination of enfortumab vedotin and pembrolizumab has reshaped treatment for urothelial cancer, showing strong results across multiple stages of the disease. In metastatic patients, it nearly doubled median overall survival compared to chemotherapy (31.5 vs. 16.1 months). In perioperative settings for cisplatin-ineligible muscle-invasive bladder cancer, it reduced the risk of progression or death by 60%, while for cisplatin-eligible patients it significantly improved event-free survival.
As resistance emerges, researchers are exploring next-generation antibody-drug conjugates (ADCs). HER2-targeted T-DXd (Enhertu) showed a 39% overall response rate, rising to 56% in HER2 3+ tumors, earning tumor-agnostic FDA approval based on protein expression. Disitamab Vedotin is another promising HER2 ADC, active even in HER2-low tumors, with ongoing trials combining it with immunotherapy. New strategies are also exploring ways to re-sensitize tumors that downregulate Nectin-4, the target of enfortumab vedotin.
Future precision medicine approaches aim to match patients to the best ADC based on RNA sequencing rather than just DNA mutations. Researchers at Memorial Sloan Kettering Cancer Center are developing assays to guide treatment choices, helping overcome resistance and optimize targeted therapy in urothelial cancer.