Treatment Sequencing in Advanced Urothelial Cancer

Abstract

Treatment paradigms for advanced urothelial carcinoma have evolved rapidly with the introduction of antibody-drug conjugates and novel immunotherapy combinations. Enfortumab vedotin plus pembrolizumab has redefined first-line therapy, demonstrating unprecedented survival benefits compared with platinum-based chemotherapy. However, high cost and limited availability remain major barriers to its global implementation. Accordingly, gemcitabine-cisplatin with nivolumab and platinum-based chemotherapy followed by maintenance avelumab remain validated evidence-based alternatives, particularly for cisplatin-eligible patients or in regions where enfortumab vedotin plus pembrolizumab is not readily accessible. These advances have created new challenges in treatment sequencing, particularly for patients who progress after enfortumab vedotin plus pembrolizumab, where prospective evidence remains limited. Enfortumab vedotin monotherapy retains activity post-platinum and immune checkpoint inhibition, erdafitinib provides a targeted benefit in fibroblast growth factor receptor 3-altered tumors, and trastuzumab deruxtecan has emerged as a later-line option for HER2-positive disease. In parallel, circulating tumor DNA is an emerging biomarker with potential to individualize sequencing strategies, although its clinical application remains investigational. This review synthesizes current evidence and highlights practical considerations, emphasizing the need to balance therapeutic innovation with cost effectiveness, equitable access, and global applicability, while identifying critical research priorities in the post-enfortumab vedotin plus pembrolizumab era.