Advancements in First-Line Treatment of Metastatic Bladder Cancer: EV-302 and Checkmate-901 Insights and Future Directions

Simple Summary Bladder cancer represents a significant global health burden, particularly affecting elderly males. Incidence rates vary globally, with higher rates observed in western Europe than in South Asia. Metastatic bladder cancer has historically had poor outcomes, with platinum-based chemotherapy as the standard first-line treatment. In this review, we delve into the two pivotal trials, Checkmate-901 and EV-302, that addressed the need for improved first-line treatments and resulted in a paradigm shift with the incorporation of antibody-drug conjugates (ADCs) and immunotherapy combinations in the advanced bladder cancer conundrums. We also provide a comprehensive review of the novel therapeutic approaches, including fibroblast growth factor receptor inhibitors (FGFR), human epidermal growth factor receptor (HER) pathway inhibitors, and various other ADCs targeting antigens, such as nectin-4, Trop-2, and tissue factors that are available to improve the survival of advanced bladder cancer.Abstract Advanced bladder cancer patients have historically failed to achieve prolonged duration of response to conventional chemotherapy and needed better first-line treatment regimens. The approval of nivolumab in combination with gemcitabine and cisplatin and pembrolizumab with antibody-drug conjugate enfortumab vedotin has revolutionized the first-line treatment of advanced bladder cancer in many countries. In this review, we summarize the intricate differences between the two landmark clinical trials that led to their incorporation into the current standard of care for advanced bladder cancer. We further discuss newer novel treatment options in the second and subsequent lines of treatment on progression, like immunotherapy in combination with other agents, including fibroblast growth factors receptor inhibitors, human epidermal growth factor inhibitors, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Finally, we discuss the integration of these novel therapies into current clinical practice amidst the rapidly evolving landscape of advanced bladder cancer treatment, aiming to enhance patient outcomes.