Systemic Treatment-Decision Algorithms in Muscle-Invasive Bladder Cancer: Clinical Complexities and Navigating for Improved Outcomes

Muscle-invasive bladder cancer has poor prognosis. If organ confined, it is potentially curable; however, across all prognostic groups, approximately half of patients will relapse. For patients with advanced disease, the median overall survival remains under two years. Systemic treatment options are centered on the use of platinum-based combination chemotherapy, with the choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function. PD-1/PD-L1 checkpoint-directed immunotherapy has been established for use in advanced disease with modest overall improvements in survival outcomes. Based on current data, optimal utilization appears to be a switch maintenance strategy on completion of chemotherapy. In the curative setting, cisplatin-based chemotherapy provides modest improvements in cure rates in those fit to receive it. Data on the use of adjuvant immunotherapy are currently contradictory, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed. The Nectin-4 directed antibody drug conjugate enfortumab vedotin is an established treatment option for patients previously treated with both chemotherapy and immunotherapy. The emerging therapeutic targets under evaluation include Trop-2 with sacituzumab govitecan, fibroblast growth factor receptors, HER2, and DNA repair deficiency in biomarker-selected patients. The development of properly validated predictive biomarkers has proven challenging for this disease and should be a central priority in the future development of treatment options. This review summarizes the available systemic treatment options in both palliative and curative disease settings, and highlights the available evidence and current limitations for making treatment recommendations.