Shining light on immunotherapy in metastatic urothelial carcinoma: trends and prospects

Urothelial carcinoma (UC), particularly in its advanced and metastatic stages, poses major treatment challenges. Platinum-based chemotherapy remains the standard front-line treatment due to its superior initial disease control. However, its long-term efficacy has frequently hampered by chemoresistance. Immune checkpoint inhibitors (ICIs) have transformed the treatment of UC, offering durable responses, particularly in the metastatic urothelial carcinoma (mUC) setting. The strategic integration of ICIs, like avelumab in the first-line maintenance setting following chemotherapy, has significantly improved overall survival, representing a key shift in treatment sequencing. Concurrently, advancements in tumor molecular profile have enabled the development of novel targeted therapies for mUC, including fibroblast growth factor receptor inhibitors, Poly (ADP-ribose) polymerase (PARP) inhibitors, anti-HER2 agents, and antibody–drug conjugates specifically targeting Nectin-4. Furthermore, numerous ongoing clinical trials are actively exploring additional molecular targets and pathways to further enhance treatment options for mUC. This review outlines the evolving therapeutic landscape of mUC, emphasizing the limitations of ICI monotherapy, the promise of maintenance strategies, and the emergence of rational combination regimens for improved patient outcomes. Advances in biomarker-guided approaches, including circulating tumor DNA, tumor mutational burden, and ligand programmed death-1 expression, along with emerging biomarkers, such as T-effector gene signatures, ApolipoproteinB mRNA editing enzyme catalytic (APOBEC) mutagenesis patterns, and tumor microenvironment, are also discussed as essential tools for optimizing personalized treatment in the era of precision immunotherapy.