LAUSR

Simple Summary In recent years, there have been several advances in the care of advanced bladder cancer, highlighted by the addition of immune checkpoint inhibitors to the care of advanced disease. Despite these advances, there is a need for further improvement; the morbidity and mortality associated with advanced bladder cancer remain high. With the recent incorporation of advanced molecular techniques, there is more clarity regarding key genetic alterations of the disease. Therapies directed at specific genetic aberrations in bladder cancer provide both proven and potential paths forward. This review discusses the key targetable genetic aberrations and summarizes the current status of targeted therapies in muscle-invasive bladder cancer. Abstract Despite the introduction of immune checkpoint inhibitors and antibody–drug conjugates to the management of advanced urothelial carcinoma, the disease is generally incurable. The increasing incorporation of next-generation sequencing of tumor tissue into the characterization of bladder cancer has led to a better understanding of the somatic genetic aberrations potentially involved in its pathogenesis. Genetic alterations have been observed in kinases, such as FGFRs, ErbBs, PI3K/Akt/mTOR, and Ras-MAPK, and genetic alterations in critical cellular processes, such as chromatin remodeling, cell cycle regulation, and DNA damage repair. However, activating mutations or fusions of FGFR2 and FGFR3 remains the only validated therapeutically actionable alteration, with erdafitinib as the only targeted agent currently approved for this group. Bladder cancer is characterized by genomic heterogeneity and a high tumor mutation burden. This review highlights the potential relevance of aberrations and discusses the current status of targeted therapies directed at them.