| Summary: | The recommended treatment for metastatic urothelial carcinoma (mUC) patients is platinum-based chemotherapy. Although initial response rates are moderate, the vast majority of patients experience a relapse due to chemoresistance and eventually succumb to their disease. Furthermore, platinum-based chemotherapy is toxic and approximately 30% of mUC patients are unfit for chemotherapy. Thus, there is a clear unmet need for novel, more efficacious treatment options in mUC with a safer toxicity profile. To propel the advancement of novel treatment options, we present a summary of key signaling pathways and molecular mechanisms that are known to be involved in bladder cancer tumorigenesis with a focus on promising candidate druggable molecular targets and innovative targeted therapies currently under clinical investigation. Targetable alterations were mainly described in fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (ErbB) tyrosine kinase receptor (RTK) families, downstream pathways, and chromatin remodelers, which are major bladder cancer driver genes. Drugs targeting the FGFR family members are emerging as personalized treatment options for selected mUC patients with tumor-specific FGFR alterations. The pan-FGFR inhibitor, erdafitinib, was first-in-class to receive U.S. Food and Drug Administration (FDA) approval in 2019, while inhibitors of ErbB family members have shown less potential. Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that deliver cytotoxic drugs in close proximity to cancer cells by targeting RTKs or other transmembrane proteins. Enfortumab vedotin is the first-in-class ADC that was FDA approved for the treatment of locally advanced or mUC in 2019.
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