Metastatic urothelial carcinoma (mUC) remains a fatal malignancy, despite the recent addition of immune check point inhibitors (ICIs), an FGFR inhibitor and an antibody-drug conjugate (ADC) to the therapeutic armamentarium. The survival rates are particularly dismal after first-line treatment failure, entailing an urgent need for more effective therapies. Advances in understanding biomarkers and identifying targetable molecules have broadened the pathways under investigation in mUC.

This review summarizes mUC salvage therapy options, including chemotherapy, ICI, and novel promising agents, including targeted therapies, ADCs, cytotoxic agents and vaccines. For the literature review, a PubMed search and relevant data presented at international conferences were used.

The approval of ICIs, FGFR inhibitor erdafitinib and ADC enfortumab vedotin in the salvage setting has transformed the mUC landscape. Yet there are additional promising agents currently under study. Toxicities are observed with ADCs and FGFR inhibitors, but appear manageable in most patients. The molecular heterogeneity and complex tumor biology are challenging barriers for progress in the therapy of mUC. Advances in molecular profiling, defining validated predictive markers, rational combinations of agents and therapeutically actionable targets will help develop personalized compounds with higher efficacy and less toxicity with hopes to improve outcomes for mUC.