Systemic treatment for advanced urothelial cancer: an update on recent clinical trials and current treatment options

After cisplatin-based chemotherapy became the standard treatment for metastatic urothelial cancer (mUC), very little progress has been made in the treatment landscape of this condition until recently. With increased knowledge about the molecular biology of mUC and advances in the field of cancer immunobiology, there has been an explosion in the number of clinical trials for mUC, and systemic treatment of mUC is rapidly changing. Despite the availability of several novel therapeutic agents, cisplatin-based cytotoxic chemotherapy remains the standard, first-line treatment option. Immune checkpoint inhibitors (ICIs), including programmed death-1 and programmed death ligand-1 inhibitors, are preferred second-line treatment options that are also used in first-line cisplatin-ineligible settings. For patients with actionable fibroblast growth factor receptor 2 (<i>FGFR2</i>) or <i>FGFR3</i> genomic alterations, erdafitinib can be considered after platinum-based treatment. Enfortumab vedotin, a monoclonal antibody targeting nectin-4 conjugated to monomethyl auristatin E, has been approved for patients who do not respond to both cytotoxic chemotherapy and ICIs. In this review, we address the clinical trial data that have established the current standard treatments and ongoing clinical trials of various agents with different mechanisms as well as provide a brief overview of current practice guidelines and recommendations in patients with mUC.