Abstract
Cisplatin-based chemotherapy has long been the standard first-line (1L) treatment for metastatic urothelial carcinoma (mUC). However, up to 50% of patients with mUC may be ineligible for cisplatin owing to comorbidities, necessitating alternative primary treatment options. Immune checkpoint inhibitors (ICIs) have emerged as a vital alternative for those unable to receive cisplatin. Nevertheless, the prognosis of advanced UC remains dire and challenges persist in optimizing 1L therapy. Recent medical advancements have redirected attention towards innovative drug combinations for the primary treatment of mUC. The combination of enfortumab vedotin (EV) and pembrolizumab has shown significantly improved overall and progression-free survival rates compared to those with chemotherapy alone. This combination can be used as a 1L treatment for patients with mUC who are cisplatin-ineligible or require alternatives to standard chemotherapy. While platinum-based chemotherapy continues to be essential for many patients, the approval of EV and pembrolizumab as 1L treatments for cisplatin-ineligible patients signifies a major breakthrough in primary cancer care. These therapies offer enhanced outcomes in terms of survival and response rates and highlight the increasing relevance of ICI-containing regimens in frontline cancer care. This review provides an exhaustive overview of the current frontline treatment landscape of mUC and explores new therapeutic strategies, with the aim of facilitating clinical decision-making and guiding therapeutic strategies in patients with mUC.