Advancing therapeutic frontiers in urothelial carcinoma: targeted strategies and clinical implications

Urothelial carcinoma poses significant challenges in clinical management due to its aggressive nature and high prevalence. While most diagnoses involve localized disease, advanced urothelial carcinoma (aUC) often leads to short overall survival (OS). Historically, platinum-based chemotherapy has been the primary treatment for aUC, although its efficacy is limited. However, recent therapeutic advancements, such as immune checkpoint inhibitors (ICIs) and targeted therapy using antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs), have shown promise in clinical trials, initially among patients who have undergone platinum-based chemotherapy. Recently, phase III clinical trials have assessed the effectiveness of ICIs, ADCs, and TKIs either in combination or as monotherapy in the first line setting for patients with aUC. As a result of this expanding knowledge, the combination of enfortumab vedotin (EV) with pembrolizumab in the front-line scenario became the new standard of care for aUC, demonstrating significant enhancements in OS and progression-free survival compared to platinum-based chemotherapy. Additionally, other ADCs and targeted therapies have exhibited promising efficacy in clinical trials. This review summarizes recent advancements in the treatment landscape of aUC, focusing on the efficacy and safety profiles of ICIs, ADCs, and TKIs, highlighting the evolving standards and promising combination approaches in the management of this challenging malignancy.