Frontline Systemic Treatment for Metastatic Disease: Optimizing First-Line Systemic Approaches for Advanced Urothelial Cancer

How to cite: Palaskas NJ. “Frontline Systemic Treatment for Metastatic Disease: Optimizing First-Line Systemic Approaches for Advanced Urothelial Cancer.” Grand Rounds in Urology. November 13, 2025. Accessed Feb 2026. https://grandroundsinurology.com/frontline-systemic-treatment-for-metastatic-disease-optimizing-first-line-systemic-approaches-for-advanced-urothelial-cancer/

Summary

Nicolaos Palaskas, MD, PhD, Assistant Professor and member of the Jonsson Comprehensive Cancer Center’s Cancer and Stem Cell Biology Program, University of California, Los Angeles, Los Angeles, California, reviews current standards and emerging strategies for frontline systemic treatment of metastatic urothelial carcinoma, emphasizing that enfortumab vedotin plus pembrolizumab is now the preferred first-line regimen, while multiple targeted approaches aim to further improve outcomes. He outlines how evolving antibody drug conjugates and molecular targets may reshape the frontline landscape.

Dr. Palaskas provides a concise review of guideline-supported Category 1 regimens for metastatic disease. He emphasizes that the current preferred regimen is enfortumab vedotin plus pembrolizumab, supported by the EV-302 trial, which demonstrated significant improvements in progression-free survival, overall survival, and complete response rates without the use of conventional chemotherapy.

Dr. Palaskas explores opportunities for optimization beyond existing standards. These include improved toxicity management, dose modifications, and supportive care, but the primary focus is on new targets and next-generation agents. Four key targets are highlighted: Nectin-4, HER2, FGFR3, and TROP2, with detailed discussion focused on the first three.

Data from EV-302 are reviewed, showing large separations in progression-free and overall survival curves and high complete response rates with Nectin-4 targeting. Dr. Palaskas discusses potential improvements through enhanced tumor penetration, more stable linkers, and alternative payloads to refine antibody drug conjugates.

HER2-directed therapy is presented through phase III data evaluating disitamab vedotin combined with immunotherapy. Results show substantial improvements in progression-free and overall survival compared with chemotherapy, with a manageable toxicity profile, suggesting HER2 targeting may rival current first-line standards in selected patients.

Finally, FGFR3 is discussed as a promising target. Early phase data with vepugratinib demonstrate favorable response rates, durable responses, and low rates of high-grade toxicity. Preclinical data showing increased Nectin-4 expression with FGFR3 inhibition provide a rationale for future combination strategies with enfortumab vedotin.

Dr. Palaskas stresses that while enfortumab vedotin plus pembrolizumab remains the frontline standard, HER2- and FGFR3-targeting strategies may soon further expand treatment options.

About the 32nd Annual Perspectives in Urology: Point Counterpoint conference: Presented by Program Chair and Grand Rounds in Urology Editor-in-Chief E. David Crawford, MD, this conference brought together leading experts in urology, medical oncology, and radiation oncology to discuss and debate the latest topics in genitourinary cancers, primarily prostate cancer and bladder cancer. This interactive conference offered topical lectures, pro/con debates, interesting-case presentations, interactive panel discussions, and interactive audience and faculty networking.