How to cite: Petrylak DP. “Advanced Disease Sequencing.” Grand Rounds in Urology. August 2026. Accessed Oct 2026. https://grandroundsinurology.com/advanced-disease-sequencing/
Summary
In this presentation from the UroCancer Interdisciplinary Forum 2026, Daniel P. Petrylak, MD, Professor of Medicine and Chief of Genitourinary Oncology, Smilow Cancer Center, Yale University, New Haven, Connecticut, reviews the rapidly evolving treatment landscape for advanced urothelial carcinoma. He traces the evolution of systemic therapy from methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) through gemcitabine plus cisplatin and modern immunotherapy combinations, highlighting how enfortumab vedotin plus pembrolizumab has fundamentally changed first-line management.
Dr. Petrylak discusses rechallenge with immune checkpoint inhibitors, treatment after neoadjuvant enfortumab vedotin plus pembrolizumab, persistence of Nectin-4 expression, and mechanisms of resistance. He reviews preclinical evidence suggesting that monomethyl auristatin E (MMAE) may enhance antitumor immune responses by promoting immunogenic cell death, providing a biologic rationale for combining antibody-drug conjugates with checkpoint inhibition.
Dr. Petrylak addresses treatment-related toxicity, emphasizing careful monitoring for skin reactions, hyperglycemia, peripheral neuropathy, and pneumonitis. He notes that maintaining adequate dose intensity early in treatment appears more important than preserving full-dose therapy throughout the entire course, allowing later dose reductions when toxicity develops.
Dr. Petrylak highlights the growing importance of molecular testing, including fibroblast growth factor receptor (FGFR) alterations and human epidermal growth factor receptor 2 (HER2) expression. He argues for investigational approaches, including dual-payload ADCs, bispecific antibodies, and theranostic strategies, emphasizing that future sequencing decisions will increasingly depend on biomarkers, resistance mechanisms, and individualized treatment selection.
ABOUT THE AUTHOR
Daniel P. Petrylak, MD, is a Professor of Medicine, specializing in Medical Oncology and Urology, and Chief of Genitourinary Oncology at Yale University Cancer Center in New Haven, Connecticut. Dr. Petrylak is an internationally renowned medical oncologist and is considered a pioneer in the research and development of new drugs and treatments to fight cancers of the prostate, bladder, and kidney.
