Enfortumab vedotin (EV) plus pembrolizumab is the first-line standard of care for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). However, randomized data to guide treatment after progression on EV plus pembrolizumab are limited. Datopotamab deruxtecan (Dato-DXd), a trophoblast cell surface antigen 2-directed antibody-drug conjugate, has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC. TROPION-Urothelial03 is a global, multicenter, randomized, open-label, phase II/III trial comparing the efficacy and safety of Dato-DXd plus platinum chemotherapy versus gemcitabine plus platinum chemotherapy in patients with la/mUC and disease progression on or after EV plus pembrolizumab. In Part A (phase II), ~60 patients will be randomized 1:1 to Dato-DXd 4 or 6 mg/kg plus platinum chemotherapy to determine optimal dosing. In Part B (phase III), ~570 patients will be randomized 1:1 to receive Dato-DXd at the recommended phase III dose plus platinum chemotherapy or gemcitabine plus platinum chemotherapy. The primary endpoint of Part A is objective response rate (ORR); the dual primary endpoints of Part B are progression-free survival (PFS) by blinded independent central review (BICR) and overall survival. Secondary endpoints include duration of response by investigator (Part A), and PFS by investigator and ORR by BICR and investigator (Part B).Clinical trial registration: www.clinicaltrials.gov identifier is NCT07129993.
Patients diagnosed with a type of bladder cancer called urothelial carcinoma (UC) that has spread to other parts of the body typically receive a combination of two drugs, enfortumab vedotin (EV) and pembrolizumab, as their first treatment. Unfortunately, this therapy eventually stops working for many, and their cancer gets worse. Datopotamab deruxtecan (Dato-DXd) is a cancer medicine that combines an antibody with a chemotherapy drug to target and kill cancer cells. Previous studies have shown that Dato-DXd, given by itself, may help people with UC that has spread. This study, called TROPION-Urothelial03, is designed to find out how well Dato-DXd works when given alongside chemotherapy to patients with UC whose cancer has worsened while on or after their initial treatment. The first part of the study will determine the best dosing levels, and the second part will compare the combination of Dato-DXd plus chemotherapy with the current standard treatment for such patients. The main aims of the study are to determine how long patients live without their cancer growing or spreading, and how long they live overall.
Future oncology (London, England). 2026 May 16 [Epub ahead of print]
Matthew D Galsky, Alexandra Drakaki, Arnab Basu, Bradley McGregor, Jens Bedke, Yohann Loriot, Eiji Kikuchi, Jun Guo, Benjamin Garmezy, Srikala S Sridhar, Parminder Singh, Vadim S Koshkin, Mark Fleming, Gunnar Klauss, Daisy Lin, Chelsea Liu, Andrea B Apolo, Thomas Powles
Department of Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Medical Oncology, UCLA Health, Los Angeles, CA, USA., Department of Oncology, Mayo Clinic, Jacksonville, FL, USA., Department of Medical Oncology, Dana-Farber/Harvard Cancer Center, Boston, MA, USA., Department of Urology & Transplantation Surgery, Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Germany., Department of Oncology, Gustave Roussy Cancer Institute, Paris, France., Department of Urology, St. Marianna University School of Medicine, Kawasaki, Japan., Department of Oncology, Peking University Cancer Hospital and Research Institute, Beijing, China., Department of Genitourinary Cancer Research, Sarah Cannon Research Institute, Nashville, TN, USA., Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada., Department of Genitourinary Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA., Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, Helen Diller Family Comprehensive Cancer, San Francisco, CA, USA., Department of Medical Oncology, Virginia Oncology Associates, Brock Cancer Center, Norfolk, VA, USA., Department of Global Oncology Research & Development, Daiichi Sankyo, Inc., Basking Ridge, NJ, USA., Department of Clinical Science Therapeutic Area Oncology, Daiichi Sankyo, Inc., Basking Ridge, NJ, USA., Department of Biostatistics & Data Management, Daiichi Sankyo, Inc., Basking Ridge, NJ, USA., Department of Oncology, National Cancer Institute, Bethesda, MD, USA., Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK.