TROPION-Urothelial03: a phase II/III study of datopotamab deruxtecan (Dato-DXd) for locally advanced or metastatic urothelial carcinoma.

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.