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). 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.
Galsky et al. (Sat,) studied this question.