Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity ★

• Dasatinib, a Src inhibitor, was feasible as neoadjuvant therapy for bladder cancer.
• Overall, significant Src pathway inhibition was seen in tumor tissue.
• Cell proliferation and apoptosis were unaltered overall.
• Src inhibition appears ineffective in unselected bladder cancer patients.
• The neoadjuvant trial paradigm may complement drug development.

ObjectivesPreclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).Materials and methodsA prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2–T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100 mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.ResultsThe study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had