Phase II Study of Dasatinib in Patients with Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC). Experimental Design Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks. Results Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved ≥40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate. Conclusions This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…QTc prolongation was frequent (>5% of patients experiencing CTCAE scale grade I QTc prolongation) in patients treated with dasatinib, vandetanib, sorafenib, or sunitinib. Dasatinib is used to treat hematological malignancies and has been associated with QTc prolongation in 8% of treated patients (range, 1%–70%), but QTc >500 ms was seen only in <1% 13, 18, 20, 21, 22, 25, 32, 40, 42, 75…”

Current Status of Src Inhibitors in Solid Tumor Malignancies

“…A phase II study of dasatinib in chemotherapy-naïve men with castration-resistant prostate cancer demonstrated 43% and 19% stable disease (SD) rates at 12 weeks and 24 weeks of treatment, respectively. Additionally, a reduction in N-telopeptide in the urine, an accepted marker of bone resorption predictive of adverse skeletal events, was also noted in 80% of the study patients with known bony metastases [62]. A phase I/II trial of dasatinib combined with docetaxel showed no significant drug-drug interactions and manageable toxicities, and 21 of 21 patients demonstrated a partial response (PR) or SD at Ͼ6 -21 weeks of follow-up [63].…”

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

“…Dasatinib inhibits proliferation, cell adhesion, migration and invasion of prostate cancer cells in vitro (58). A phase II study CA180085 investigating the activity of dasatinib in patients with metastatic CRPC has been started (59). The primary endpoint is the composite response/stable disease (SD) rate, achieved in 13 of 47 (28%) patients with 95% confidence interval above the minimum anticipated response rate of 10%.…”