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

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 prostatespecific antigenwere treatedwith dasatinib 100 or 70mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), andmarkers of bonemetabolism. 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. (Clin Cancer Res 2009;15(23):7421–8) Prostate cancer is the most common cancer, with high mortality rates, affecting men in the United States and Europe (1, 2). The natural progression of prostate cancer that is not cured with local therapy results in metastases, most commonly to bone, and resistance to androgen deprivation therapy. Second-line hormonal therapies (steroidal/nonsteroidal antiandrogens, ketoconazole, and diethylstilbestrol) may be added to luteinizing hormone-releasing hormone agonists or orchiectomy; however, this produces a relatively short response in less than half of castrate patients (3). No second-line hormonal therapies have been associated with an improvement in survival. Additionally, patients with castration-resistant prostate cancer (CRPC) with bone metastases are often treated with bisphosphonates to prevent skeletal-related events (4, 5). Docetaxel chemotherapy is used in men with metastatic CRPC and has been shown to extend survival (6–8). However, it is associated with adverse events, including fatigue, myelosuppression, and neuropathy, toxicities that may not be acceptable to asymptomatic patients, and as such, the optimal timing for starting chemotherapy remains uncertain. For both the Authors' Affiliations: University of Washington, Seattle, Washington; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin; University of Chicago, Chicago, Illinois; Cedars-Sinai Medical Center, Los Angeles, California; CRLC Val d'Aurelle, Montpellier, France; Institut Gustave Roussy, Villejuif, France; Memorial Sloan-Kettering Cancer Center, New York, New York; Fox Chase Cancer Center, Philadelphia, Pennsylvania; San Camillo Forlanini Hospital, Rome, Italy; and BristolMyers Squibb, Wallingford, Connecticut Received 7/1/09; revised 8/5/09; accepted 8/11/09; publishedOnlineFirst 11/17/09. Grant support: Department of Defense Prostate Cancer Clinical Trials Consortium awards W81XWH-07-1-0097, W81XWH-06-1-0258, and W81XWH-06-10241; Prostate Cancer Foundation Therapy Consortium; and Bristol-Myers Squibb. Editorial assistance for this article was provided by StemScientific and funded by Bristol-Myers Squibb. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: E.Y. Yu, G. Wilding, and M.J. Morris are members of the Prostate Cancer Clinical Trials Consortium sponsored by the Department of Defense. Prior presentations: 2008 ASCO Annual Meeting, Chicago, IL, May 2008. J Clin Oncol 26: 2008 (Suppl; abstract 5156). Clinical trials registry number: NCT00385580. Requests for reprints: Cora N. Sternberg, Department of Medical Oncology, San Camillo Forlanini Hospital, Nuovi Padiglioni, 4th floor, Circonvallazione Gianicolense 87, Rome 00152, Italy. Phone: 39-06-5870-4356; Fax: 39-06663-0771; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1691 7421 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals.org Research. on April 20, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 17, 2009; DOI: 10.1158/1078-0432.CCR-09-1691