Cancer Therapy : Clinical Phase II Study of Androgen Synthesis Inhibition with Ketoconazole , Hydrocortisone , and Dutasteride in Asymptomatic Castration-Resistant Prostate Cancer

Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5α-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). Results: Prostate-specific antigen response rate (≥50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. Conclusion: The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation. (Clin Cancer Res 2009;15(22):7099–105) Prostate cancer that progresses after androgen deprivation therapy (ADT), termed castration-resistant prostate cancer (CRPC), expresses androgen receptor (AR) and multiple androgen-regulated genes at high levels (including PSA and TMPRSS2:ERG fusion genes), indicating that AR transcriptional activity has been reactivated despite castrate serum androgens levels (1–3). Mechanisms that may contribute to this AR reactivation include increased AR expression (increased AR mRNA in most patients Authors' Affiliations: Dana-Farber Cancer Institute; Harvard Medical School; Dana-Farber/Harvard Cancer Center; Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Defense Prostate Cancer Clinical Trials Consortium, New York, NY; Sunnybrook Health Science Centre, Toronto, Ontario, Canada; Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon; M. D. Anderson Cancer Center, Houston, Texas; Johns Hopkins University School of Medicine, Baltimore, Maryland; Tulane Cancer Center, New Orleans, Louisiana; and GlaxoSmithKline, Research Triangle Park, North Carolina Received 7/2/09; revised 8/18/09; accepted 8/27/09; published OnlineFirst 11/3/09. Grant support: GlaxoSmithKline, Department of Defense Prostate Cancer Research Program grant PC060807, NIH grants R01CA111803 and P01CA89021, and Prostate Cancer Foundation Challenge grant. 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:M.-E. Taplin,M.M. Regan, andY.-J. Ko contributed equally to thiswork. Presented inpart as an abstract at AmericanSociety of ClinicalOncology2008. Requests for reprints: Steven P. Balk, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115; Phone: 617-735-2035; Fax: 617-735-2050; E-mail: sbalk@bidmc.harvard.edu. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1722 7099 Clin Cancer Res 2009;15(22) November 15, 2009 www.aacrjournals.org Published Online First on November 3, 2009 as 10.1158/1078-0432.CCR-09-1722 Research. on April 4, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 3, 2009; DOI: 10.1158/1078-0432.CCR-09-1722