BERKELEY, CA (UroToday.com) - In the online edition of the Journal of Clinical Oncology, Dr. Daniel Danila and collaborators report a Phase II trial of the selective CYP17 inhibitor abiraterone acetate (AA) in combination with prednisone in patients with docetaxel treated castration-resistant prostate cancer (CRPC). AA is a selective, irreversible and potent inhibitor of CYP17, an enzyme involved with androgen synthesis, and recently demonstrated as part of the intracrine androgen biosynthetic pathway. AA monotherapy, while effective, was associated with hypokalemia, fluid retention, and hypertension that required treatment with the selective aldosterone inhibitor eplerenone or low dose steroids to suppress the hypothalamic-pituitary axis. The goal of this trial was to validate the effectiveness of AA after failure of docetaxel chemotherapy in combination with prednisone at 5mg twice daily to decrease the steroid precursors upstream of CYP17 and to suppress the side effects of AA. In this study, circulating tumor cell (CTC) number was also measured using a validated assay, with a decrease from >5 CTCs (unfavorable baseline count) to <5 CTCs considered a favorable conversion.
Patients with castrate testosterone levels who had PSA progression following docetaxel chemotherapy were eligible to receive AA 1,000mg daily with prednisone 5mg twice daily. Up to one year of therapy was permitted. A PSA decline >50% with a confirmatory value obtained 4 weeks later was a primary study endpoint. In 2007, 58 men were enrolled at seven study centers. Only 19% had disease limited to bone, while the majority had soft tissue disease or visceral spread. Median PSA level at baseline was 190ng/ml and median testosterone level was 4.8ng/dL. A total of 43% of patients achieved a >50% decline in PSA. Overall, confirmed PSA responses of >30%, >50%, and >90% decline were observed in 47%, 36%, and 16% of patients, respectively. Partial responses in soft-tissue lesions were noted in 18% and among patients with bone disease 59% had stable bone disease and 41% had disease progression. An improvement in ECOG performance status was noted in 28%. The median time to PSA progression was 169 days. Unfavorable baseline CTC cell counts were noted in 69% of 38 patients having specimens available and 10 of these (34%) converted to a favorable count after treatment. The side effect profile was improved over AA alone, with the incidence of hypokalemia, hypertension, and fluid retention (5%, <5%, and <10%, respectively) compared with 55%, 17%, and 15%, respectively in a previous study of AA alone.
Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, Taplin ME, Bubley GJ, Kheoh T, Haqq C, Molina A, Anand A, Koscuiszka M, Larson SM, Schwartz LH, Fleisher M, Scher HI
J Clin Oncol. 2010 Mar 20;28(9):1496-501
10.1200/JCO.2009.25.9259
PubMed Abstract
PMID: 20159814