Originally published as JCO Early Release 10.1200/JCO.2008.20.0642 on May 26 2009

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Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer

From the Royal Marsden National Health Service Foundation Trust; The Institute of Cancer Research, Sutton, Surrey, United Kingdom; and Cougar Biotechnology, Los Angeles, CA.

Corresponding author: Johann S. de Bono, MB ChB, FRCP, MSc, PhD, Section of Medicine, The Institute of Cancer Research, the Royal Marsden National Health Service Foundation Trust, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: johann.de-bono{at}icr.ac.uk.

Purpose It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.

Patients and Methods This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; = .05; β = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued.

Results A decline in PSA of 50% was observed in 28 (67%) of 42 phase II patients, and declines of 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of 50% PSA decline and TTPP on abiraterone acetate and dexamethasone.

Conclusion CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.

Supported by Cougar Biotechnology. G.A., A.H.M.R., C.M., L.R.M., G.M., E.T., D.O., R.S., S.B.K., and J.S.d.B. are in the Section of Medicine, which is supported by a Cancer Research UK program grant and an Experimental Cancer Medicines Centre grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). G.A. and A.H.M.R. were also supported by the Royal Marsden Hospital Research Fund. G.A. is also supported by the Prostate Cancer Foundation, Santa Monica, CA. C.P. was supported by Cancer Research UK and the National Cancer Research Institute Prostate Cancer Collaborative. R.A. is in the Cancer Research UK Section of Clinical Trials at The Institute of Cancer Research, Surrey, UK. We also acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00473512 [ClinicalTrials.gov] .

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