Abiraterone acetate has been shown to significantly prolong overall survival among patients with metastatic castration-resistant prostate cancer (CRPC) who previously received chemotherapy. The results of the Phase III study were published in the May 26, 2011 edition of the New England Journal of Medicine (N Engl J Med 2011;364:1995–2005).
Based on this pivotal Phase III trial, the FDA approved abiraterone acetate (Zytiga) in combination with prednisone(Drug information on prednisone) for men with metastatic castration-resistant prostate cancer who have received prior docetaxel(Drug information on docetaxel) chemotherapy. The application received a priority review and was approved on April 28, 2011. Zytiga is marketed by Horsham, Pa.-based Centocor Ortho Biotech, Inc.
Abiraterone is an oral, small molecule inhibitor. The drug is a pregnenolone analog that irreversibly inhibits cytochrome P450 c17 (CYP17), the rate-limiting enzyme in androgen production. Abiraterone works by blocking synthesis of androgens in the testes, adrenal glands, and prostate without causing adrenal insufficiency in the patient.
The international, randomized, placebo-controlled Phase III study, COU-AA-301, tested whether abiraterone improved overall survival in patients with CRPC whose disease had progressed after chemotherapy. The study also evaluated time to to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
1195 patients were randomly assigned to receive 5 mg prednisone two times daily with either 1000 mg of abiraterone or placebo. Patients were randomized in a 2:1 ratio.
After a median follow-up of 12.8 months, overall survival for the abiraterone therapy group was 14.8 months compared with 10.9 months for the placebo group (hazard ratio 0.65, P < 0.001). The median duration of treatment was 8 months for the abiraterone group compared to 4 months for those on the placebo. Secondary endpoints were favored by the abiraterone-treated group. PSA progression was 10.2 months compared to 6.6 months (P < 0.001) and progression free survival was 5.6 months versus 3.6 months (P < 0.001). The data had been unblinded at the interim analysis as the results exceeded the criteria for study termination, as recommended by the independent data and safety monitoring committee. Patients who were in the placebo group were subsequently able to receive abiraterone if they met the study crossover criteria.
Adverse events related to elevated mineralocorticoids associated with CYP17 inhibition were all more frequently reported in the abiraterone cohort (55% vs 43%, P < 0.001) and included fluid retention, hypertension, and hypokalemia. Both abnormalities in liver function and cardiac events were not significantly different between the two patient groups. “Overall, compliance with abiraterone acetate treatment was high, and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population,” according to the authors.
The authors conclude that this study validates the hypothesis that “the biosynthesis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands.”