One critical enzyme involved in intracrine androgen biosynthesis is CYP17A. Abiraterone acetate (AA) is a selective oral inhibitor of CYP17. In the New England Journal of Medicine, Dr. Johan de Bono and international collaborators report the positive results of a phase III trial comparing AA (1gm) with prednisone (5mg) vs. prednisone alone for patients with CRPC.
A total of 1,195 men in 13 countries with CRPC were enrolled between 2008 and 2009. They had CRPC, serum testosterone <50ng/dL, prior treatment with docetaxel chemotherapy and EGOC performance status 0-2. The primary study endpoint was overall survival and secondary endpoints included PSA response rate, time to PSA progression, and progressive disease. The planned sample size was 1,158 patients to provide 85% ability to detect a hazard ratio of 0.80 for death in the AA group compared to controls. A 2:1 randomization resulted in 797 patients assigned to the treatment group and 398 patients to the prednisone group.
A planned interim analysis was performed and found a 35.4% reduction in the risk of death compared to the prednisone (HR 0.65). A total of 552 men in the intention to treat population died: 333 in the AA group (42%) and 219 in the placebo/prednisone group (55%). Median overall survival was 14.8 months for AA and 10.9 months for controls. Secondary endpoints were also positive for AA: 29% vs. 6% for PSA response rate, 14% vs. 3% for objective response rate, 10.2 vs. 6.6 months for time to PSA progression, and 5.6 vs. 3.6 months for median progression-free survival. The time to 25% of patients having a skeletal event was 9.9 months vs. 4.9 months for AA and placebo, respectively. Patients in the AA arm had significant improvement in pain scores. Fatigue was the most frequent adverse event and occurred equally in the two groups. Other adverse events were back pain and nausea (about 30% in each group), constipation, arthralgia and bone pain. More common in the AA group were events related to mineralocorticoid increase including fluid retention, edema, hypokalemia, and hypertension.
AA has recently been approved by the FDA for use in men with CRPC who have progressed after docetaxel chemotherapy.
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI