Abiraterone acetate (AA) in patients with metastatic castration-resistant prostate cancer (mCRPC) and prior therapy with ketoconazole: A Prostate Cancer Clinical Trials Consortium study.

Abstract

4500 Background: AA and ketoconazole (keto) both inhibit CYP 17, the rate limiting enzyme in androgen synthesis. Since mechanisms of resistance to these agents may be overlapping, patients (pts) with prior keto exposure were excluded from the AA randomized phase III trials. In the current study patients with mCRPC who have received prior therapy with keto were treated with AA. Methods: Eligibility required progressive mCRPC and prior keto for >28 days. Prior chemotherapy was not allowed. Pts were required to have normal baseline organ function and ACTH stimulation test. Therapy consisted of a fasting daily dose of AA at 1000 mg with 10 mg of prednisone. Response is defined as a >50% decline in PSA from baseline value. The study is designed to detect a ≥30% PSA decline in ≥30% of patients. Results: Sixteen pts were enrolled in the initial cohort, the median follow up is 13.1 weeks (range 1-18). The median age and baseline PSA are 72.5 years and 62.5 ng/dL, respectively. The median duration of prior keto therapy was 58 weeks (range 9 – 206) and the median duration since last keto therapy was 17 weeks (range 4–187). Ten of 16 (63%) enrolled patients had experienced a ≥50% decline in PSA while on keto. Of the 16 enrolled patients, 11 have completed 12 weeks of therapy, two have completed <12 weeks of therapy and three patients have discontinued therapy (two developed symptomatic progression and one withdrew consent). AA therapy resulted in a confirmed ≥50% decline in PSA at 12 weeks in 3/14 (21%) (95% confidence interval (CI): 5%-51%) and a confirmed ≥30% decline in 6/14 (43%) (95% CI: 18% 71%). Of the pts without a ≥30% PSA decline, one had developed RECIST defined disease progression at 12 weeks and the remainder had stable disease. Grade 3/4 toxicities included hypertension in one patient. Expanded accrual is ongoing. Conclusions: A substantial number of pts with prior ketoconazole exposure respond to AA indicative of the greater CYP 17 inhibition induced by AA and retained CYP 17 dependence in mCRPC. The lower responses observed in this study compared to keto naïve mCRPC suggests the potential for overlapping mechanisms of resistance to AA and keto.