Impact of prior ketoconazole therapy on response proportion to abiraterone acetate, a 17-alpha hydroxylase C17,20-lyase inhibitor in castration resistant prostate cancer (CRPC)

Abstract

5018 Background: Abiraterone acetate (AA) is an inhibitor of CYP 17 (17 α hydroxylase and C17,20-Lyase), a dual enzyme responsible for androgen synthesis. The mechanism of action of abiraterone is similar to ketoconazole (keto), which inhibits multiple adrenal CYP enzymes including CYP17, and is also used in CRPC. The impact of prior keto therapy on AA response is examined in this analysis. Methods: Eligibility for this Phase I study required progressive CRPC by consensus criteria and normal organ and adrenal function. Dose escalation was performed in both fasted and fed states at doses of 250, 500, 750 and 1000 mg daily. Patients (pts) were evaluated monthly during therapy. Medical records were reviewed to identify which pts had received prior therapy with keto, whether a PSA decline had been achieved and the duration of therapy on keto. Reasons for discontinuing keto were classified as due to disease progression (PD) or toxicity. Results: 18 of 33 pts (55%) experienced a decline in PSA by >50%. Of 30 pts completing 12 weeks of therapy, 13 (43%) have experienced a decline in PSA by >50%. 6 of 12 (50%) pts treated at the 1000 mg dose (the recommended phase II dose) responded. Of 14 pts who had not received prior keto, 8 (61%) responded to AA. Of the 19 pts previously treated with keto, 10 (53%) experienced a 50% or greater decline in PSA while on AA and the median time to progression for these patients is 21 weeks. 3 of 4 pts who discontinued ketoconazole due to toxicity experienced a PSA decline on AA and 7/15 (47% ) patients who had experienced disease progression on ketoconzole experienced a PSA decline on abiraterone with a median time to progression in these patients is 17 weeks. 16 of 19 pts (84%) had previously experienced a 50% decline in PSA while on ketoconazole, 4 did not. 15/19 (79%) had discontinued keto due to progressive disease and four (21%) had discontinued ketoconazole due to toxicity. The median duration of keto therapy in these 19 patients was 15 months (range 4.2–38 months). Conclusions: Most pts treated with AA had a prior response to keto. AA exhibits anti-tumor activity in CRPC even in pts experiencing PD on keto. Despite overlapping mechanisms of action, responses to AA occur in pts with keto refractory disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cougar Biotechnology