Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients.

Abstract

BackgroundKetoconazole is a well-known CYP-17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had prostate specific antigen (PSA) response rate (greater than 50% decline) of 21% to 62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.MethodsMen with CRPC and performance status (PS) 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg PO three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (greater than 50% reduction from baseline) where a PSA response rate of 25% was to be considered promising for further study (versus a null rate of less than 5%); 25 patients were required. Secondary endpoints included PSA response greater than 30% from baseline, progression-free survival (PFS), duration of stable disease, and evaluation of adverse events (AEs).ResultsThirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng/ml (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the 2 grade 4 AEs was considered related to treatment.ConclusionsIn docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.