A prospective international randomized phase II study evaluating the food effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC).

Abstract

176 Background: AA is a standard of care for the treatment of metastatic CRPC, with an approximate retail cost of $8000/month. Despite a large food effect (~17-fold increase in CMax with a high-fat meal), AA was administered under fasting conditions in its pivotal trials. There are no randomized continuous dosing studies examining prandial state dosing on AA PK/PD. We sought to test the hypothesis that LOW (250mg w/food) would have similar PK/PD and safety to standard (STD, 1000mg fasting) in patients with progressive CRPC. Methods: Patients (n = 72) with progressive CRPC from seven institutions in the US and Singapore were randomized to treatment with STD or LOW (with low-fat breakfast). Both arms received prednisone 5mg twice daily. PSA was assessed monthly, and testosterone, DHEA/DHEAS were assessed every 12 weeks along with standard disease burden assessments. PK samples were collected at day 1, 8 and months 2, 3, 4. Log change in PSA response rate from baseline to week 12 was examined as the primary endpoint, with a non-inferiority design based on a non-inferiority margin of 15%. This margin corresponds to a 0.51 standard deviation (SD) difference in the mean log changes between the groups. Results: Accrual was completed with n = 36 on STD and n = 36 on LOW. Median (range) age was 74 (52-89) and baseline PSA was 39.2(range 0.6-1789). Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). The 95% confidence for the difference (STD-LOW) ranged from -0.40 to 1.19, with lower limit corresponding to -0.24SD. Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms (p = 0.53). Preliminary analysis of PK showed no difference in CMaxbeyond the first cycle with lower PK variability in the LOW arm. Conclusions: Low-dose (250mg/day) abiraterone acetate with a low-fat breakfast is non-inferior to standard dosing in a fasted state with respect to PSA and PK metrics. Although PSA response and progression are not clinically validated surrogates, given the pharmacoeconomic implications, these data warrant consideration by prescribers and payors. Clinical trial information: NCT01543776.