Abiraterone acetate is a standard first-line therapy for men with metastatic castration-resistant prostate cancer (CRPC), and is the most common prostate cancer treatment prescribed in the United States. While the standard dose of abiraterone 1000 mg is taken under fasting conditions, early studies indicated a potential increase in drug exposure when abiraterone was administered with food. A prospective phase II noninferiority study (N = 72) compared standard abiraterone (STD) with low-dose abiraterone (250 mg) taken with a low-fat breakfast (LOW) in patients with mCRPC. In addition, abiraterone patients in both arms received prednisone 5 mg twice daily. The primary objective of the study was to compare the antitumor activity of LOW with STD, as assessed by change in serum prostate-specific antigen (PSA).
At 12 weeks, there was a greater PSA effect in the LOW arm (mean log change of -1.59) compared to the STD arm (-1.19), which was sufficient to establish LOW as noninferior at a 90% confidence limit. The PSA response rate was 58% in the LOW arm and 50% in the STD arm. The median progression-free survival was 8.6 months in both arms. There were also similar levels of testosterone decrease in both arms (6.1 µg/dL vs 6.2 µg/dL at end of study). Extragonadal serum androgen (DHEA-S) levels also decreased substantially during treatment and to a similar extent regardless of treatment arm. Pharmacokinetics favored the STD dose of abiraterone, with significantly lower plasma trough concentrations in the LOW arm (2 ng/mL vs 8 ng/mL). Of note, neither arm achieved the trough concentration typically associated with >50% PSA response with abiraterone.
The investigators concluded that these results support the noninferiority of lower-dose abiraterone when given with a low-fat meal, and that this approach should be considered for the future, particularly given the potential for substantial pharmacoeconomic benefit. However, the authors of an accompanying editorial disagreed, arguing that this study failed to sufficiently demonstrate noninferiority of low-dose abiraterone. In particular, the authors felt that the use of log PSA change over 12 weeks as primary endpoint was a failing, given that this is not a clinically validated surrogate endpoint, and use of local PSA testing in place of the preferred central testing makes the noninferiority determination questionable. Additionally, neither treatment arm reached a clinically beneficial concentration of abiraterone, and the PFS of 8.6 months was much lower than 16.5 months observed with abiraterone in the pivotal trial. They suggested investigation of the target abiraterone trough concentration predictive of response and consideration of therapeutic drug monitoring to determine an association among drug dose, plasma concentrations, and response.