Prospective International Randomized Phase II Study of Low-Dose Abiraterone With Food Versus Standard Dose Abiraterone In Castration-Resistant Prostate Cancer

Abstract

Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% reduction), change in androgen levels, and pharmacokinetics were secondary end points. Results Thirty-six patients were accrued to both arms. At 12 weeks, there was a greater effect on PSA in the LOW arm (mean log change, -1.59) compared with STD (-1.19), and noninferiority of LOW was established according to predefined criteria. The PSA response rate was 58% in LOW and 50% in STD, and the median PFS was approximately 9 months in both groups. Androgen levels decreased similarly in both arms. Although there was no difference in PSA response or PFS, abiraterone concentrations were higher in STD. Conclusion Low-dose AA (with low-fat breakfast) is noninferior to standard dosing with respect to PSA metrics. Given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers, and patients. Additional studies are indicated to assess the long-term efficacy of this approach.

Trial registration: ClinicalTrials.gov NCT01543776.

Figures

Fig 1.

CONSORT diagram. LOW, 250 mg abiraterone acetate with a low-fat meal; STD, standard dose of 1,000 mg abiraterone acetate fasting.

Fig 2.

Decrease in prostate-specific antigen (PSA) while receiving treatment. Waterfall plot showing percent reduction in PSA at (A) landmark 12-week time point and (B) maximum nadir. Patients whose best PSA response was progression are denoted with (*). LOW, 250 mg abiraterone acetate with a low-fat meal; STD, 1,000 mg abiraterone acetate fasting

Fig 3.

Prostate-specific antigen (PSA) progression. Kaplan-Meier plot of time to progression while receiving 250 mg abiraterone acetate with a low-fat meal (LOW) or standard dose of 1,000 mg abiraterone acetate fasting (STD), showing a median progression-free survival of 8.6 months in both arms (log-rank P = .38).

Fig 4.

Abiraterone drug levels. (A) The abiraterone trough drug concentration (Cmin) was higher in the standard dose of 1,000 mg abiraterone acetate fasting (STD) arm compared with the 250 mg abiraterone acetate with a low-fat meal (LOW) arm (P < .001). (B) There was no correlation between abiraterone Cmin and change in prostate-specific antigen (PSA; P = .37).

Fig 5.

Effect of dehydroepiandrosterone-sulfate (DHEA-S) levels on treatment. DHEA-S levels decreased substantially and to a similar extent regardless of treatment arm. C4, cycle 4; LOW, 250 mg abiraterone acetate with a low-fat meal; STD, standard dose of 1,000 mg abiraterone acetate fasting.

Fig A1.

Distribution of log PSA changes. A. Statistical assumption of normal distribution curves for STD (left) and LOW (Arm). B. Normal probability plot for STD arm. C. Normal probability plot for LOW arm.

Fig A2.

Abiraterone drug concentrations. Abiraterone Cmax (A) and 2 hour post treatment drug levels (B) were higher in STD compared to LOW arms. (C) There was no significant difference in likelihood of PSA response based on AA trough concentration (p=0.11) irrespective of treatment arm (LOW, triangle; STD, circle).