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.

The Effect of Using Pazopanib With Food vs. Fasted on Pharmacokinetics, Patient Safety, and Preference (DIET Study)

“…Many of these oral oncolytic agents have a proven food effect and an alternative dosing strategy could be interesting to investigate . However, only two other oncolytic agents with an alternative dosing strategy combined with food has been studied (e.g., abiraterone and ceritinib) . Even more, the bioequivalence study performed on the reduced dose of ceritinib with a meal resulted in an adjustment of the drug's registration label even before the safety data were known .…”

“…9 However, only two other oncolytic agents with an alternative dosing strategy combined with food has been studied (e.g., abiraterone and ceritinib). 7,10 Even more, the bioequivalence study performed on the reduced dose of ceritinib with a meal resulted in an adjustment of the drug's registration label even before the safety data were known. 11 Our study aimed to complement the bioequivalent results with GI-toxicity data and patient preference, which results in a more complete understanding of the advantages of the altered intake regimen in patients with cancer.…”

Prostate Cancer, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology

“…Abiraterone with prednisone can be given at 250 mg/day and administered following a low-fat breakfast, as an alternative to the dose of 1,000 mg/day after an overnight fast (see "Abiraterone Acetate in M1 CRPC," page 493). 165 The cost saving may reduce financial toxicity and improve compliance.…”

“…A randomized phase 2 noninferiority study of 75 patients with M1 CRPC compared 1,000 mg/day abiraterone with prednisone after an overnight fast with 250 mg/day after a low-fat breakfast. 165 The primary endpoint was log change in PSA, with secondary endpoints of PSA response ($ 50%) and PFS. The primary endpoint favored the low-dose arm (log change in PSA, 21.59 vs 21.19), as did the PSA response rate (58% vs 50%), with an equal PFS of 9 months in both arms.…”

Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations

“…In fact, recent work suggests that aggressive treatment strategies can hasten the emergence and spread of resistance [30][31][32][33][34][35][36][37][38][39][40][41]. In addition, numerous studies, both experimental and theoretical, provide evidence that less aggressive treatment strategies may be called for under some conditions [42][43][44][45][46][47][48][49][50], while several clinical trials have also demonstrated advantages of lower dose therapies [50][51][52][53][54][55][56][57][58]. The most frequently cited advantages of less aggressive therapies are reduced off-target selection for resistance and fewer adverse effects for the patient.…”