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Low-fat meal enhances efficacy of reduced-dose abiraterone for prostate cancer

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March 28, 2018

Russell Z. Szmulewitz

Administration of low-dose abiraterone acetate with a low-fat meal demonstrated comparable activity to standard treatment for men with metastatic castration-resistant prostate cancer, according to results of a randomized controlled trial.

A lower dose also reduced costs — with savings estimated to reach as high as $300,000 per patient — and prevented digestive issues.

“The patient gets a simplified schedule, slightly more control over his daily life, the convenience of eating whenever he chooses and the opportunity to share the cost-savings with his insurance company,” Russell Z. Szmulewitz, MD, associate professor of medicine at The University of Chicago, said in a press release. “Taking this medicine while fasting is wasteful.”

Standard treatment for metastatic castration-resistance prostate cancer is 1,000 mg oral abiraterone acetate (Zytiga, Janssen) — four 250-mg pills — once daily with 5 mg prednisone while fasting.

Previous research showed more than 70,000 claims were filed through Medicare Part D in 1 year related to prescriptions of abiraterone acetate, which indicated it is used frequently as first-line medication by this patient population.

Other research indicated that when administered with food, drug exposure of abiraterone acetate increased compared with the fasting method. The drug label also indicates drug concentration increases five- to sevenfold if taken with a low-fat meal, the researchers wrote.

However, Szmulewitz and colleagues hypothesized that a lower dose of abiraterone acetate combined with a small meal would confer a similar effect as standard treatment and further improve patient quality of life while lowering costs.

“[The current] schedule is not only inconvenient for patients, it’s also wasteful, in several ways,” Szmulewitz said.

Researchers randomly assigned 72 patients with progressive disease from six clinical sites across the United States and Singapore to standard treatment (n = 36) or 250 mg abiraterone acetate with a low-fat meal (n = 36). Both arms also received 5 mg prednisone twice daily.

Researchers excluded patients who received prior therapy with abiraterone acetate, enzalutamide (Xtandi; Astellas, Medivation) or other potent targeted therapies.

Patients in the standard-dose arm received 1,000 mg abiraterone acetate in early morning after an overnight fast of at least 8 hours and a minimum 2 hours prior to any food intake.

Patients in the low-dose abiraterone acetate arm received treatment concomitantly or within 20 minutes of a low-fat breakfast. Researchers advised patients to avoid high-fat foods, including sausage and bacon.

Change in serum PSA served as the primary endpoint. Secondary endpoints included PFS, minimum 50% reduction in PSA, change in androgen levels and pharmacokinetics.

Final analysis included 34 patients in each arm who received treatment per protocol.

At 12 weeks, patients in the low-dose arm had higher reduction of PSA than the standard-dose arm (mean log-change, –1.59 vs. –1.19), for a pooled standard deviation of 1.62.

The upper one-sided 90% confidence limit for the difference between the two arms was 0.11 (standard deviation, 0.068), which met the predefined criteria for noninferiority of the low-dose regimen, the researchers noted.

PSA response rate was 58% in the low-dose arm and 50% in the standard-treatment arm. The lower one-sided 90% confidence limit for the difference between the two arms in PSA response was –7%, which indicated that the low-dose regimen was, at most, 7% worse than standard treatment.

Median PFS was 8.6 months for both arms. Androgen levels decreased similarly in both arms.

Although abiraterone acetate concentrations were higher in the standard-treatment arm, researchers observed no significant differences in PSA or PFS, indicating no clear association between drug concentration and efficacy.

More patients from the low-dose arm experienced grade 3 or higher adverse events (32.4% vs. 17.6%); however, this difference was not statistically significant.

Median time of 16.5 months on low-dose treatment — at an average cost of $10,000 per month — would confer a per-patient cost savings of more than $100,000. With median PFS estimates of 33 to 44 months observed among patients with metastatic castration-sensitive prostate cancer, per-patient savings could exceed $300,000, according to the researchers.

“Although it should be validated with a larger trial with more robust clinical endpoints, given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers and patients,” Szmulewitz said. – by Melinda Stevens

Disclosure: Szmulewitz reports consulting/advisory roles with AbbVie, Amgen, AstraZeneca, Exelixis and Merck; research funding from AbbVie, Astellas Pharma, Incyte, Janssen Oncology and Macrogenics; a patent licensed by University of Chicago to Corcept Therapeutics for combination AR/GR inhibition in prostate cancer; and travel, accommodations or expenses from Corcept Therapeutics. Please see the full study for all other author’s relevant financial disclosures.

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The study by Szmulewitz and colleagues and accompanying editorial by Kolesar and Liu, leave this reviewer with a question: Eggs, sausage and abiraterone — what’s a doctor to do?

The randomized trial met the noninferiority endpoint: Abiraterone 250 mg once daily with a low-fat meal — described as no sausage, bacon or deep-fried foods, etc — is noninferior with respect to log change in PSA response and appears similar in pharmacodynamic response, measured by reduction of testosterone and DHEA-S, to a 1,000-mg once daily dose taken while fasting. However, a measure of pharmacokinetic response — trough concentration — strongly favored the fasting/standard dose.

Kolesar and Liu disagree. They were not pleased by the lack of validation of the response endpoint and the response measurement — community measurement of PSA — and pointed to the pharmacokinetic “inferiority” of 250 mg with a low-fat meal. They also drew attention to the literature that indicates that enhancement of abiraterone by food may be much more pronounced among normal volunteers than men with prostate cancer.

The refuge of the clinical scientist is: “We need to do more studies.” But, what’s a doctor to do? Food does appear to enhance the absorption of the available abiraterone formulation, but does it enhance it enough? While further studies are being done, for those patients in whom acquisition of abiraterone is prohibitively costly because of the vagaries of their insurance or lack thereof, one can easily rationalize 250 mg once daily abiraterone with a high-fat meal — eggs, sausage and abiraterone — compared with not using abiraterone at all.

A new formulation of abiraterone, DRGT-45 (DRGT), is under development, and its absorption is reported to be better, but among normal volunteers! Trials among men with prostate cancer are beginning. Clinical availability seems some time away. If past experience is any predictor of future performance, I would not bet on Kolesar and Liu’s hope that DRGT-45 will be priced more reasonably.

In the meantime, for highly selected patients, eggs, sausage and 250 mg daily abiraterone with careful monitoring is a consideration.

Donald L. Trump, MD

HemOnc Today Editorial Board Member

Inova Schar Cancer Institute

Disclosure: Trump reports no relevant financial disclosures.