Low-dose Zytiga (abiraterone acetate) with a low-fat breakfast as effective as full dose on an empty stomach, study finds

A small randomized Phase II study for men with progressive castrate-resistant prostate cancer has tested the effects of taking one-fourth the standard dose of Zytiga (abiraterone acetate) after a low-fat breakfast instead of standard dose on an empty stomach.

Taking one-fourth the standard dose with a low-fat breakfast, the study found, can be as effective – and four times less expensive – as taking the standard dose as recommended: on an empty stomach. The finding has significant financial implications.

Abiraterone acetate is a standard treatment for metastatic CRPC. Retail cost is about $8000 per month.

A group of doctors led by Russell Szmulewitz, MD, assistant professor of medicine at the University of Chicago and a specialist in medical treatment of patients with advanced prostate cancer, observed that "despite a large food effect (about a 17-fold increase in CMax with a high-fat meal), abiraterone acetate was administered under fasting conditions in its pivotal trials."

CMax refers to the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose.

The standard drug label and drug maker's website warn patients:

Take ZYTIGA® on an empty stomach. Do not take ZYTIGA® with food. Taking ZYTIGA® with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects.
No food should be eaten 2 hours before and 1 hour after taking ZYTIGA®.

Dr. Szmulewitz and his team were struck by the fact that this standard prescription warning had never been tested on men with advanced prostate cancer. "There are," the trial team writes "no randomized continuous dosing studies" examining the effect of the patient's food-related state on the pharmacokinetics (PK) and pharmacodynamics (PD) of Zytiga.

Going back to square one, Dr. Szmulewitz and his team ran a Phase II trial, which took place in seven hospitals in the USA and Singapore. "We sought to test the hypothesis that LOW (250 milligrams w/food) would have similar PK/PD and safety to standard (STD, 1000 milligrams fasting) in patients with progressive CRPC."

The trial randomized 36 patients with progressive CRPC into 2 arms (standard dose fasting versus LOW dose with low-fat breakfast). Patient ages ranged from 52-89; median age 74.

Methods

"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

"Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). . . . Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms." Preliminary analysis showed "no difference in CMax beyond 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."

"We know this drug is absorbed much more efficiently when taken with food," Dr. Szmulewitz said. "It's inefficient, even wasteful, to take this medicine while fasting, which is how the drug's label says to take it."

"Given the pharmaco-economic implications," he added, "our results warrant consideration by doctors who care for prostate cancer patients as well as payers."

The researchers note the small number of participants in their study as a limitation and warned that patients with prostate cancer should not begin experimenting with their medication.

“This was a relatively small study, too small to show with confidence that the lower dose is as effective,” Szmulewitz said. “It gives us preliminary, but far from definitive, evidence. Physicians should use their discretion, based on patient needs.”

SOURCES:
ASCO http://meetinglibrary.asco.org/content/179146-197
University of Chicago Medical Center
Russell Szmulewitz, MD