Giving patients with metastatic castration-resistant prostate cancer (CRPC) just one quarter of the normal dose of abiraterone acetate (AA) (Zytiga, Janssen) with food achieves at least as great a reduction in prostate-specific antigen (PSA) levels as the standard dose without food, the results of a prospective, randomized trial reveal.
AA, which is a standard of care in CRPC, was administered under fasting conditions at a dose of 1000 mg during its pivotal trials, despite early clinical studies that showed that drug exposure was significantly increased when the drug was administered with food.
The study included 72 patients with CRPC. The results show that after 12 weeks, giving a quarter dose of AA with a low-fat meal was not only noninferior to the standard dose without food in terms of reducing PSA levels but also that the duration of response was comparable, all at a lower plasma concentration.
The research was published online March 28 in the Journal of Clinical Oncology and was first presented at the 2017 Genitourinary Cancers Symposium.
The team writes: “The pharmacoeconomic implications of this study’s findings are compelling.
“AA has an approximate retail cost of $10,000 per month. With a median time receiving treatment of 16.5 months in metastatic CRPC, the per-patient cost savings with the LOW dosing would exceed $100,000,” they say.
They add: “Given the prevalent paradigm of developing drugs with large food effects under fasting conditions, there are multiple other opportunities to lower drug costs by administration with food.”
Lead author Russell Z. Szmulewitz, MD, assistant professor of medicine at the University of Chicago, in Illinois, told Medscape Medical News, “Our trial provides crucial but not definitive data to support low-dose abiraterone with food.”
Szmulewitz believes this use is appropriate for some patients. “I do not think that physicians should use it indiscriminately without a more robust trial with clinically validated endpoints,” he said. “However, for cases in which patients have cost issues, it is now reasonable for physicians to discuss the option with those patients, which is what I do in my practice.”
A larger clinical trial in castration-sensitive metastatic prostate cancer is in the planning stages.
Janssen Says Stick to the Labeling
In the current trial, the team randomly assigned 72 patients with progressive CRPC to receive either low-dose AA (250 mg with a low-fat meal) or standard AA (1000 mg during fasting) along with prednisone 5 mg twice daily.
The patients, who were from seven institutions in the United States and Singapore, were well balanced and typical of a standard CRPC population. The median age was around 73 years, and the patients’ ECOG (Eastern Cooperative Oncology Group) status was 0 or 1. The only difference was that there were more African Americans in the low-dose AA group, at 31% vs 14% in the standard arm.
PSA levels were assessed monthly. Every 12 weeks, testosterone/dehydroepiandrosterone sulfate (DHEA-S) levels were determined, and disease burden was assessed radiographically. Drug concentrations were calculated from plasma samples.
There was a greater reduction in PSA levels from baseline to week 12 with low-dose AA, at a mean log change of -1.59 vs -1.19 in the standard dose group. These findings established the noninferiority of low-dose AA on predefined criteria.
At 12 weeks, three (9%) standard-dose AA patients experienced primary PSA progression, vs one (3%) patient in the low-dose AA group.
The absolute PSA response rate at 12 weeks was 58% in the low-dose arm and 50% in the standard-dose arm. The duration of response was comparable, at a median progression-free survival of 8.6 months in both arms.
The low-dose intervention yielded changes in androgen levels that were similar to the standard dose; at the end of the study, DHEA-S concentrations were 10.2 µg/dL and 9.1 µg/dL, respectively.
The team found that the maximum plasma concentrations of AA were higher in the standard-dose group than in the low-dose group (P = .012).
Approached for comment, Daniel M. Geynisman, MD, assistant professor in the Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News that the study was “important” and “well-designed.”
He said: “Abiraterone is an extremely commonly used drug in men with metastatic prostrate cancer, and it is a very expensive drug, costing thousands of dollars a month.”
The investigators revealed that “exposure of the drug can be increased significantly if it’s given, instead of on an empty stomach as it’s normally prescribed and approved, but rather with food,” Geynisman said.
The low-dose treatment is now “an important option” for some clinicians and their patients, who will have “seemingly with very similar results.”
In circumstances “where cost and access to drugs are an issue…paying for 25% of the drug is a huge deal,” he added.
Geynisman also noted caveats: the trial was small, and the endpoint of PSA levels at 3 months is not standard.
He explained: “You look for things like progression-free survival or radiologic progression or overall survival. This is sort of an intermediary endpoint. It’s not as hard of an endpoint as the others, and so one could question whether or not they’ve really proven noninferiority.
“But at the same time we know that PSA is great surrogate for all the other endpoints in prostate cancer, and so it’s reasonable to assume that it is,” he added.
The new results will not change practice widely, although they will give clinicians “some wiggle room,” he said.
Crucially, Geynisman warned that although it is possible that a similar food effect could be seen for other oncology drugs, it is not a given.
He said that, instead, it’s going to be “drug dependent, and you have to take it on a case-by-case basis.
“I certainly wouldn’t use these results to translate that to any other medication in oncology,” he said.
Geynisman added, however, that in general, the study “does open the door to the question of how drugs get approved and how they are evaluated.”
In a statement, Janssen said that AA should be taken, in accordance with the prescribing information, “on an empty stomach.”
It warns that taking AA with food “may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects.” It noted that “the use of food as a way to increase bioavailability in patients with cancer could present problems and risks.”
The company said that “given the variation in the content and composition of meals, the recommendation is to take [AA] exactly as described in the prescribing information.”
The research received institutional funding from OncoTherapy Science and Dicerna. The original article contains a complete listing of the authors’ relevant financial relationships.
J Clin Oncol. Published online March 28, 2018. Full text
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