We have known for some time that taking abiraterone acetate (Zytiga) with food (as opposed to on an empty stomach) might well allow patients to be able to take significantly lower doses of this product and gain the same clinical benefit as is currently known to be beneficial from taking 1,000 mg/day when fasting.
The results of a randomized Phase II clinical trial designed to test this hypothesis have just been published in the Journal of Clinical Oncology by Szmulewitz et al.
This was a small, pilot study that enrolled just 72 patients with progressive, castration-resistant prostate cancer (CRPC) at eight different institutions (seven here in the US and one in Singapore).
The patients were randomized to one or other of two groups:
- Treatment with low-dose abiraterone acetate (250 mg/day) with a low-fat meal
- Treatment with a standard dose of abiraterone acetate (1,000 mg/day) while fasting
All patients also received prednisone (5 mg twice daily).
Here are the core results of the trial:
- 36 patients were accrued to each arm of the study.
- At 12 weeks of follow-up, the PSA response was
- 58 percent in the low dose + food arm
- 50 percent in the standard dose arm
- Also at 12 weeks of follow-up, the average (mean) log changes in PSA levels were
- –1.59 in the low dose + food arm
- –1.19 in the standard dose arm
- The non-inferiority of the low dose + food was established compared to the standard dose according to predefined criteria.
- The average (median) progression-free survival (PFS) of the patients was approximately 9 months in each of the two groups.
- Androgen levels decreased similarly in both arms.
- Despite the lack of difference in PSA response or PFS, abiraterone concentrations were higher in the standard dose arm.
The research group concluded that:
Low-dose [abiraterone acetate] (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.
On the basis of these data, The “New” Prostate Cancer InfoLink would similarly conclude that larger studies should be implemented as fast as possible to confirm this set of data. It is also a possibility that a lower dose of abiraterone acetate with food might permit a lower dose of prednisone (e.g., 2.5 mg twice a day), but this would also need careful evaluation before it was to be clinically implemented.
It is possible that some physicians will be willing to alter the dosing of abiraterone acetate for their patients on the basis of this early data. The cost implications for individual patients (not to mention for payers) are very significant.
Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: abiraterone, dose, food, low, standard, with, without |
THE "NEW" PROSTATE CANCER INFOLINK 
AS SItemaster points out, this is the second small population trial pointing out the food effect .
What will it take to do a large trial? Clearly Janssen has little or no incentive. The drug is expensive — about $10,000/month in the USA; adding up the cost for a trial of several hundred men is prohibitive! Surely it is in the best interests if the insurance provides to step up to the financial plate.
It is worth pointing out that there was an earlier randomized trial that found a similar effect with a high fat meal.
To address whether plasma abiraterone levels got higher with a high-fat meal or a low-fat meal, there was a small (n = 36) randomized study that compared them. They found that, “In mCRPC patients, abiraterone [plasma levels] was two-fold higher with a high‐fat meal and similar with a low‐fat meal versus modified fasting state.”
So if you’re going to do this (under doctor supervision), you might get an equivalent effect from taking 250 mg abiraterone with a high-fat meal as from 500 mg with a low-fat meal. I expect there are individual variations, so this should not be done without close monitoring.
I congratulate the team for an exciting study. But it is not sufficient to make a new recommendation for standard dose abiratrone.
There is a question of compliance. How was the check of the patients really took all drugs all days as prescribed?
How was the decline of testosterone with the two dose levels of abiraterone?
And how are the long term effects as today abiraterone might be used early in the sequence of treatment. The difference in PSA change might only be seen later.
Also the endpoint was change of PSA. How will the effect be on other outcome points like PSA progression-free survival, metastasis-free survival and prostate cancer-specific survival.
Most likely the study was not made by big pharma.
So the study has wide implications for trials generating recommendations for guidelines that are not generated by big pharma.
I believe it’s unlikely that a lower dose of abiraterone acetate will allow for a lower dose of prednisone since the lower dose taken with food is enabling greater bioavailability and hence somewhat equivalent blood levels of abiraterone acetate. In any case, the low doses of prednisone taken with abiraterone acetate are generally not associated with the adverse effects of higher doses used for other medical conditions (autoimmune and inflammatory) which could result in osteoporosis, hypertension, diabetes, etc.
Dear Len:
The reason I raised the issue of whether a lower does of prednisone might be possible with a lower dose of abiraterone taken with food is twofold.
First, in this study, the systemic abiraterone levels in plasma were lower for the men taking the lower dose.
Second, historically, most men have only been on abiraterone for a few months to a year or so. With the data from the LATITUDE trial, men could be and will be on abiraterone for 2 years or more. I can assure you that if you are on even 10 mg/day of prednisone then the long-term side effects of corticosteroid therapy become a problem for a lot of patients because they build up over time. This issue was immediately brought up by the rapporteur who commented on the findings of the LATITUDE trial the day the data were presented at ASCO last year.