Long-term use of abiraterone acetate at 250 mg/d: is this really viable?


It has been suggested that, after an initial “loading dose” for a period of time, abiraterone acetate could potentially be used to treat metastatic, castration-resistant prostate cancer (mCRPC) at a much lower daily maintenance dose than that currently approved.

In two messages left on this site (on February 2 and on February 4, 2012), Prof. Gerry Potter (one of the original developers of abiraterone acetate) has stated his opinion that, after initial treatment with a “loading dose” of abiraterone acetate at 1,000 mg/d for a period of 1 month, many patients could potentially be managed with a much lower daily (maintenance) dose of this agent at just 250 mg/d.

We have the greatest respect for Dr. Potter as a medicinal chemist, and we feel very sure that his opinion is based on data available to him that gives him confidence in this clinical strategy … but, we feel it is important to note the following:

  • We know of no large-scale clinical trial that has ever tested this concept in men with metastatic prostate cancer.
  • No completed, ongoing, or proposed trial of abiraterone acetate currently listed on the ClinicalTrials.gov web site has tested or appears to be designed to test this concept.
  • The currently approved dose of abiraterone acetate (in the treatment of men with mCRPC who have previously received at least one cycle of docetaxel-based chemotherapy, in both the USA and Europe) is four 250 mg tablets of abiraterone acetate once daily for a total daily dose of 1,000 mg/d — in combination with prednisone at a dose of 5 mg twice daily.
  • Dr. Potter is not a physician, and he does not treat patients with prostate cancer. He is a medicinal chemist with considerable experience in the development of therapeutic agents for the treatment of cancer and other disorders.

Having carefully stated these facts, we have to say that the concept presented by Dr. Potter is intriguing. Abiraterone acetate at a dose of 250 mg/d was tested clinically in a very small number of patients in Phase I trials, and data on the pharmacokinetics of this dose level were reported by Ryan et al. in 2010. It was the lowest dose of the drug used in these early stage trials and may well have significant clinical activity after an appropriate loading dose.

However, we really have no idea whether such a clinical strategy would have the same level of effectiveness as the currently recommended and approved dose of abiraterone. It also seems unlikely that the manufacturer of abiraterone would be interested in testing such a concept. This does not, of course, mean that others could not implement a clinical trial to test the concept; after all, maintenance with a lower dose of abiraterone might impact any cumulative side effects of this agent and would most certainly impact the cost of treatment with this drug over time. One also has to ask whether use of such a maintenance dose level of abiraterone acetate could be associated with a reduction in the daily dose of predisone (which would reduce the impact of the side effects of corticosteroid therapy as well).

We wish to be extremely clear that The “New” Prostate Cancer InfoLink is not recommending (and is in no position to recommend) the use of abiraterone acetate at anything other than the dose approved by regulatory authorities in the USA and Europe. We are merely responding to the suggestion made previously by Prof. Potter.

17 Responses

  1. Your comments are perfect! Any doctor prescribing a lower dose of the drug would be subject to liability issues in the event a patient did not do well, so it is highly unlikely that the lower dose will ever be an issue. One wonders, however, whether testing a lower dose in men with a rising PSA without metastases would be worthwhile.

  2. HOW ABOUT BIOMARKERS TO MONITOR CONTINUED FAVORABLE RESPONSE AT LOWER DOSE, PRESCRIBED “OFF-LABEL”?

    I’m viewing this issue from a different perspective, based on my own experience as a 13-year survivor of a challenging case of prostate cancer treated to date only with intermittent triple androgen deprivation therapy (ADT) and supporting drugs plus lifestyle tactics, much of this based on “off-label” prescriptions that many doctors worry about.

    Could this question whether a reduced dose would be effective be resolved by appropriate biomarker monitoring? (This is [or should be!] standard with the therapy I’m on, which has key points in common with abiraterone therapy.)

    What biomarkers are recommended on the abiraterone label? Monitoring PSA is probably a given (probably with an ultrasensitive test for lower PSA levels), so I’ll leave PSA monitoring aside for now. I’m thinking that testosterone should be monitored, at the least (unless it is proven that abiraterone is virtually 100% effective in reducing testosterone to < 20 ng/dl). While testosterone is commonly seen in the medical community as a fuel for prostate cancer, many oncologists are convinced that DHT (dihydrotestosterone) is a far more potent fuel and one that for some of us does not decline sharply even when testicular testosterone is greatly reduced, thereby enabling continued fueling of the cancer. Therefore, monitoring DHT would also seem appropriate. Perhaps, especially in mCRPC patients, other markers would also be appropriate (perhaps CTC, PAP, CEA, NEA, CGA, others?). Emerging imaging may also be useful, such as the Na18F PET scan for bone metastases and one of the emerging scans for nodes and other soft tissue metastases.

    I'm visualizing such an approach this way … assuming that just PSA, testosterone, and DHT would need monitoring for the sake of this example. Biomarkers would be checked before and after the approved dose of abiraterone. Once a satisfactory response had been obtained, the dose would be reduced, and biomarkers would be monitored to make sure they did not reflect weakening in the control of the cancer. If they did, the dose of abiraterone could be adjusted. This is a common tactic for dose adjustment of many drugs, and it would seem suitable in the case of abiraterone, setting aside the litigation issue for the moment.

    Such an approach would be similar to what is done with well-managed ADT. I've learned that about 10% of men do not respond adequately, due to delivery or personal biology issues, to the standard doses of LHRH agonists, with testosterone of 20 ng/dl or higher judged too high unless the PSA is behaving as desired. One solution I've learned about is shortening the dosing interval. Another issue with ADT is the dose of the antiandrogen. While there is some disagreement among the physicians using ADT3, whose views I follow, in general it seems that a dose of 50 mg of Casodex/bicalutamide (the generally preferred antiandrogen) is often sufficient for men without detectable metastasis; for men with detectable metastasis, 150 mg seems to be standard, with at least one doctor sometimes using even higher doses. If testosterone is below 20 ng/dl, but the PSA is not dropping fast or far enough, the dose of the antiandrogen may be increased. Similarly, if DHT is not falling sharply, achieving a level less than 5 ng/dl (in one doctor's view), a 5-alpha-reductase inhibitor (finasteride [Proscar] or dutasteride [Avodart]) will likely be used. In my case, with a DHT of 11 ng/dl late in my third vacation period, I recently was shifted from two finasteride tablets per day (total: 10 mg) to one Avodart tablet , which cut the DHT by more than half.

    It is unfortunate that the liability issue so influences medical practice, and as a survivor I dearly hope political leaders will appreciate the impact and work out a solution. However, until that happens, I personally will look for doctors who make wise and prudent use of "off-label" prescription procedures. Key elements as I understand them are that there must be a reasonable medical rationale and communication of possible risks and benefits to the patient. In other words, the patient shoulders an appropriate portion of the risk. A number of the drugs for my care have been so prescribed, including, for example, finasteride, Avodart, and thalidomide.

    While a formal Phase III study, ideally (from a scientific standpoint, not necessarily a patient's standpoint) a large and sufficently long, randomized, double-blind, placebo-controlled, one, would probably settle the issue, there are obstacles, such as opposing motivation for the drug manufacturer, as Sitemaster noted. Indeed, such obstacles appear to have been key to scuttling a proposed trial of ADT3 in the late 1990s. In the meantime, I hope that some physicians, at the request of patients, will make wise and prudent use of off-label prescription procedures to try the lower dose proposed by Prof. Potter, with careful monitoring of biomarkers. I suspect that is already happening. If it does happen, I'm hopeful that some of those doctors will carefully track results and share them via published papers.

    It would be nice if we patients, scientists, and physicians could wait until that day comes when all the science lines up perfectly and clear guidelines are published. However, patients with challenging cases, like me and the mCRPC patients, often lack the luxury of time!

  3. No particular comment other than both Sitemaster’s and Jim’s comments are well explained. With the cost of abiraterone/Zytiga at four 250 mg tablets daily somewhat prohibitive and this protocol apparently lasting somewhere between six and eight weeks before ending and then monitoring continuing results, the subsequent prescribing of Zytiga/abiraterone at a lower dose and monitored for continued effectiveness appears to be to be a reasonable “maintenance” protocol.

  4. I think oncologists are more flexible with the abiraterone dose than many might realize. My dad is prescribed 500 mg a day WITH food as opposed to 1,000 mg a day in a fasting state. The rational is taking the medication with food will induce more absorption of the drug; at least equivalent as the dose tested in the clinical trial in a fasting state. Its common sense people, and this drug is expensive. For half the price, his PSA has dropped 80% after 2 months of treatment.

  5. For what is worth … I know a patient that was on the 1000 mg dose for 2 months. He had a PSA reduction response of 95% (10.5 to 0.5 ng/ml). At that point he reduced the dose (on his own) to 500 mg. Now with PSA trending down (0.2) he is contemplating going to 250 mg/day. This patient has used ketoconazole before and was able to titrate the dose to fit his need. Now he is doing the same while saving mega $$$s. This fits with Dr. Potter’s advice.

  6. Dear Tom:

    There is a reason that it is recommended that abiraterone acetate not be taken with food. I quote from the instructions to 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.”

    It is certainly possible that by cutting the dose to 500 mg/d one may be able to avoid the risk of excessive side effects, but there are no data to support such a clinical strategy, and there are therefore unknown risks associated with this strategy. “Common sense” may have great value under appropriate circumstances, but not everything that appears to make “common sense” is necessarily sensible in retrospect.

    Over the years, clinicians have done all sorts of things that appeared at the time (at least to the physicians concerned) to make “common sense” (e.g., “cupping,” deliberate bleeding of patients, treatment with arsenic and mercury, I could go on for hours). There are a whole host of such “common sense” treatments that we would consider to be horrifically bad medical practice today.

    Obviously I am pleased to hear that this strategy is working for your father to date … but please beware of generalizations.

  7. This discussion has raised another question and that is, “Can abiraterone be taken with food?”

    This is a somewhat controversial area, so I will give my opinion as a pharmacologist rather than as a doctor.

    The manufacturer’s prescribing instructions for abiraterone (see section 5.4, Food Effect) state clearly that it should not be taken with food:

    “ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.”

    This is because the clinical data for this disease indication has been conducted at a dose of 1 g daily taken without food.

    It is worth re-stating the fact that abiraterone is an exceedingly potent drug, so that it has always surprised me when such high doses (1 gram) of abiraterone acetate are used. Abiraterone is five times more potent than letrozole (Femera), an aromatase inhibitor used to treat breast cancer, which is taken at a daily dose of 20 mg. So why isn’t abiraterone taken at a dose of 20 mg. The main reason is the poor uptake of abiraterone acetate in the un-fed state. Abiraterone acetate has been specially formulated as the acetate to help increase intestinal absorption and bioavailability through absorption by digestion. Without food digestion, there is poor absorption. The main reason for such high doses is therefore due to the very poor absorption of abiraterone acetate by the intestine in the un-fed state. Given on an empty stomach, only about 5% of abiraterone is absorbed by the intestine, so for a 1 g (1000 mg) dose only about 50 mg is absorbed and the remaining 950 mg is excreted. What a waste of drug when 95% is excreted. It would make far better sense if the absorption of the drug can be increased somehow, as is found when the drug is taken with food. Abiraterone was designed as an orally active drug, and as such was designed to be absorbed with food. When abiraterone is taken with food, the absorption increases dramatically — by 10-fold. The area under the curve (AUC) exposure is a measure of the volume of the drug absorbed into the bloodstream and this increased 10-fold when abiraterone was administered with a meal. So it is important to realise that the concentration of abiraterone in the body increases 10-fold when taken with food. In this way a 100 mg dose will deliver the same amount of drug as a 1000 mg dose without food. This means a dose as low as 100 mg could be taken with food to deliver the same pharmacological effect as 1000 mg without food.

    Since it appears that some clinicians are already administering abiraterone with food, it should be borne in mind that a single tablet dose of 250 mg taken with food will deliver 2.5 times more drug than 4 tablets taken without food.

  8. Thanks Dr. Potter. This is very helpful for people.

  9. I have been on a Zytiga/prednisone regime for almost 2 months now. The treatment seems to be having little or no effect and my PSA continues to rise. Admittedly I have a very aggressive PCa (Gleason 10, Stage IV mCRPC).

    I would be very interested in trying smaller doses, say 250 mg taken with food and will approach my oncologist about this at our next meeting. I have little hope that he will go along with this because of the general reluctance of physicians to expose themselves to litigation. So if he opposes the idea, I believe I will experiment on my own with reduced dosage plus food. I believe I have very little to lose by doing so. The advanced state of my disease leaves me very few options to explore. Thank you Dr. Potter for your information. That and some of the testimony of readers will help me make a final decision.

  10. Dear Frank:

    There does appear to be some variation in how long it can take the effects of abiraterone acetate to “kick in” for individual patients. Regardless of what you and your oncologist do (or don’t) agree to do about the dose level, let’s hope that you start to see a drop in your PSA level some time in the next 30 days or so.

  11. I have been on abiraterone for about 6 months, after docetaxel made me feel really rotten. I feel great, but my PSA has risen from 10 to 350 ng/ml, so my consultant has decided I should switch to MDV3100 [enzalutamide] in the next few weeks.

    For the record, it is 11 years since I was diagnosed (Gleason 8+), and 10 years since I had brachytherapy followed by radiotherapy. I am starting to feel that my luck is running out … but 10 years of very good quality of life is something to be very grateful to my medics for.

  12. And you could still respond well to enzalutamide (MDV3100) and other therapies that are still in the pipeline David, so don’t get ready to throw in the towel yet!

  13. No chance of that, Sitemaster!

    After Casodex, Zoladex, diethylstilbesterone, brachytherapy, radiation, docetaxel, abiraterone, prednisolone etc, and a few others I cannot remember, … on we go to enzalutamide, and I bet my doctors here at the MacMillan Centre in London have a good few more unpronounceable treatments to keep me propped up when that stops working!

  14. After 10 years of Zoladex, flutamide, Casodex, proton and photon radiation and spinal surgery, I came to the end of my rope at 75 facing chemotherapy for prostate and bone cancers. I opted instead of chemo for 4 months of dendritic treatments (6) plus massive infusions, and a new diet. This massive immunotherapy worked. My final PSA 5 months ago was 2.8 and with abiraterone went down to 0.01 (1000 mg, no food).

    I developed high blood pressure which I will try (very very carefully) to reduce by switching to abiraterone 250 mg with food. I will post some results (to share, not to follow) on my blog. Good luck to all you independent thinkers. This is the ultimate on-job-training for educated dudes who work well with their understanding oncologists. (You have to select them carefully. A good sign: Mine keep retiring on me.)

  15. 83 years old; have had prostate cancer for 17 years; have been under treatment at MSKCC for most of that time. Tried a number of drugs, all of which worked for a short time but made me ill. Best results were with Lupron + Casodex, but Casodex ultimately failed. Have been on Zytiga + Lupron for 1 year (Z daily 1000 mg + prednisone 10 mg). Excellent results: PSA down to below 1.0 ng/ml, but have had a recent high spike in blood pressure and skin splotching (possibly from the prednisone).

    Am not wealthy so received the drugs from J&J assistance program for the first year. Must renew application for assistance every year. This time around, J&J is not renewing my prescription (I’m not indigent enough). Many thousands of dollars for a 1-month supply are not possible for me or most of you. J&J’s marketing plan is beyond understanding. Patient must either be indigent, very wealthy or has to face dismantling his family’s economic well-being so as to gain the possibility of a year or two more of life. There are millions of men with prostate cancer throughout the world, only 10% of them can afford to pay the retail price of Zytiga. Wouldn’t J&J do better selling its great product to many more men at a lower price? But who needs common sense (or compassion)?

    So, beware Johnson & Johnson, and do take note: foreign sources (Israel, Canada, maybe India) are becoming available — but still around $1,000 per month.

  16. Reblogged this on The Psychology of Investing and commented:
    stating that Dr. Potter has a PhD and not an MD makes this article biased. I will be the first one not to “like” it. Dr. Elior Kinarthy.

  17. My last comment was on April 2, 2013. Today is March 11, 2016. PSA 0.008. Dendritic therapy every 2-3 years. I do very very well, My HBP is gone. Yearly MRIs show no trace of cancer anywhere in my body. I spoke at Humboldt University in Berlin about “my system” (video on Google). I am down to 80 mg abiraterone and 1.25 mg prednisone, with food. My oncologist and I haven’t decided on the next step but I think that I will start taking the A and P every other day at the low, low, low doses.

    Good luck to everyone.

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