An article by Mohler and Pantuck, published on line last week in the Journal of Urology, provides two perspectives on the future potential of abiraterone acetate in the treatment of prostate cancer.
The article — which is framed as a pro/con debate — focuses largely on the impact of abiraterone acetate on the control of the underlying biochemical mechanisms of castration-resistant prostate cancer (CRPC). However, looked at from a patient perpective, this intellectual scientific question is really of rather less importance than future data from well-designed, well-executed clinical trials.
It is true that we know a good deal more now about the roles of androgens and the androgen receptor in CRPC than we did 10 years ago. This has led to a growing stream of new therapies being tested for effectiveness and safety in the treatment of CFRPC and metastatic CRPC over the past 3 years. Abiraterone acetate is just the first of this potential flood of products. Others following close on its heels include MDV3100, TAK-700, VN124-1, and more are still to come.
We have already seen that abiraterone acetate + prednisone can extend overall survival by 4.4 months compared to a placebo + prednisone in men with metastatic CRPC who have progressed after treatment with docetaxel-based chemotherapy but who continue to receive standard hormone therapy with an LHRH agonist. A second Phase III trial should soon provide data on the use of abiraterone + prednisone in men with chemotherapy-naïve, metastatic prostate cancer. From this point on, however, things are going to become a lot more difficult.
What — if any — is the potential role for abiraterone earlier in the disease state? At this time we simply don’t know. It is perfectly possible that using abiraterone earlier may actually be disasterous because of effects it may have in long-term use on the peripheral androgen pathways. On the other hand, maybe men with advanced disease can be alternately treated on intermittent therapy with standard hormone therapy and abiraterone acetate + prednisone and gain a significant survival benefit compared to intermittent hormone therapy followed by abiraterone once standard intermittent hormone therapy has failed. Who knows?
What is very clear is that clinical trials for men with progressive prostate cancer are about to become a great deal more complicated. We will no longer be living in a world where a new product is tested against a placebo. As of now we are going to start to see the type of complex multi-drug clinical trials that have been customary in some other forms of cancer for many years. Acronyms like BLAP (bicalutamide + leuprolide + abiraterone + prednisone) and alt-BLAP (alternating bicalutamide + leuprolide with abiraterone + prednisone) are in our future. And what is going to be extremely important will be to watch how men react to some of these therapies over time, not just in the short term.
Filed under: Drugs in development, Management, Treatment | Tagged: abiraterone, androgens, castration-resistant, CRPC, intermittent, mechanism of action, metastatic, trials |
THE "NEW" PROSTATE CANCER INFOLINK 
Please can you remind us, in layman’s terms, how abiraterone works?
Thanks, rd
Rick: Please see the very next post …
VN124-1, also known by TOK-001 (Tokai Pharmaceuticals).
I was hopeful (and confident) that abiraterone for chemo-naive patients would have an OS benefit similar to that of the post-chemo abiraterone usage. However, the abiraterone trial for docetaxel-naive patients, as opposed to the trial that studied abiraterone after the patients were treated with docetaxel, was not terminated early. Thus, I’m not anymore that confident that abiraterone should be (and will be) used before chemo. However, I still can’t think of any reason why later (post-chemo) abiraterone usage would work better than a pre-chemo usage. Do you have any possible explanation of this possibility?
Also, I agree that clinical trials in this field will become too complicated but for a good reason. At this moment, we don’t know how the availability of the new treatment options (e.g., abiraterone, cabazitaxel) would affect the other current trials as the patients will try the newly approved treatments after failing the clinical trials which puts a major burden on the new drugs currently tested against placebo.
For example, assuming abiraterone wins regulatory approval and becomes widely available in the next 12 months, how do you think abiraterone’s availability will affect the OS of the patients who started on the OGX-011 trial before the approval? Any idea?
Dear Summer:
First and most importantly, it makes perfect sense that the Phase III trial of abiraterone in mCRPC patients who have not received chemotherapy has not yet reported any results (let alone been terminated early).
This trial started 13 months later than the post-chemotherapy abiraterone trial; it took slightly longer to enroll the full complement of patients for this study than for the first study; and the patients enrolled were significantly earlier in their disease progression than the patients in the post-chemo trial (because they had to be asymptomatic or have only mild symptoms associated with their metastatic disease). We have consistently told people that the very earliest we expect results from this study would be late in 2011 and that some time in 2012 might be more realistic. (Even if there were no impact from anything else, the fact that the pre-chemo trial started 13 months later than the post-chemo trial would make it likely that we wouldn’t see results until late in 2011.)
Our expectation is that this study will show at least the same survival benefit in favor of abiraterone + prednisone as the post-chemo trial. It could be longer. However, we also think that it could easily be anything from 9 to 18 months from today before the results from this trial are available.
With regard to the impact of abiraterone’s approval on the survival of patients in other trials … That is impossible to tell at this time. If we use the custirsen (OGX-011) trials as an example, we would expect the trial managers to be tracking the post-trial use of all other drugs by patients in the trials, and their options will include everything from cabazitaxel to abiraterone (on the compassionate use protocol, even if it isn’t approved) to a host of other investigational drugs. These therapies will be available to men in both arms of the custirsen trials (just as other investigational drugs have potentially been available to men in the two abiraterone trials). There is no way anyone could make a meaningful prediction about the impact of such treatment — we are just going to have to wait and see what the data have to tell us.
Thanks
You seem to be right about the timing of the second trial for chemo-naive patients. I was using the completion date published on the ClinicalTrials.gov website in which April 2011 was marked as the final data collection date for primary outcome measure.
However, a quick search revealed the following quote about abiraterone from Sheri McCoy, chairman of J&J’s worldwide pharmaceutical group, in an investor presentation on October 19, 2010: “We are very aggressively working to file [and NDA] by the year end. We have a second trial for chemo-naive patients and what we’re planning there is potentially filing in 2012, based on an interim review by an independent panel of the overall survival data in 2012.”
So it seems you are right that we are at least 12 months away from any result.
Thanks for this great web site and sharing your opinion about the interaction of OGX-011 and abiraterone.
My brother was newly diagnosed with prostate cancer that has spread to some other areas and in parts of the bone in some areas. He has never had chemotherapy or radiation, so we were hopeful of this new treatment with abiraterone. After looking up all the things about it I am seeing only a 4-month difference in life expectancy and am very disheartened. Why is the 4 months so celebrated to a family facing this?
Am I reading this information wrong? Any help will be appreciated.
Thanks
Dear Dave:
There are several aspects to your question that need clarification.
First, I would ask whether your brother has ever had any form of hormonal therapy. Hormonal therapy of some type may well lower your brother’s PSA level and temporarily eliminate signs of some of the tumors in his bones and other areas for an extended period of time (years and years).
Second, to date, the survival benefit shown by abiraterone acetate is limited to men who have already failed both hormone therapy and standard chemotherapy. When seen from that point of view, the average additional benefit of 4 months of survival can be seen as important to many men, particularly since the side effects of abiraterone therapy are relatively minor compared to chemotherapy. Abiraterone acetate is only the fourth drug in the past 60 or so years that has been able to show any impact at all on the survival of prostate cancer patients who had failed hormone therapy. It may not be much, but …
Third, that 4-month figure is a type of average (a median) for all the men on abiraterone in the trial (nearly 800 of them). Some of those men did much, much better than 4 months. Some got almost no apparent benefit at all.
Finally, you need to understand that, at the present time, use of abiraterone is only approved for men who have progressed after treatment with androgen deprivation (hormone) therapy and received at least one cycle of docetaxel-based chemotherapy. A series of ongoing studies are now investigating the use of abiraterone acetate to treat men with aggressive forms of prostate cancer earlier in the disease state. It may be years yet before we fully understand the potential of abiraterone acetate and other, similar drugs (like MDV3100 and TAK-700) earlier in the development of aggressive forms of prostate cancer.
First of all great compliment for this site …
I wonder if anyone could provide me with quantities regarding the numbers of patients eligible for use of abiraterone, meaning are there any data available which tell what is the (annual) incidence of mCRPC patients before or after docetaxel chemotherapy who would be eligible for treatment with abiraterone?
Are there also any data about the percentage of mCRPC patients who are eligible for docetaxel-based chemotherapy?
Is it correct to say that the majority of people dying from prostate cancer have mCRPC?
Finally I would be very grateful for references to answers concerning my questions.
Thanks very much
Dear Florian:
I am not aware of any well-established and published data on the incidence and prevalence of metastatic castration-resistant prostate cancer (mCRPC) in the USA or Europe. Having said that, I can tell you that I am sure that the manufacturers of drugs like docetaxel, abiraterone acetate, and MDV3100 have conducted detailed studies to try to make estimates of these numbers … but as far as I know they have not been published.
What is quite clearly the case is the following:
(a) Almost all men who actually die of prostate cancer die with metastatic disease.
(b) The survival time of men with evident metastatic disease has been slowly increasing over the past 20 years, and may now be as high as 7 to 10 years in some cases.
(c) The increase in the survival of men with mCRPC over time has led to more men been seen to have metastasis to sites like the brain, which used to be rare.
(d) The potential utility of drugs like abiraterone acetate and MDV3100 extends far beyond mCRPC; we already know of many men being treated (outside clinical trials) with abiraterone acetate who have non-metastatic CRPC and we expect to see men getting treated much earlier with various types of combination therapy that include drugs like abiraterone and MDV3100 in attempts to stop or significantly delay progression of hormone-sensitive prostate cancer.
All I know is that I am doing 200 percent times better .
Thanks for the reply. That gives me hope since his PSA levels have come down a lot since starting on Lupron or hormone therapy.
Dave