The results of a randomized, double-blind, placebo-controlled, multi-center, Phase III clinical trial comparing abiraterone actetate + prednisone to a placebo + prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) were presented today at the annual meeting of the European Society for Medical Oncology in Milan, Italy.
This first Phase III trial of abiraterone acetate, initiated in early 2008, enrolled 1,195 men with mCRPC who had progressive prostate cancer following one or two courses of chemotherapy, including one course of docetaxel-based chemotherapy.
Patients could not have received prior treatment with ketoconazole, abiraterone acetate, any other drug that acts as a CYP17 inhibitor, or any other investigational drug that targets the androgen receptor. They also had to have an ECOG performance status of 0 to 2. Eligible patients were enrolled at 147 clinical sites in Australia, Europe, the USA, and Canada.
The key data presented by Dr. de Bono on behalf of the investigators are as follows:
- Patients were randomized in a 2:1 fashion, with 797 patients randomized to abiraterone acetate + prednisone and 398 patients randomized to a placebo + prednisone.
- Patients treated with abiraterone + prednisone had a 35 percent reduction in their risk of death (hazard ratio [HR] = 0.65) compared to those receiving a placebo + prednisone.
- Median survival of patients receiving abiraterone was 14.8 months compared to 10.9 months for those receiving the placebo.
- Time to disease progression was 10.2 months among those on abiraterone and 6.6 months for the placebo patients.
- The two most evident adverse effects of abiraterone acetate + prednisone were fluid retention and hypokalemia (elevated potassium levels).
- Most adverse events of abiraterone acetate + prednisone appear to be manageable and do not include any of the classic side effects of chemotherapy.
Marketing applications for abiraterone in the U.S. and Europe are scheduled to be filed by the end of this year. Additional details about the results of the trial are available in a media release from subsidiaries of Johnson & Johnson.
Abiraterone acetate becomes the second drug this year to demonstrate a clear median survival benefit in men with mCRPC and with progressive disease after treatment with docetaxel-based chemotherapy, representing a practice-changing advance in the management of late-stage prostate cancer.
Filed under: Drugs in development, Management, Treatment | Tagged: abiraterone, castration-resistant, CRPC, metastatic |
THE "NEW" PROSTATE CANCER INFOLINK 
I wonder how important is gaining <4 months and what price does it come at?
Reuven: If you are referring to what the manufacturer intends to charge for abiraterone, we will have to wait and see. The importance of an additional average 4 months of survival is an entirely personal matter for the individual and his family. However, I think you might be surprised at just how important that is for many, many men.
So between Provenge and abiraterone we have a median increase in survival of 8 months?
Mike,
Don’t know if you have access to more detail, but what always interests me is the range, rather than the median in studies like this.
So if the median survival of patients receiving abiraterone was 14.8 months compared to 10.9 months for those receiving the placebo, what was the range?
We know that half the men died in less than 14.8 months — how much less? We also known that half the men survived longer than 14.8 months — how much longer?
The point being that for some men the cost and the therapy would have been of miniscule benefit and might not have improved their risk of dying. For others, the life extension could have been a good deal longer than the 4-month differential.
Any additional pearls you can cast would be appreciated:-)
Terry: I do not have that information yet, but I will see if I can obtain it.
Please note that the abstract of the presentation by de Bono et al. is now available on line as abstract LBA5 in Annals of Oncology Vol. 21 (Supplement 8): viii1–viii12, 2010.
Thank you, Mike.
Regrettably that abstract does not supply any more information on the survival range, apart from the observation that median time to death after time to PSA progression was about the same in both arms.
Well, it does also give you the upper and lower 95% limits of the hazard ratio for the overall survival benefit.
Hi Chris (and colleagues), on October 11, 2010 at 1:55 pm you asked:
“So between Provenge and abiraterone we have a median increase in survival of 8 months?”
Actually, real world survival time should be considerable better.
First, if memory serves me right, survival time for the key Provenge trial was “censored” when patients hit the 3-year mark after treatment. In other words, even if a patient was alive with a study survival time of, say, 48 months when the study ended, he would have been credited with only 36 months survival in the study. Obviously you don’t have the same effect on the short-survival side of the scale. This means that the 4.1 month (memory here) added survival for the Provenge arm would certainly have been longer if actual survival had been tracked to the end of the study rather than censored at 3 years.
I suspect that actual data was not collected and cannot now be gathered in a disciplined way needed for publication. However, we do have the figures for the proportions of patients in the Provenge and the placebo arms surviving at the 3-year point: 33% for Provenge, and 11% for the placebo arm.
A second key factor that makes survival averages appear less impressive than they would be in a real-life clinical situation is that non-responders to the drug are averaged in with patients who do respond, including many with good responses. That pulls the reported averages downward. In real life outside of the trial situation, a good oncologist is going to notice fairly quickly that a patient is not responding and will switch him to a different regimen to see if he will respond.
What I would like to see is reporting of the median survival for patients who DO respond in trials, in addition to the usual statistics. That’s really important because so many patients do not understand the significance of trial survival results. They are not the only ones in the dark: I’m no longer surprised that many doctors and researchers, and, of course, the media, don’t understand either. Unfortunately, you cannot expect our lawmakers to be any more enlightened.
Some of us survivors were invited to the IMPaCT conference (Innovative Minds in Prostate Cancer Today) conference in Atlanta in 2007 (focused on 10 years of the Prostate Cancer Research Program under the sponsorship of the Congressionally Directed Medical Research Program), and I was able to raise this point to some well-known researchers. The question generated substantial back-and-forth conversation among the panelists and favorable responses. The next time an FDA drug approval hearing comes up, we should raise this issue in advance.
The third key point is that oncologists will often take a newly approved drug and start combining it with other drugs, often achieving superior results.
I’m looking forward to reports of actual success with Provenge and other new drugs as they are used outside the clinical trial setting.
Dear Jim;
Not to seem overly pedantic, but how can one possibly know the median survival time of people who “respond” to a specific drug (or drug combination) in a clinical trial? Respond how? And for how long? It is for exactly this reason that the preferred endpoint in pivotal clinical trials is overall survival rather than any other form of surrogate endpoint. Surrogate endpoints have an annoying tendency not to correlate well to overall survival.