MORE on the COU-AA-302 trial on Abiraterone acetate in Chemo-naive Castration-resistant Prostate CancerMORE on the COU-AA-302 trial on Abiraterone acetate in Chemo-naive Castration-resistant Prostate CancerPosted 13th March 2012RajeenNOTE: The following are strictly my views and opinionsIt is a matter of time (maybe a few months) before abiraterone acetate is approved for the indication of
Chemo-naive Castration-resistant Prostate Cancer. Although the pharma company is planning to send their application for approval for chemo-naïve mCRPC by the end of this year, it would be NOT necessary for them to rush into this, as clinicians can ALREADY start prescribing abiraterone for this indication once the COU-AA-302 study is formally presented or published.
Arbiraterone has
already been approved for post-docetaxel mCRPC last year. NOTE: Once a
drug has been FDA approved, it actually means that the drug's health benefits outweigh its known risks, and hence the drug is approved for sale. FDA approval only implies that the benefits of the approved agent are judged to be greater than the harms. Hence (PS: Corrrect me if I am wrong,) until the drug is approved for this indication, the pharmaceutical companies cannot promote the drug for the indication of chemo-naïve mCRPC, but clinicians can still start to prescribe the drug on this indication if there is already a proven benefit. However, the study on this benefit must first be published or presented in a major conference to verify and analyze the data.
By June this year, the COU-AA-302 trial is already
scheduled to be presented at the ASCO conference. It may even make it as breaking news in the coming AUA meeting. By that time, once verified on its benefits, abiraterone can be prescribed for chemo-naïve mCRPC.
However, also NOTE THE FOLLOWING CAREFULLY:1. When abiraterone was
first approved for post-docetaxel mCRPC, it was based on the COU-AA-301 trial, for which, based on the interim results (showing a statistically significant improvement in overall survival and an acceptable safety profile), The Independent Data Monitoring Committee (IDMC) for the trial not only recommended stopping and un-blinding the study; they also recommended that patients in the placebo arm of the study be offered immediate treatment with abiraterone acetate + prednisone
2. The action of the IDMC was ethically justified, but has
caused a clinical conundrum.
3. Similarly in the recent COU-AA-302 trial on chemo-naïve mCRPC, the
interim results showed a benefit of the co-primary endpoints; namely radiographic progression-free survival and overall survival. For this, the IDMC not only recommended stopping and un-blinding the study; they also recommended that patients in the placebo arm cross-over to the treatment arm.4. BUT NOTE THE FOLLOWING: On
breaking the randomization as proposed by the IDMC, we will now never know the ACTUAL survival BENEFIT of this drug over the placebo (or any standard drug) as the randomization has been broken, and further survivals cannot be compared to any pre-existing control arm any longer.
5. FURTHERMORE, the
un-blinding of this chemo-naïve mCRPC trial (ie. COU-AA-302 trial) was based primarily on data related to the radiological progression-free survival and NOT ON OVERALL SURVIVAL DATA. This means that we may never know what the real and ACTUAL survival benefits of abiraterone in these groups of patients are.
6. With the above results, it is very unlikely the pharma sponsors will proceed with any further trials on these group of patients because abiraterone will now be widely prescribed, and there will be no necessity for any further trials to promote this drug
7. It would have been better if the chemo-naïve mCRPC trials were conducted as a 3-4 arm trial, even though it might have taken a longer time to accrue. If the arms were abiraterone vs early docetaxel (vs Provenge) vs MDV-3100 vs placebo; and even if the interim results were assessed and the IDMC decides to break off the placebo arm randomization, abiraterone can still continue to be compared to docetaxel, MDV-3100 (and Provenge)arms for early mCRPC and the actual survival BENEFIT of all these drugs may be observed and documented
8. What will be the 1st line drug of choice for asymptomatic or minimally symptomatic chemo-naïve mCRPC? Abiraterone, docitaxel, Provenge? Or is it MDV 3100?
9. The phase 3 AFFIRM trial on MDV-3100 recently presented at the genito-urinary conference under ASCO exceeded expectations. This study was also prematurely un-blinded. It also used placebo as its control. We will now, yet again, never know the ACTUAL survival benefit of MDV-3100 for this indication as the placebo randomization has been broken
10. The current PREVAIL trial on MDV-3100 for chemo-naïve mCRPC are being conducted with placebo as its control (a similar situation as in the recent abiraterone trial COU-AA-302 ). It would not require one to be a rocket scientist to presume that again this trial will be prematurely un-blinded, and the control placebo arm will be asked to cross over to the treatment arm
11. We are going to be left with
MANY drugs for early mCRPC, but we will not know their ACTUAL survival benefits as their randomizations were un-blinded. And it will take a long time before the pharma companies will sponsor trials on abiraterone vs MDV-3100 vs Provenge vs TAK-700
Rgds
Dr Rajeentheran Suntheralingam
Source:
MORE on the COU-AA-302 trial on Abiraterone acetate in Chemo-naive Castration-resistant Prostate Cancer
