ASCO GU 2013

ASCO GU: Comments from the principal investigator of the COU-AA-302 study

Dr Charles Ryan – UCSF Cancer Center, San Francisco, California, USA

Being the principal investigator for the COU-AA-302 study, tell us why you decided to set this trial up?

Abiraterone is an extension on hormonal therapy; it’s a very potent form of inhibiting androgen production and, in many ways, we have long felt that this was the natural place for this drug to be utilised which was in a patient population with castration resistant disease who had not yet been treated with chemotherapy. One of the major reasons we did this study in this particular patient population was that these are patients who are in, let’s put it this way, good clinical shape and the goal was to preserve quality of life, preserve the time until they required more therapy or had a decline in their clinical status due to the disease. So it was really more about, instead of treating a disease per se, it was really more about preserving a good clinical state.

The other two reasons are this is a very common clinical state and patients can live in this situation for a couple of years without any standard of care, really. And the other issue is that many, many patients, not only in the United States but worldwide, actually never receive chemotherapy for prostate cancer because of a variety of reasons due to advanced age, comorbid illness or just a desire never to get chemotherapy. While the treatment is not completely without side effects, the goal of preserving function and preserving quality of life was paramount in this study.

Can you give us an overview of the study?

Very simple randomised trial, one to one randomisation between abiraterone 1000mg, plus prednisone 10mg a day, versus prednisone 10mg a day. The prednisone was also combined with placebo in that control arm. Now an interesting observation, and this trial has been previously reported and published but the observations made yesterday were that the control arm of the study has done extraordinarily well. 30% of the patients enrolled on the prednisone alone arm responded to the treatment and the median survival in that group of patients is over 30 months. Now this is longer than the median survival in any previous treatment trial in this same patient population so this tells us that this was an active control and that overall the conditions for patients with castration resistant prostate cancer are improving.

So what results did you get in the active arm?

The active arm showed a 35 month median survival and that’s the longest survival yet observed in a phase III study in this patient population. There were more mature data on the other primary endpoint of the study, which was radiographic progression free survival and essentially what happened here is compared to the prednisone control, remember which was active and 30% of patients responded, compared to that the treatment arm had a doubling of their progression free survival which settled in at a little bit over 16 months compared to about 8 months for the prednisone alone arm. So that’s a highly statistically significant result and a clinically significant one as well.

So what is this telling us about the treatment for patients with mCRPC?

We knew that this drug had activity in this patient population before but I think the results of this study, many would argue, creates a new standard of care for this patient population and it says that for castration resistant prostate cancer chemotherapy is not the only option and now you have this option available. Again, the way I think about it is I can tell my patients that this will prolong the time or delay the time or even possibly prevent the likelihood that you will need chemotherapy, that you will experience pain from this disease or that your clinical condition will deteriorate. It allows you to preserve essentially the more positive clinical picture in which you find yourself now.

Expand more on the point you made about the use of steroids?

Well that’s controversial but the observation made by Dr Scher in his presentation yesterday was a provocative one, which was when they went back and they looked at the patients on the enzalutamide study which, just to rehash very briefly, this was a trial in post-chemotherapy patients, enzalutamide versus placebo. But in the study patients who had been on steroids were allowed to continue on steroids and patients were allowed to use steroids for palliative benefit or other reasons during the course of treatment. So the question asked simply was, ‘Was the outcome of those patients who received steroids better or worse or the same than those who didn’t?’ And the answer to the question in this study was that the patients who got steroids had a shorter survival, a statistically significant and a clinical significant shorter survival. But this is subject to all kinds of bias and Dr Scher even acknowledged this in his talk. This is a retrospective, unplanned analysis and it’s well known to those of us who treat this disease on a regular basis that steroids have a palliative benefit. So the way that that works into this story is that if you’re using steroids for palliative benefit, it would just naturally occur that you will use it more frequently in patients who are sicker, more advanced disease. And so that brings into it a, what I guess I would call, selection bias where the patients who are on corticosteroids are naturally going to be more advanced, sicker patients who may have a worse outcome. Dr Scher proposed, and I’m open to this discussion, that perhaps as the disease evolves there’s a possibility that the corticosteroids could become activators or agonists of the disease. That’s a very provocative, interesting, observation but I don’t think this proves anything and it just makes us wonder if we need to study that a little bit more.

Should clinicians be worried about using steroids?

For years, for decades we’ve had study after study showing that steroids are associated with modest response proportions, palliative benefits and there have been enumerable studies, phase III studies, where steroids are part of the control regimen so I don’t think we should abandon the use of steroids as something that can help patients.

What do you think about the potential partnership of using enzalutamide and abiraterone?

This observation about enzalutamide and steroids says that we shouldn’t use those two drugs together for whatever reason but the other thing is that, in a way, this actually supports the use of abiraterone earlier in the clinical course where we have now prospective data that the steroids are actually associated with a clinical response in many patients. And, you know, in the steroid alone arm in the study the median progression free survival was still 8 months which isn’t too bad when one considers that this was the control arm of the study.

What do you make of the negative results from READY and VENICE?

Unfortunately we’ve spent a lot of time, a lot of money, a lot of patient and clinician effort now in trying to add to the chemotherapy backbone. And we’ve had negative study after negative study now where we just have not found a partner for docetaxel. And we may never find it. There are some studies that are underway, I wish them well, I hope they’re positive, but it’s beginning to be quite a signal that combination studies with docetaxel seem to be going nowhere.

It continues to be a very positive time and we continue to see lots of developments and many options emerging for patients. It’s actually very gratifying to see that abiraterone, for example, which was first approved in that post-chemotherapy setting is actually being moved now into the pre- or the chemotherapy-naïve setting which is a bigger patient population so there’s more benefit to be achieved by dosing it in those patients. And we also see that this is not the end of the story for this type of approach; enzalutamide and abiraterone are the first in class of these two new types of hormonal approaches. There are other drugs that are very similar, maybe even a little bit more potent or a little bit less toxic, that are being developed. So there are still a number of trials that are under way with new agents. It will be important and exciting to see how those develop over the next couple of years.

What is your take home message for the clinician?

Prostate cancer is a very treatable condition; that intervening early in the setting of metastatic castration resistant prostate cancer may delay the things that we all associate with suffering from cancer such as pain and decline in clinical condition and the need for chemotherapy and, of course, death and progression of disease.