ASCO GU 2013

Review of new data presented in mCRPC

Dr Karim Fizazi – Institut Gustave Roussy, France

Can you tell us about the newest data being presented at ASCO GU: the negative results?

We had both good and bad news. The bad news included mainly two large phase III trials with negative outcomes; one was actually testing aflibercept, a VEGF trap drug which is targeting angiogenesis, together with docetaxel and it didn’t report better results compared to docetaxel only, so this was obviously the bad news, a large phase III trial. And a very similar phase III trial in design also tested dasatinib that targets the Src family of proteins and also it’s negative with really no benefit over docetaxel alone.

Why were there negative results with the VENICE study?

It’s difficult to say. Five years ago, or so, everybody was very excited with angiogenesis in oncology in general because we had a good example in colorectal cancer and kidney cancer where it really works. But it seems that this is not really the case in prostate cancer and I have to say that in other cancers, even in breast cancer, lung cancer, angiogenesis is not a major, major player. So cancers are not the same, obviously.

Why were there negative results with the READY study?

Dasatinib is really probably more a bone targeting agent, really targeting the osteoclast, rather than targeting cancer cells themselves. So probably this explains why the trial is negative.

Why was it hoped to work?

Because there was some rationale that it could also target cancer cells but unfortunately it’s not potent enough.

Can you tell us about the newest data being presented at ASCO GU: the positive results?

Most of the good news that we had at this meeting were really about new generation endocrine therapies including both CYP17 inhibitors and AR, androgen receptor, inhibitors. So, for example, we had the results from the further interim analysis of a large III trial, COU-302, which is really testing abiraterone acetate together with prednisone in patients with asymptomatic castrate resistant disease. And with a longer follow up compared to what we had almost a year ago at the ASCO meeting, the data are confirmed with an obvious improvement in progression free survival, actually PFS is almost doubled with abiraterone acetate, and also a very nice trend for overall survival improvement.

Tell us more about the AFFIRM study?

Enzalutamide was tested in this trial, in the AFFIRM trial, in more advanced stages - patients progressing after chemotherapy. And we already know that the trial is positive with an improvement in overall survival on top of progression free survival. What we’ve learned here at this meeting is really about the role of corticosteroids in this setting with something that is really open to debate because obviously patients who are on steroids do poorly but we don’t really know whether this is due to steroids themselves or to the general performance status of the patients justifying why steroids were prescribed.

Tell us more about corticosteroid use with abiraterone or enzalutamide?

With abiraterone anyway you need to use steroids just to prevent the toxicity. This is really something you must do to prevent hypokalaemia and also to prevent hypertension. So it is as it is, you have to use it. With enzalutamide you don’t need to use steroids but many of us have been using steroids, not for relief of the enzalutamide but to improve either pain and fatigue, anaemia, all of these things. And what we saw in the trial, in the enzalutamide trial again, was that patients who were on steroids did not do as good as patients who were not. But again it’s difficult to know whether steroids really harm these patients or simply whether their prescription reflects a poorer general status simply.

Is there a potential strategy for steroids?

You can, you really can. With enzalutamide, for example, you can spare the use of steroids but we don’t really know whether we should because steroids really have advantages. Of course they are pretty good anti-pain drugs; many of these patients have inflammation and symptoms due to inflammation so steroids improve that. So really we don’t really know whether we should avoid steroids in these patients so it’s still an open debate, I should say.

Abiraterone and enzalutamide – what are your suggestions on using these agents in mCRPC patients?

First of all, obviously, those two drugs are very active and that’s really great news for all the patients. That’s true in terms of overall survival but also progression free survival and also obviously quality of life, pain control, etc, etc. So that’s really good news. What we don’t really know is whether one drug is better than the other; whether we should combine them in the future, things like that. Now we have different data: abiraterone we have data indicating that this compound is active in very advanced patients progressing after docetaxel, but also in patients pre-docetaxel who are asymptomatic and I suspect that abiraterone is going to be used more and more in these kinds of earlier stages, in asymptomatic CRPC. Enzalutamide is a different story; at the moment we have only a trial demonstrating that it’s active in patients progressing after chemotherapy but we don’t really have data for patients in the pre-docetaxel setting. We should probably wait one or two additional years before that.

Quality of life – what are the results on toxicity with these two agents?

This is also the very good news. Those two agents are very well tolerated overall; it’s really minor toxicity. Enzalutamide may be a little fatigue and it’s not that clear, some very rare seizures, so really nothing bad. With abiraterone together with prednisone you will nicely avoid the hypokalaemia and the hypertension in the large majority of patients. So if you really handle correctly these two agents, patients do very well in terms of tolerance.

What are the benefits with symptom control and overall survival improvements?

Between the two drugs, if this is your question, both really are active against symptoms and also in terms of overall survival improvement. Now really whether one is better than the other, it’s really too early to say.

Tell us more about the newer agents ODM-201 and ARN-509?

Those are also two androgen receptor inhibitors with obviously very high activity. ODM-201 is currently in phase II, in large phase II, it’s finishing its phase II, but even in the phase I programme we saw quite tremendous efficacy and very nice tolerance. ARN-509 data were presented yesterday at this meeting showing that it’s also active in a quite large phase II programme. So we really have two new drugs, the question is now whether they can do even better than the one we have, enzalutamide, maybe abiraterone, or whether those are similar drugs.

How are the phase I studies going?

In animals these agents might be even more potent than enzalutamide but animals is just part of the truth, obviously, humans can be very different. So we really need to conduct the trial to have a firm idea but it’s really nice to see now at least four new endocrine therapies with quite tremendous efficacy in these patients.

What is your take home message for clinicians treating mCRPC?

The great news is, compared to what we had four or five years ago only, is that we now have different families of agents with proven activity. New endocrine therapies – abiraterone, enzalutamide, for example, chemotherapy – docetaxel, cabazitaxel, bone targeting agents – radium-223, denosumab, zoledronic acid, including some overall survival improvement, and also immunotherapy with sipuleucel-T and maybe in the future a new drug. So it means that we really have a very nice armamentarium for treating all patients. Now we just need to begin to become intelligent and find a good way to find the good treatment for the right patients. This is really the future.