Androgen blockade and ipilimumab against castration resistant prostate cancer
Dr Karim Fizazi - Institute Gustave Roussy, Paris, France.
Karim, it’s pretty exciting here about prostate cancer because it’s castration resistant prostate cancer is yielding. There’s a few studies, let me reel them off the top if I may, there’s one with ipilimumab, tell me about that, that’s from Gerritsen and co.
Correct, this is the phase III trial that was presented at the oral session here at ECCO/ESMO. It’s a brand new phase III trial never seen before and it was really expected for a long while because it’s really the first time we have data with ipilimumab, not only in prostate cancer but also in another disease than melanoma. So ipilimumab was tested because there’s a rationale to test in and through rapid treatment for prostate cancer. So first of all it was tested in patients with quite advanced disease with castrate resistant prostate cancer progressing after chemotherapy, so patients for whom you would expect approximately a year of survival or so. In this trial patients were randomised to receive either radiation to the bone alone or radiation to the bone plus ipilimumab. What the data show is that overall survival is improved but not significantly with a p-value of 0.05.
What sort of activity did you detect, or did the investigators detect, for ipilimumab?
There was obviously proven activity, in terms of progression free survival the difference is significant. There were also some PSA responses and some clinical benefit as well. The overall survival, that was just missed by a couple of events, unfortunately, and that’s probably because some patients were simply too sick to benefit from the drug because if you look at the shape of the curves they actually cross after a couple of months indicating that some patients were too sick and died very rapidly though others just survived for a longer time.
This is a completely fresh approach to this severe disease, isn’t it? Do you foresee a way of tweaking this so that you could get the necessary positivity?
Fortunately there is another phase III trial that’s currently on-going, it has completed accrual and this is for patients before chemotherapy. Actually in this particular trial the one that was presented here at ECCO, if you look at patients with good prognosis disease and good performance status, no visceral metastases, they do benefit even in terms of overall survival. So the hope is that really in the second trial where we’re really studying these patients in better condition we might have a positive phase III trial by overall survival.
So it’s looking as if an immunotherapy orientated approach is perhaps more effective earlier in the disease?
Right, and that truly makes sense. We know that for quite a long time for immunotherapy for prostate cancer; we already have sipuleucel-T, for example, which was demonstrated to improve overall survival in patients with less advanced disease. So really the hope is that we will show the same thing with ipilimumab.
Let’s get on to androgen blockade. ODM201, an agent you’ve been investigating, what did you do here?
ODM201 is an androgen receptor antagonist that is chemically different when compared to the other ones including enzalutamide, ARN509. So what we presented at the meeting was a phase I to the final data from a phase I/II trial that we conducted and it was quite impressive to see from the very first patient in the phase I that, number one, there was no detectable toxicity with this agent and, number two, the drug was active with most patients benefitting by PSA at least and some clinically when they had symptoms as well. So we could increase the dose up to 1800mg with no detectable toxicity and then we moved from phase I to phase II and we explored three dose levels. Efficacy was confirmed, lack of toxicity was confirmed with no real side effect that can be drug related and we could demonstrate approximately 75% response rate in patients who are chemotherapy naïve and abiraterone naïve. We also could demonstrate quite important efficacy for patients failing chemotherapy and even in patients failing abiraterone you still see some patients benefitting. So this compound is now quite ready to go to phase III and the phase III trials are under discussion at the moment.
And what’s the difference mechanistically between ODM201 and the more classical advanced new generation androgen blockade agents?
As compared to enzalutamide, for example, we know that both drugs have a high affinity and antagonise the wild-type androgen receptor but, at least in the lab, ODM201 does it better than enzalutamide or ARN509. Now whether this will translate into better efficacy in the clinic, of course, we don’t know and it’s really impossible to say at the moment that one drug is better than the other one. This is really something we need to study in humans.
But very interesting. Moving on, however, to abiraterone and enzalutamide, there’s news here as well, isn’t there?
Yes, there were some new presentations. For example, for the first time we had at this congress the first data about combining abiraterone plus enzalutamide. So, of course, this is phase I data and what you would expect from a phase I data is really showing you that this is something you can do without additional toxicity and that was proven by Dr Eleni Efstathiou from MD Anderson. Also that there is no drug to drug interaction, and that is fine, and there is obviously also activity, anti-cancer activity. Now whether the detected activity in this trial is higher than what you would expect with the single agent abiraterone or single agent enzalutamide still remains to be demonstrated of course.
But you’ve got more options and now there’s a thought that you could use some of these new agents in hormone sensitive disease, disease that’s not yet castration resistant.
Correct, that’s also some data that we had from Dr Smith at the meeting studying enzalutamide as a single agent for patients who have not been treated previously with androgen deprivation therapy. Obviously enzalutamide is an active drug in this setting, it’s quite well tolerated. Now, again, that’s not a comparative trial so whether that will become eventually a standard treatment also needs to be studied in phase III. But I guess it’s very reassuring to see very strong efficacy from an AR targeting drug without the need for castration for these patients.
It’s very interesting to see all of these new developments coming along, a lot of different weapons in the armoury, but what do you suggest ordinary doctors should pay attention to among all this news?
For the future we have… the last three years really have been fantastic in prostate cancer, I have to say. We have five, six new agents with proven efficacy mostly including overall survival. So that’s very good for the patients. For the future we really need to demonstrate how we can smartly use this drug, should we use that sequentially or in combination or, even better, should we personalise treatment for the patients and really give the right drug to the right patients rather than just testing and testing and testing?
And in doctors making decisions today about their patients, have you got some words of wisdom that you can distil in just five or ten seconds?
It’s really very difficult a question, you’re very right. I would just say that for patients failing castration resistant disease, probably the best parameter to decide at the moment whether a patient should get, say, a new AR pathway targeting drug like abiraterone and enzalutamide or a classical chemotherapy approach is simply looking at the time that it takes for the disease to become castrate resistant. If it’s a short amount of time, say six months or less than a year, then the patient seems to be quite likely to benefit from the new generation AR targeting drugs. So probably this would be more patients for chemotherapy. On the other hand, the larger majority of patients would progress after a longer time on ADT, more than a year or even more than two years and these patients are very good candidates for the new generation AR pathway targeting drugs.
We live in a genomic era too, are there any labels you can look for?
Yes, the problem with the biology is that, number one, you need to harvest some tissue from a metastatic deposit which is not that easy and in prostate it’s even more difficult because we’re talking about bone disease which is even more difficult to access. So we’re working on that but that’s really not for today, it’s really for tomorrow and we really hope to be able to demonstrate that some biomarkers will help us for the future for making decisions.
So your overall impressions of prostate cancer reporting at this lovely meeting here in Amsterdam, just in a couple of words?
That’s been really a quite fantastic session, oral session. We had nine or ten presentations, most of them were brand new data and it’s been quite fantastic. When you compare the quality of what we heard at this meeting, as compared to what we used to hear, let’s say, five years ago it’s really black and white. It’s been really impressive.
Let’s keep it that way. Karim, thank you very much.