Recent advances in treatment practices in prostate cancer

Dr John Fitzpatrick - Irish Cancer Society, Dublin, Ireland
Dr Bertrand Tombal - Catholic University of Louvain, Louvain-la-Neuve, Belgium
Dr Alberto Bossi - Institut Gustave Roussy, Villejuif, France
Dr Heather Payne - University College Hospital, London, United Kingdom

JF: We’re here at the Prostate Cancer Current Treatment Practice meeting in Dublin and we’re here for ecancer.tv. So welcome and here’s the panel. I’m John Fitzpatrick, I’m a urologist from Dublin and beside me is Heather Payne who is a clinical oncologist from London and then we have Bertrand Tombal who is a urologist from Brussels and finally Alberto Bossi who, in fact, is of course Italian but in fact works in Paris and is a radiation oncologist. May I say it’s a pleasure to have all of you here today. So just to kick off with a few questions, first of all we’ve had a very interesting discussion over the last 24 hours but one of the questions that headed the whole discussion was the fact that the EAU guidelines committee have changed their guidelines recently. I just want to put to you, and perhaps to Bertrand first, the effect that this has had, or potential effect, that it’s had on practice and does it change anything?

BT: Yes, it changes because, as you may remember, the guidelines had decided on a specific sequence when patients become metastatic in CRPC by imposing of either withdrawing or adding an antiandrogen which for many of us seems a little bit obsolete considering the many drugs we have now. Suppressing this as an obligation doesn’t mean there is no role anymore for antiandrogens of the older generation but at least it is not perceived as an obligation. It has implications when we know that many reimbursements or regulation authorities in countries are taking guidelines for granted. So I think it is an important move because it will allow us to more individualise the treatment and not stick to a pre-defined sequence that has become obsolete in the last few years.

JF: Great. Alberto, do you have any other comments on that?

AB: The guidelines, you certainly agree on that, I have to stick to what the evidence is in the literature and indeed I think that this is, for us, the doctors managing patients with castration resistant prostate cancer, certainly something that will help us in our daily practice. Indeed, we also have to bear in mind that there is each day some new piece of information coming from the literature that may change our daily practice. I think that we also have to be flexible in order to take into account what the research and the clinics will tell us about those patients.

JF: Heather, do you think that these changes in the guidelines will be observed by everybody or by the majority or are there specific practitioners who will observe them?

HP: I think with this particular change it makes sense, doesn’t it really, because castrate resistant implies that you are progressing after castration treatment. Certainly there was quite a lot of discussion at the meeting yesterday about those men who start with combined androgen blockade and what it means for them because they’re already taking bicalutamide. I think we were in agreement that for those men it would still mean a withdrawal of bicalutamide or any other antiandrogen. But I think this is a great way forward.

JF: It’s a good thing. So that’s the easy question out of the way, now we’re going to start asking the difficult ones. I think what you’re going to find out is that everybody will probably have differing views and so there are views and they’re what we feel about things, just maybe too you can discuss them among yourselves as it were. But this is what we have to say, you may disagree, and hopefully you will on a number of things, let’s see what happens. So the first question: when should we start treating metastatic castrate resistant prostate cancer patients? And Bertrand, we start with you again.

BT: That’s an excellent question because it’s not a question that is tested by the evidence we have. We have five randomised controlled trials, they all say that drug A that is tested, for instance enzalutamide, is better than drug B that is a comparator but none of these trials is giving clues on what would be the best time to start the drug. So I will give a very simple answer – it’s not too early, not too late. I think that honestly there is, I would even say, a threat that because we have a drug we consider less toxic just to manage the anxiety of the patient we would start the drug when the patient has a first rise in PSA. I wouldn’t recommend that. On the other hand there is always the possibility that waiting that the patient is very symptomatic, is deteriorating, I wouldn’t do that either. So we need to be in between and my personal view would be that at least we need to wait for some sign of objective progression – bone scan, lymph node, visceral disease – and then there may be other biomarkers, sometimes extremely simple like alkaline phosphatase for instance which is a biomarker I like very much because when they start rising, to me, it’s a good indication that maybe it is time to start something. But I do insist at the early stage of the disease I believe, and that’s my personal opinion, that active surveillance is an extremely valid option to try and test how the disease will progress in the next few months.

JF: OK, Heather, what do you think? Bertrand was just mentioning about biomarkers and things like that. But basically am I right in saying that it really comes down to the way the patient is getting on? Is it a clinical decision as opposed to a marker decision? We’ll come back to everybody else but just what’s your view on that? Agree or disagree?

HP: I think it’s a combination of both; I think the most important person in front of you is the patient. One of the things that has come over at this meeting is that it’s very difficult to have a sequence or a definite protocol or order of any of these drugs because every patient that you see is different and they’re going to have different problems with their life, different comorbid factors so it has to be a very individualised patient-centric process as to when you start treatment. But I agree with you, it’s the person in front of you, it’s the clinical progression which is important but I also feel it’s very important to treat people before they have significant symptoms because that’s failing, actually, in oncological and prostate cancer management.

JF: So, Alberto, do you agree or other views?

AB: I do, I do, because I think that we have to put the patient in the central position in all this decision making. We have a little bit as professionals the wrong habits to impose treatment to patients but in this particular category of patients in-depth discussion and in-depth understanding of this quality of life of what he wants also, how he imagines his quality of life with the treatment must be done. And there is a second aspect which is to me central is the multidisciplinary approach. We are going to discuss this later, I guess.

JF: Yes. So Heather was saying there that she would like to start treatment before the patient became symptomatic, in other words this brings the whole question of biomarkers really into play. In other words, what Bertrand has said about the alkaline phosphatase would be the right thing. So do you agree with that?

AB: I do, I do agree, yes, because we would like to identify those patients that probably need much more active treatment from the beginning of their history of the castration resistant part of their disease.

JF: OK, I think that’s very helpful as a general guideline. Let me just throw in a curveball here because we’ve had a lot of discussion recently about the clinical trials and we know that up until recently with prostate cancer overall survival was the primary endpoint. Now we’ve got co-primary endpoints, so we’ve got overall survival and radiation progression free survival. Then in all these trials there’s a whole host of secondary endpoints. Heather, I know you have a strong view on this so why don’t you share that with us, just let us know?

HP: Personally I think secondary endpoints sometimes can be more important than the primary endpoint from the patient’s perspective and looking at things like quality of life, delay for the need for chemotherapy, pain control and also most of them use PSA control as a secondary endpoint which perhaps at this stage of the disease is not such an important marker. But I think the actual patient themselves reducing the risk of further painful side effects or delaying slightly more intense treatments, or just putting those a little bit further back, because chemotherapy is still an excellent drug and it’s still something that we need to use. But being able to treat patients with oral medications, with abiraterone, with enzalutamide, I think those secondary endpoints are really important.

JF: They come, yes. So all of you in the course of our discussion have made the strong point, which we feel needs to be transmitted clearly to the audience, that the patient is really what matters and the patient… anything that improves their quality of life and, of course, their survival. But with all these recent advances have we any idea which of the new drugs for which patient? I know this is an almost impossible question to answer so because it’s an impossible question I’m going to ask Bertrand first.

BT: Yes, it is difficult, I wouldn’t say impossible. Indeed, there are contraindications to each of these products, so that’s the first thing. We know, for instance, that with enzalutamide it was not tested in patients with a history of seizure; we know that long-term administration of prednisone together with abiraterone is not something we want necessarily in somebody with unstable diabetes or severe cardiomyopathy. So once again looking at the patient themselves will already provide some information. Then we have, and I know we’re going to speak about that later on so I will be brief, but just the way the patient progresses. If it’s somebody who has a bone dominant disease developing bone pain he will be more likely to receive radium, for instance, than somebody that would have a lot of visceral metastases, osteolytic disease, in which we would go for chemotherapy. So to me, once again, that initial round of observation, the few first 3-9 months when the patient becomes symptomatic is also extremely important to feel the disease. I think that when you see a lot of these patients and you see them repeatedly you make your own idea and the choice becomes not that difficult, at least to my knowledge.

JF: So, would you be able to make a decision on which patient should, for example, get abiraterone or enzalutamide at this early stage?

BT: Abi or enza is probably the most difficult. I would say that I can quite easily make a difference between somebody who needs radium, abi or enza, or chemo. That’s kind of clear and I try to explain when I can that it’s OK. Abi/enza we must face the truth, they are extremely similar drugs with extremely similar benefit working on quite similar pathways although physiologists would say what you say, it’s unacceptable. So that comes to convenience and a lot of small differences – should I give or not prednisone which sometimes may have some advantage in patients if they feel a little bit painful or something like this. So that’s a difficult one and once again if you see many of these patients my recommendation would be don’t act like a robot, don’t say, ‘I like enza, I give enza to everybody.’ No, try a variety of drugs and you’re going to learn from your own experience.

JF: OK, so Alberto, yes.

AB: Yes, I just wanted to add that we are now at the point that we realise that the definition of metastatic castration resistant prostate cancer is a huge amount of very different patients and we need very different approaches. This, I think, is a message also for our patients and their families.

JF: So let me thrown into the mix here Radium-223, tell us that sort of patient. Is there a sort of a patient who would benefit from that? Bertrand was talking about bone dominant disease.

AB: Yes, indeed this is probably one of the characteristics of the patient that may need up front radium. The trial that has been published with radium-223 shows us that these are the category of patient that may mostly benefit from this treatment. But just to mention something else, we are not that sure that radium should be used alone; we may even imagine that this could be part of the treatment for those patients.

JF: And indeed there are trials ongoing.

AB: And there are trials ongoing asking these questions. So the landscape is really moving and has an incredible amount of different possibilities for those patients.

JF: Good. So let me come round to, we’ve mentioned those and now let’s talk about the chemotherapy end of it. I think we’re all agreed that chemotherapy has a significant role to play but do we know where, which patient, which type of patient?

HP: I think that chemotherapy you see outstanding responses to both docetaxel and cabazitaxel. I think for many patients it’s getting over the fear of the word when in fact when they come to have the treatment it is very well tolerated and lots of my patients will continue to work. It’s a difficult decision but perhaps easier than the ones that Bertrand was talking about. To me, anybody with visceral disease I would give chemotherapy to as opposed to the new generation hormones although visceral disease…

JF: Forgive me for interrupting, well maybe you were just about to say it.

HP: The 11% in the…

JF: Yes, but the visceral disease obviously is lung and, to a degree…

HP: Liver, yes.

JF: … multiple lymph nodes and liver. Chemotherapy for all of those or would you…?

HP: I think certainly for those men with liver metastasis I would feel very strongly that I would want to give them chemotherapy whilst they have that window of opportunity. The lung metastasis is slightly more difficult and it depends on the number and they’re often an incidental finding whilst you’re staging. Certainly in the PREVAIL study that 11% of men did have visceral disease and had good responses. But visceral disease would make me start to think towards chemotherapy. Those men who had significant pain and significant symptoms requiring opiates I would give chemotherapy to sooner rather than later. Those men who have had less than a six month response to their first line LHRH agonist or antagonist I tend to think about chemotherapy for them but in light of all the other factors of their…

JF: So in relation to visceral metastases we know that abiraterone didn’t in the pre-chemotherapy trial have visceral metastasis but did in the post-chemotherapy. So that’s just worth pointing out but at the same time the visceral metastasis issue is something that’s probably going to become more and more prevalent, would you say?

HP: And I’ve seen great responses post-chemotherapy with abiraterone, I have to say, for lung mets.

JF: Right. Anything to add from either gentleman?

BT: I think, to me, once again I’ll try to explain, I think that they are still around here patients that are truly androgen insensitive because we often refer to castration resistant, that’s most of the patients, they adapt to the mechanism, we know, we target with abiraterone and enza. But I think there are patients that from the beginning are probably absolutely androgen insensitive. Those patients we do a high risk prostatectomy for high risk disease and we end up with a low PSA, Gleason 9-10, multiple lymph nodes. You give six months of hormone to these guys, they progress. Patients who have major radiographical progression and PSA drop or minimal PSA change. To me that discordance between the PSA response and the non-PSA response is probably the most important argument. A guy like this that would have been operated one year ago who has had a rapid progression with a very high Gleason, 9-10, signs of neuroendocrine differentiation, I would do everything I can to convince that guy that his best chance is probably chemotherapy.

HP: I think one of the things that brings up is monitoring as well, isn’t it? There’s a risk that some of these patients are then sent away for six months, they phone in with a PSA and you’d miss that.

JF: This is extremely important and in fact, Alberto, I just want to come to you. There are just a couple of questions relating to this. The first of these is primary resistance. We know that there is, certainly in the post-chemotherapy group, if we look at the rPFS curves we know that there’s something like whatever percentage it is of primary resistance to abiraterone and also to enzalutamide. Have we any way of predicting this? What do you tell your patients?

AB: Yes, unfortunately for the moment we have no clear indications of which patients will not respond so well to those drugs. So what I think it’s correct to tell to our patients is we don’t know, we don’t have any clear-cut indication about who will respond to these drugs. So I think this is something else that we should look at in terms of biology of the tumour, in terms probably also of, and we have been discussing this, the idea of biopsying metastasis in these tumours. Because we have to know exactly what kind of disease we have to fight and this may be a route.

JF: I think you made that point about the biopsying which is extremely important. But Bertrand, you start your patient on enzalutamide or abiraterone, they come back at three months, their PSA is up. What’s your next step?

BT: When PSA is up that’s a difficult one because PSA…

JF: Do you actually do an imaging?

BT: No, I do an imaging for everybody, independently of their PSA response. And you know we had a consensus that has been recently published in the European Journal of Cancer and that was one of the only points everybody agreed that when you use… And that’s strange because it was really based on the people’s feeling because there is very little data. But all the experts who were participating to the trial and they said if you give hormone therapy, so enza/abi, to somebody please after three months check for discordant response because we know some patients who have a major PSA drop and massive radiographic progression. So at three months you should do a radiographic assessment, that is my personal view. Now, if the PSA hasn’t dropped anymore, or just maintained, then I would really need a strong argument to keep the patient on the drug, like real clinical improvement, real pain disappearance or real radiographic progression. But clearly to me it’s always a tripod – the clinical feeling, the radiographic progression and the PSA. Taking a decision based on one of these isolated…

JF: No. So, the final question I want to ask you is another very important one and it’s a question that is increasingly being spoken about and that’s the question of cross-resistance and, of course, whether there is a sequencing issue. Do we know the answer to these? So I’m going to start off, each of the three of you I want to get an answer, but let’s just start off with Alberto to just give me your impression, then we’ll go to Heather and then finally to Bertrand.

AB: Again, this is another point which has been discussed in these two days here in Dublin. We know that whenever we start with a drug in this particular situation and then we switch to the other one we risk to have patients that are not responding as we would like to have. Again, for sure, the idea would be to rapidly identify those patients in order not to lose time with manipulation in order to give them probably something else. But still we don’t have any real clue about this cross-resistance. Studies that have been done and published are not randomised trials, are just trials, phase II trials with little numbers of patients and we have, as Bertrand said, some clinical intuition behind that but still there is a lot to do in this field. I would guess that for the moment it’s extremely difficult to have a complete answer to such a question.

JF: Heather, anything to add to that?

HP: I just think that it is an extremely confusing field, there’s conflicting evidence. But I think when one is thinking about sequencing, personally I would think about using the drugs that are the best tolerated with the least toxicity first. Assuming equal efficacy.

JF: So, Bertrand, just to ask you. I know, because you were computing earlier on the number of patients you’d have to put into such a trial, but people say that there is no answer to these questions because we don’t have level 1 evidence because we haven’t had a randomised trial. My contention has always been that we can’t do a randomised trial because it’s going to take too long and the answers are required now. So do you want to give me your views on…?

BT: My view is quite simple, I think that we should use every possible patient we treat and explain that to the patient and we should optimise the way we use data when we treat patients. Because if tomorrow instead of a series of 450 patients, or 45 patients, we have a series of 500 patients coming from ten centres, that consistently show that if you have that characteristic you’re going to fail that treatment then I’m OK. And clearly there may be multiple trials but if they all go into the same direction that is going to be OK to make a choice. At the present time the cross-resistant problem is linked to abi/enza enza/abi and so if somebody fails on enza do we have enough evidence not to recommend abi like the NICE did recently? I don’t believe, no. We should reassess the drug minus one and decide once again on the same basis.

JF: So it’s a difficult problem, like all of the problems we’ve been discussing. I think you can see that even though we’ve actually been discussing these for 24 hours there is still a great deal of… I wouldn’t say disagreement but just disputation among the whole group. I hope that we’ve tried to get all of these concepts across to you and that it’s been of interest to you to actually hear how people feel having just come out of a meeting where all of these things have been discussed. So, having said that, I’d like to thank my panellists and I’d like to say good afternoon from Dublin.