Professor Karim Fizazi - Department of Cancer Medicine, Institut Gustave Roussey, France
Professor Nicholas James - Queen Elizabeth Hospital Birmingham & University of Birmingham, UK
KF: Good evening or good morning, or whatever, everybody. This is an ecancer event and we're here in San Francisco for the ASCO GU meeting. I'm sitting here next to Professor Nick James from the UK and I'm Karim Fizazi from France. So we would like to have a discussion about what is the current situation and perhaps what is the future for patients with metastatic prostate cancer. So first of all, Nick, can we perhaps summarise what is the current situation worldwide in terms of approval and availability of treatments, what we are doing and then we will discuss maybe what's next?
NJ: Yes, so the situation in the UK at the moment, well the situation is we had two trials as of course you're very well aware - a series of docetaxel trials showing benefit from docetaxel in metastatic patients. There is a debate about high volume low volume, which I personally think is spurious, and then there's the LATITUDE and STAMPEDE abiraterone data. So we have two different standards of care. The regulatory status is that in the UK docetaxel is funded and approved by NICE, abiraterone is approved but not funded at the moment. In some countries it's the other way around; so I've just been doing a webcast to Japan and in Japan they're not allowed to use docetaxel up front because it's an off label use whereas they are funded and able to use abiraterone. So the situation clearly varies. The other thing that I know we're going to discuss in a minute is clearly one treatment has a very different cost to the other. So choice of treatment is going to be partly driven by the funding mechanism for the drug in the country that the person lives in.
KF: But let's forget about the current situation and approval or reimbursement, let's say we have these two drugs available and many of our colleagues are now asking us what we should do, knowing the data, the overall survival, hazard ratios, the benefit that we saw with the two drugs, the different toxicity patterns, convenience etc. So, again, let's just talk about medicine and not approval of these things. If your patient is coming to you with hormone disease, de novo disease, you have the availability to use both drugs, what are you going to do outside of a trial, let's say, first.
NJ: Yes, it's an interesting question, isn't it, because on the face of it it depends how you put the thing to the patient. Always you have to find out what's important to the patient. If you say to the patient, 'Do you want to take these pills or do you want me to inject this chemotherapy drug into you?' everybody is going to say, 'I'll take the pills, thank you very much.'
KF: I think so too.
NJ: But there are other ways of putting the question, of course. So if you say, 'Do you want a treatment that goes fifteen weeks from the first to the last treatment then it's done, gives you the same survival benefit, probably, as coming every four weeks for monitoring for the next three years with pills that are going to make you put on weight, put your blood pressure up, do all sorts of other things?' then you may actually say, 'Well, I'll just take the short, sharp shock treatment, thank you very much.' So I think the decision you'll get will be dependent on how you put the choices to people.
KF: Sure. Actually there might be some cultural differences here because I don't know yet, because I haven't been facing a patient in this situation because, as for the UK, abiraterone is approved in this indication but it's not reimbursed yet. So I cannot do that with my patients. I would expect, though, that many patients will still tell me, 'I prefer the pill,' even with the hypertension risk etc. just because of the chemotherapy idea. But, again, I don't know yet.
NJ: Yes, and you're obviously right, there are a lot of patients who are very frightened of chemo. But if you talk to them about why they're frightened about it it's because their dad had chemotherapy for lung cancer twenty years ago and this is not chemotherapy itself that is the problem, it's that chemotherapy for lung cancer is unpleasant, lung cancer itself is unpleasant. So a lot of the time people have a sort of proxy bad experience that is not necessarily going to be very representative of what happens with docetaxel which is not that toxic a drug. Obviously it has to be handled with care, yes, it has to be treated with respect.
KF: So regarding the efficacy and the toxicity we know is very different and difficult to compare. But efficacy, let's say assessed as duration of life, quality of life, whatever the definition is. Of course it's difficult to compare different trials, also STAMPEDE has the various arms etc., but do you really believe that the two drugs have the same impact on efficacy? Because I'm not that sure, I would think that abiraterone actually has a little stronger efficacy, maybe on overall survival, we'll know in the future thanks to your trial, but also quality of life was perhaps more dramatically improved. What do you think?
NJ: I think the efficacy thing is interesting because a number of papers have been written on this already and there's two ways you can compare the efficacy. You can treat each of the various trials as a separate trial and do a conventional meta-analysis. So we've just had a paper approved looking at doing exactly that, Claire Vale is the lead author on it, and that paper concludes that probably, as you just said, abiraterone is a little bit better than docetaxel. But there is other data on this because within STAMPEDE the docetaxel and abiraterone arms overlapped to the tune of around 600 patients. What you see in that is that one of the things that has emerged from our analysis with that is that the last patients going to the docetaxel arm do much better than the first patients because they have more options available to them.
KF: Correct.
NJ: So looking at trials like CHAARTED and GETUG-15 which were finished recruitment before abiraterone was licensed compared with the later patients going into STAMPEDE, for example, where they had very good access to these treatments. Basically comparing them head to head is therefore very interesting because you predict a longer survival in patients who have got access to better drugs because that's what you're seeing in the abiraterone trials compared to the docetaxel trials. So Matt Sydes did a very nice job of presenting the head to head comparison from within STAMPEDE, about 600 patients so not obviously fully powered up. The thing that is quite striking in that is the time to progression is clearly much better with abiraterone but you've used up a treatment completely whereas you're still docetaxel sensitive when you relapse if you've just had six cycles of docetaxel. So when the docetaxel patients relapse, although they relapse earlier, they've got more options available.
KF: Are we sure about it because, again, when we looked at this data, say in GETUG-15, for the docetaxel sensitivity, patients who had seen docetaxel for castration sensitive disease did not respond the same way to rechallenge to docetaxel as compared to patients who were naïve.
NJ: Yes, and I've seen you present that data. I think GETUG-15 used up to nine cycles, didn't you?
KF: Right.
NJ: So I think you've got patients who have had more chemo are more likely to be resistant to rechallenge whereas in CHAARTED and STAMPEDE it was only six cycles. So our experience was that these patients were still reasonably docetaxel sensitive. Coming back to the head to head things, you're right, they may not be quite as docetaxel sensitive as if they've never had it but they certainly are to a degree. But when we started looking at later endpoints, like time to symptomatic skeletal events which both drugs reduce, there was no difference between the drugs.
KF: Don't you think that the follow-up for this analysis is too short to show?
NJ: Well, it's the same follow-up as… well, it's longer than the median follow-up for the whole abiraterone arm in STAMPEDE so it's reasonably -
KF: Right, because the curves that were shown were actually cut to two years plus.
NJ: It's exploratory data, obviously, it's not definitive. But the very striking thing was that the hazard ratio for the prostate cancer specific survival was spot on one and the hazard ratio for skeletal events was slightly in favour of abiraterone but only very slightly.
KF: Do you plan to reanalyse that with a longer follow-up?
NJ: We will do, yes.
KF: I think it makes sense.
NJ: But the other very striking thing in that was that there was an excess of non-prostate cancer deaths on the abiraterone arm compared to the docetaxel arm. So the overall survival actually shaded in favour of docetaxel.
KF: I think yes.
NJ: So one of the concerns I have about if you move any of these AR targeting agents very early, and obviously SPARTAN and PROPSER presented data which essentially did the same sort of thing, is that if we're not careful we will harm some patients by overtreating them. For sure there are oncological benefits but there may be non-oncological harms.
KF: Yes, we need to look at that. Now let's talk about the future maybe. We have several ongoing trials, I guess it's fair to say that there are now two standards of care for M1, either ADT docetaxel or ADT abiraterone, and for frail patients ADT alone remains a possibility. But still these patients die from their disease, those treatments are not curable. So we need to do a better job. Obviously one option is to integrate new drugs or perhaps to use three drugs instead of two. So what are you guys doing at the moment in STAMPEDE, for example?
NJ: Within STAMPEDE the live arms at the moment, they're not new drugs, in fact. The two arms we're recruiting to at the moment, one of them is metformin because there's a lot of epidemiological data suggesting that diabetics on metformin live longer than diabetics on insulin, say, by quite a margin, so 25% longer. So it seemed worth testing in a trial, it's a simple pill to take and we feel it may also modify the long-term hormone therapy toxicities as well, weight gain and stuff - metformin makes you lose weight. So that's recruiting nicely, actually, ahead of schedule. Silke Gillessen and Noel Clarke are the lead investigators for that and that's got a few years to run before we can read that out. The second thing we're recruiting to at the moment is again a bit what you might term left field. There has been a long time running a trial in the UK called PATCH which is using oestrogen patches as a way of ADT instead of Zoladex or whatever. The rationale for this is that a lot of the side effects of ADT like bone loss, energy level loss, things like that, are not driven by testosterone depletion, they're driven by oestrogen depletion and GnRH analogues deplete oestrogen. Now, if you give oestrogen to suppress testosterone you therefore don't get things like the bone density loss and some of the cardiovascular effects.
KF: Those are the two arms you're looking at at the moment?
NJ: Yes, so that's recruiting. We've added PATCH onto STAMPEDE and the PATCH trial is separately still recruiting and we're going to merge the two trials. There's an interesting statistical methodological change here because we'll end up with two trials which are on their own are not powered, they're only powered when we put them together. Which is quite an interesting model, I think, for international collaborations in the future because it's ferociously difficult running cross-border trials. I think we maybe should be looking at running multiple trials, each underpowered on its own as a way of doing that.
KF: We are also addressing other questions, for example, in the PEACE1 phase III trial as you well know we are looking at the question as to whether three drugs with castration, abiraterone and docetaxel, are better than just two with ADT and docetaxel. The trial is running quite well in terms of accrual so hopefully we will be able to complete the accrual this year and to get some readouts. You know also that all our colleagues from Australia and other countries are doing the same trials with enzalutamide. So I think that's going to be interesting because there's a chance for these agents not to have so much cross-resistance, which is what we know from the clinic, so their benefit might be incremental. So we will see. Talking about metformin…
NJ: Absolutely. I was just going to ask you about the docetaxel thing. How powered up do you think you're going to be to answer the docetaxel plus or minus abiraterone question and the same questions for enza met? Because they've made the same change that you've made in PEACE1, haven't they?
KF: I think eventually both trials will have approximately 500-600 men randomised to get abi or enza while they had already received docetaxel.
NJ: Do you think that's going to be enough?
KF: Who knows? Maybe we will have to pool data to test the concept of strong AR targeting drugs. If a big difference exists we'll see it and we're aiming to big differences, to be honest, when we are adding treatments after treatments.
NJ: That might mean managing them when they relapse though.
KF: Of course but still we are perhaps inventing new treatments, things about PSMA targeted radioisotopes or radium, the VPARP story etc. Anyway, I think it's time.
NJ: Gosh, already.
KF: That was really fun to do. Thank you very much for listening to us tonight and hope to see you next time. Thank you very much.
