Dr Elena Verzoni - Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Prof Pablo José Maroto-Rey - Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Dr Elzbieta Senkus-Konefka - Medical University of Gdansk, Gdansk, Poland
Dr Simon Crabb - University of Southampton, Southampton, UK

EV: Hello and welcome to ecancer.tv. I’m Dr Elena Verzoni, I’m a medical oncologist from Milan, Italy, and we are joining you from a current treatment practice meeting about prostate cancer patients in Brussels. I’m delighted to be joined by my colleagues. We have a lot of European countries that are represented and we had many discussions today about the treatment of patients with a diagnosis of prostate cancer and then we could analyse the most important topic that we have shared about our discussion today. Then let’s start with the hormone sensitive setting that is the most intriguing setting in the last few years because we have many news. Then could we speak about our discussion about which patients we have to treat with docetaxel up front and if all patients must receive this treatment, de novo patients or patients that become metastatic after an initial treatment? Ela, could you please?

ESK: Yes, indeed. This is probably the most hot subject over the last years because of the new treatments which really changed the fate of metastatic prostate cancer. It was something which was, at least for me, rather unexpected after all these years, nothing was happening to this population. Everybody was studying the castration resistant cancer, there were new drugs appearing and the hormone sensitive seemed to be sort of left alone. And suddenly we had these studies which really demonstrated a huge benefit. But now, of course, we have the rationale to treat the patients with the treatment but we don’t really know which patients should be treated and how we should select patients for this treatment. One is, of course, that patients have to be fit enough for docetaxel but this is probably not a major limiting factor. But the other issue is are all metastatic hormone sensitive prostate cancer patients the same? Here there can be a number of divisions but one very important one is that patients may present de novo with metastatic disease or they can develop metastatic disease later in the course of the prostate cancer, after whatever local treatment they had. So it’s probably different biology; it’s probably a different volume of disease. Patients who present with metastatic disease are, in general, symptomatic while patients who develop this progression, metastatic progression, later on are often found to be metastatic because of a PSA rise and some imaging which actually discovers the metastatic foci. So they usually have a lower volume of disease and they can also have completely different disease kinetics. Some of them recur quickly and some of them may recur after many years. So this is one point, the other was whether we should treat all patients irrespective of the volume of disease or we should divide them into low risk and high risk populations and what is the division line. Again, the CHAARTED study suggests that the benefit is larger or is limited to the high volume disease patients although the amount of patients who were low volume disease is small and actually these data are changing from the first publication to the recent data. There’s a complete switch of the effect which makes it questionable. We also had a discussion about the definition, what is really hormone naïve, what is hormone sensitive…

EV: Those are different populations?

ESK: What is castration sensitive. And these are very similar populations and it was raised, absolutely correctly, that actually we are talking about patients who are not castration resistant. I think it’s a very good definition but it’s not the commonly used definition. So we can have hormone naïve patients, that is the ones who never had any hormonal treatment. We can have hormone sensitive patients, or at least the ones we presume which they are hormone sensitive and this includes hormone naïve but this also includes patients who had hormones some years ago, for example in combination with radiation therapy, and they were free of these hormones for a number of years. Also talking about exposure to hormones, they could have been exposed to castration or they could have been exposed to antiandrogens and, again, it’s not necessarily the same population. So there are a lot of question marks about which patients are the optimal candidates for docetaxel and, on the other hand, this is a treatment which really prolongs overall survival so any decision about not giving docetaxel to any particular population has to take into account the risk that we are actually not giving a treatment which is really impacting the fate of these people. We mostly need the first longer follow-up and I think STAMPEDE is probably going to deliver a lot of useful data. So we really have to wait and learn from experience.

EV: OK. And then consider the discussion that we have, what do you think that tomorrow is the best recommendation to treat patients in clinical practice? Which is the kind of patient that you propose to up front docetaxel? Low volume, high volume, for all patients do you propose docetaxel tomorrow morning in clinical practice? What is your recommendation in different countries?

PMR: In fact, my recommendation is we are not dividing by low and high volume of disease, we are dividing patients that are fit or unfit for docetaxel. As our colleague said, if the patient is fit for docetaxel you have to explain why this patient with a therapy that prolongs life is not given to that patient. So it’s a different kind of discussion.

EV: OK. Simon?

SC: I think it’s easiest to think of the people you definitely will offer it to. So clearly they have to be fit enough to safely receive the docetaxel and I think anyone with high volume metastatic disease, again, that’s fairly straightforward. I would agree, I don’t personally divide by high and low volume disease which I think is rather an artefact of the way that the CHAARTED trial proceeded for reasons that made a lot of sense in the way that trial was designed. But if you look at STAMPEDE the trial is positive overall and I think you can make a justification for low volume disease. Then you’re left with people where I think it gets a lot more challenging. So, for example, people who have had radical therapy and have progressed many years later and have had their progression detected effectively by PSA screening and then subsequently development of metastases, whether those people derive as much benefit as people that present de novo we really don’t know but they were part of the STAMPEDE trial certainly and the trial was positive so I think there’s a rationale for doing it. It’s just less clear whether there is real benefit. The other group are people that have less than M1 disease. So in STAMPEDE we included people that had node positive but M0 disease; we also included high risk relapses after radical therapy and that’s a very challenging situation. Personally, for people that have nodal or metastatic disease, I think if you know that this is a patient you’re likely to give chemotherapy to at some stage then, for me, it makes sense to give it up front rather than for castrate resistant disease. But I know that other people would probably say that that was overtreatment and I think it is an open area for debate.

EV: OK. And then we have another challenge point that is we treat this population, and this is a new population, that have a big problem when progressing because we don’t know how to treat this population. This is the next challenge about this population of patients, then we can discuss about this. OK, let’s move to castration resistant disease. We know that there is the insurgence of castration resistant disease after a different way, it depends from the previous treatment of patients if they receive local treatment or hormonal treatment. But if we have castration resistant disease we discuss about patients that became castration resistant but with no evidence of metastases. Then, is this a population that exists and how we treat these patients. Please Pablo.

PMR: Thank you. Yes, it exists because we have more than 3,000 patients randomised in clinical trials. But in each meeting always someone says, ‘Well, it’s a population that is going down. In the future we won’t have those patients.’ I personally agree about that because we have better radiological techniques to detect metastases and probably we are not treating hormone sensitive disease without evidence of metastases, as we used to treat in the past, in the old times. But, yes, absolutely, this population of patients exists and we have randomised trials where we are awaiting results to make proper recommendations for the management of these patients.

EV: OK, but waiting for clinical trial which is your practice for these patients, if they exist? If you have patients which kind of treatment or no treatment or follow up with radiological technique?

PMR: Yes, we follow the [?? 11:31] guidelines; we always ask or calculate the PSA doubling time, we decide about management about the PSA doubling time – less than six months, less than one year or more than one year – and decide the follow-up based on the PSA doubling time. If it’s less than one year we follow them closely, more closely than if it’s more than one year, and perform radiological techniques every three months or whatever if we have a rise in PSA. It makes it interesting if things are maybe changing. Besides that, we don’t have any level one therapy for those patients prolonging life so our recommendation is just to follow up and treat it then if we don’t have a randomised trial available. Treat them when we detect metastases.

EV: OK, do you agree with him? Have you something to add?

ESK: One aspect which is specific for the subpopulation of patients is that I agree that the number of these patients or proportion of these patients is directly related to the intensity of the imaging and searching for the metastatic disease. And probably theoretically they do not exist. If somebody has rising PSA they must have disease somewhere. They may be either metastatic or local recurrence but they must have disease somewhere. The optimal situation is if we could find the disease and then possibly it’s always tempting because obviously they have low volume disease because if it’s high volume it would be discovered very easily. So if it’s low volume disease it’s always tempting to use local therapies such as in the concept of oligometastatic disease. So we tend to do an intensive, quite intensive, search for metastatic disease in these patients and if we localise a single bone spot or something, whatever, a lymph node, then we tend to try locally ablative therapy possibly with an idea of delaying of further need for systemic therapies and development of further resistance.

PMR: Yes, but again it’s something that is within some clinical trials although in clinical practice maybe you can make some recommendations about that. But something that we are analysing the real role in clinical trials. But, yes, it could be an approach.

EV: But we are waiting for the results about the trial for these patients, SPARTAN and PROSPER trial with new hormonal agents. We know that the primary endpoint is metastasis free survival, do you think that is the good point for this population?

PMR:  We have been discussing if it’s enough to start a therapy just because we are delaying metastasis. I think the panel agreed that probably we need something else – quality of life, delaying pain, delaying symptoms. Of course if we see survival it’s absolutely enough. I am very excited to see certainly if it’s just radiological progression free survival that’s something that a couple of months, that I really believe that it is not going to be. Or if we can expect something else to justify the therapy, that hopefully we will find successful therapy for these patients. In the end saying that early therapy is better than delaying therapy so let’s see what are the results of these trials.

ESK: I think the interesting bit would be to see similar studies but with crossover and really comparing early introduction of new generation hormonal therapy versus introduction of the same therapy at actual development of metastatic disease and then to compare the overall progression free survival and also compare the quality of life as a kind of sum of all quality of life results over the whole study. Because of course the moment the patients develop metastatic disease their quality of life goes down but it goes down for a while and then if they start active treatment it improves. So maybe it’s just a matter of moving this drop in quality of life in time but not necessarily of improving the quality of life. So that would be sort of conclusive studies for me and, of course, overall survival but not necessarily just a metastasis free survival which most probably will be seen.

EV: OK, good. And then they are a small group of patients but they intrigue us to discuss about them and then good point. Moving to castration resistant disease and then sequencing, we have no news from this meeting and from the last clinical trial. Then I think we discuss about changing the mechanism of action of an agent from another but there is no recommendation to add to clinical practice. Do you think that something…?

SC: So the data for castrate resistant disease hasn’t changed, it is what it has been for a few years now. The big difference, I guess, that we’re all going to start to see is people coming through to castration resistance having had docetaxel up front. We’re not going to repeat the phase III trials, we’re all going to have to make pragmatic decisions. I think also this will evolve over time; so the patients that I’ve seen so far that have relapsed after docetaxel given in the hormone sensitive setting inevitably have relapsed quite quickly or progressed quite quickly. So in those patients it’s tempting to feel that perhaps they’d be better with a hormonal agent rather than more chemotherapy. We have no evidence for that but it makes some logical sense. But inevitably those patients, and certainly this has been my experience so far, then will progress through that agent relatively quickly. So you are probably then thinking about cabazitaxel. That will be very different in five years’ time when you have someone that progresses who has not had chemotherapy for five years; you might well want to think about re-challenging or perhaps cabazitaxel. But the problem will, I think, continue to be that it will be a rather pragmatic approach and we will probably be doing it primarily on the trials that are already available to us. What I guess we would hope is that we would have better options for stratification going forward and that that might help to guide us. And probably we’re on the verge of those sorts of things coming through although it’s early days.

ESK: This one thing which may appear in the future is that there are trials ongoing testing the modern AR-targeting agents in the hormone sensitive setting. We still don’t know the results of these trials but if they are positive then there will be a tendency to move these agents to the hormone sensitive setting and then the moment the patients actually develop castration resistance they will have been exposed to docetaxel, to possibly abiraterone or enzalutamide and, depending on the disease free interval or progression free interval, there will be a possibility of re-challenge. But basically there will be not very much left for these patients so this is going to be difficult. Hopefully there will be some new treatments appearing.

SC: We talked about that a lot during this meeting. There are phase III abiraterone trials in the hormone sensitive setting that are likely to report in the next twelve months. If they’re very positive, if we see the sort of advance that we saw with docetaxel, if we add over a year to survival, then we will have very difficult questions to ask ourselves about whether we use one or the other, whether we use both, whether we use both but in sequence. We just will not have clear answers to that and will have to make pragmatic choices and, of course, there will be the overlay of access to treatment. What may of course happen is there may be a benefit but it may not be as much as a year or eighteen months that we now think is potentially possible in this setting. So I think it’s going to be fascinating in the next year, I think it’s going to leave us with difficult decisions.

ESK: The current trials actually allow for including patients who were exposed to docetaxel so this will be another solution. If these trials are positive the patients first get docetaxel and then they, as a kind of maintenance, get abiraterone or enzalutamide or any of the new agents which are coming to the market with similar mechanisms of action.

EV: Then moving to the future we have discussed about which are the best candidates to change our clinical practice in the next few years, about PARP inhibitors and what else, Simon?

SC: Yes, in terms of new agents probably the leading candidates at the moment are firstly PARP inhibitors and particularly with the potential to provide a selection strategy, to be able to identify patients that might benefit. Secondly, immunotherapy which for some time people have thought perhaps wasn’t going to be an area of particular interest in prostate cancer. We’ve seen negative ipilimumab trials but it does look from recent data, and it is very early data, that there probably is the possibility to develop a selection approach to how you might use checkpoint inhibitors. Clearly that’s going to require a lot of prospective work and certainly wouldn’t be possible at the moment outside of a clinical trial. But it does look exciting. Also we’ve seen recently evidence that it may be possible to select patients, at least by p10 loss, for targeting of PI3K AKT signalling. So those are the potential areas. If, for example, you look at PARP inhibition as we’ve seen in the TOPARP trial, this was a small study, it was an unselected trial but the benefit appeared to exist primarily in a group of patients that had a particular biomarker signature for DNA damage. We’ve seen great advances in prostate cancer but in some respects we’ve been left behind other solid malignancies in that we haven’t yet developed a stratified approach for patient selection for targeting of drugs. This is probably the key example, going forward, of how we might be able to do that. But there are loads of open questions. Firstly, TOPARP has to be validated and that trial is ongoing at the moment, taking patients who are selected on the basis of the biomarker that was developed in that trial. But we don’t know if that’s the right biomarker or the optimal biomarker so there will be other studies that will use variations on that theme and it will be interesting to understand whether or not we can come up with the optimal approach which may not necessarily be specific to a particular drug. There are a variety of PARP inhibitors which we’re going to see developed in prostate cancer. TOPARP also primarily was a trial done on fresh biopsies. We are going to see stratified phase III trials in this disease, in castrate resistant disease, and they’re going to be using archival samples and we don’t know whether that will work in the same way. So it’s fascinating but it’s definitely the way the disease needs to go. We can’t keep doing clinical trials of targeted agents in unselected populations. So this is really exciting times.

PMR: I think it’s a very important thing to take into consideration that the disease is completely different from when we started to treat it with hormones in the hormone sensitive disease, five years, seven years ago and right now with the patients right now with us after two or three therapies. So a necessity of fresh biopsies is something really disease changing but probably we will have to adapt our therapies to the changes the disease is presenting. So I think we have to develop the techniques of fresh biopsies and real life representation of the tumour to decide therapies.

ESK: A liquid biopsy may be actually a very attractive option. First, it somehow corrects a little bit for tumour heterogeneity, at least if you think about things like circulating cell-free DNA. And of course it’s easier to perform than the biopsy of a lesion and you always biopsy a single or you may biopsy two lesions but you will not biopsy thirty lesions. So this is probably a most interesting way to go in terms of searching for biomarkers and definitely we need biomarkers because there are many new drugs in general appearing and there is also the financial toxicity of this treatment. We are going to face this problem so we need to be able to select patients better.

EV: Yes, it’s a long way but we have to do this to select the best drug for the right patients. It’s a long way but we are excited to do this. Thank you to my colleagues for this discussion and thank you to ecancer.tv for permitting us to share our experience about this meeting. Thank you very much.