Latest developments in prostate cancer
Prof Axel S. Merseburger – Hannover Medical School, Hannover, Germany
Prof Peter Mulders – Radboud University, Nijmegen, Netherlands
Prof Pablo Maroto – Autonomous University of Barcelona, Barcelona, Spain
Prof Peter Iversen – Copenhagen Prostate Cancer Center, Copenhagen, Denmark
AM: Hello and welcome to ecancer. My name is Axel Merseburger and I’m here in Italy, Baveno, at the beautiful Lago Maggiore, here at the current Prostate Cancer Treatment meeting with three experts. We have an interdisciplinary group, we have Peter Mulders from the Netherlands, we have Peter Iversen from Denmark and we have Pablo Maroto from Barcelona, Spain. So we had a very interesting and intensive discussion the last couple of days on treatment options and new developments in CRPC disease and how to treat those patients. So, Peter, may I ask the question what is the new definition, the EAU guidelines have slightly changed with regards to the definition of CRPC. Could you elaborate and educate our audience how you see and how is the definition of CRPC?
PMu: One of the reasons why we are sitting here because the term CRPC started; it’s not hormone sensitive or insensitive, it becomes castration resistant. So patients are castrated level of testosterone. And we know that because in the chemotherapy data earlier on and the TAX-327 theory we know that the AR was still on, turned on. So the inclusion of the new hormonal therapies in castration resistant prostate cancer was there with a washout of antiandrogens, bicalutamide term. And that’s the slight change in the recent guidelines, that this washout period is not really necessary to start these new hormonal therapies these days.
AM: So, in other words, for daily clinical practice would you recommend and personally do not use a combined maximum androgen blockade anymore? Or would you do it traditionally or would you right away go to the new treatment options we have?
PMu: Yes, I think the complete androgen blockade still may exist in the definition and the slight differences you may achieve with complete androgen blockade on certain indications. The thing is when the washout period is by stopping, expecting the withdrawal phenomenon which does not really relate to, for instance, overall survival so that’s the reason why by having these new treatment modalities like abiraterone and enzalutamide with an overall survival benefit that the washout period is not really necessary anymore. So the manipulation of bicalutamide, adding or stopping, I think that’s something which is vanishing now with the new hormonal agents.
AM: What is still in the definition of CRPC is the evidence of metastatic disease and this was also something what we have discussed the last couple of days. Maybe, Pablo, can you find some words? Do you think there is such a thing as M0 CRPC or is this something that is an issue of just traditional imaging modalities?
PMa: I think that’s the problem. In fact M0 was a definition to perform some kind of trials in a population of patients with low tumour burden. So we are defining M0 as fifteen years ago a normal CT scan, a normal bone scan but probably they have M1 disease with low tumour burden that we are not detecting with the techniques we have now. So the implication is that…
AM: What techniques do we have now? What is the state of the art imaging when we come to your centre?
PMa: For most of the centres, the normal patient would perform a CT scan and a bone met scan.
AM: So that’s considered as standard.
PMa: That’s the standard. But with time we are asking for more NMR to define bone disease but still it’s not a standard of care.
AM: And what has been also presented throughout the various congresses is PSA where you have the specific prostate membrane antigen. Do you think it plays a role in future imaging?
PMa: Sure, the problem is to extrapolate those data and those techniques to other hospitals with less experience. It is something for the future, not in the immediate future. NMR is probably easier although it takes more time for the patient.
AM: A very interesting development. And since we have the definition now, we have the imaging, we have metastatic CRPC, Peter, from your information derived out of this meeting what are the current first line treatment options? What are the options and your preferred choice in first line CRPC?
PI: I think as physicians with a special interest in treatment of prostate cancer and CRPC in particular what we have witnessed during the recent four or five years is almost what the French revolution was to historians. It has been really remarkable, we have seen the advent of new treatment modalities and also different targets. What we discussed, especially during the meeting here, were the two endocrine new modalities, one androgen synthesis inhibitor, abiraterone, and the androgen receptor signalling blocker enzalutamide. And both these agents were evaluated in trials both in the pre- and post-chemo setting. Even though they are remarkable in terms of response and also prolongation of life, we are really talking about life prolonging treatment modalities, we are left with a large number of challenges. We need to define when to start, when to discontinue this often very costly treatment. We need to define what are the best sequencing, what are the possible combinations that we should explore. So there are a number of very, very interesting questions that were very intensely discussed during this meeting.
AM: So do you think there is a role of chemotherapy and at what point would you…? We have discussed the CHAARTED trial with early chemotherapy where we only have a small portion of patients really having this indication but what is your personal view on the chemotherapy role?
PI: I think this is very interesting because there is no doubt that the CHAARTED trial and the data coming out of that trial really has started a very intense discussion about the role of chemotherapy and when to position chemotherapy. As I said, these new modalities, abiraterone and enzalutamide, have been tried both pre and post but nobody ever compared in a randomised design the pre-chemo use versus the post-chemo use. The CHAARTED trial really raises the question whether we should use chemotherapy at an earlier point in the history of the disease. But unfortunately we don’t have the CHAARTED trial on print yet and, as you probably know, there is contradictory data in a big French study, the GETUG trial, so it’s not a solved issue by far.
AM: But for the patients with mCRPC chemotherapy still plays an important role within the sequence?
PI: I have no doubt.
AM: We are not sure at what point of the sequence?
PI: Precisely. I have no doubt that chemotherapy still has a very important role to play, the problem is when to use it in an optimal way.
AM: Let’s ask Peter Mulders, what is your opinion on the chemotherapy discussion?
PMu: So we had a very vigorous discussion here at this meeting with urologists and medical oncologists on a little bit of a revival of chemotherapy because we, as urologists, always said it’s not really active, what’s the gain of three months? But now we see that there is a place for chemotherapy even more now we have the new hormonal therapies. We don’t have the level 1 evidence because the trials were designed in pre- and post-chemo to randomise between these new hormonal therapies and chemotherapy but there is a sub-cohort of patients that really benefit from chemotherapy with more overall survival benefit than even in the traditional TAX-327. So it’s really the decision on chemotherapy or new hormonal therapies in castration resistant prostate cancer patients which is really key. We don’t have the final answer, we came up to maybe a little bit of a consensus, but on the other hand the knowledge on the role of chemotherapy has gained substantially.
AM: So myself, also being a urologist, would underline, underscore, the need for chemotherapy in the sequence. So, Pablo, do you agree with what has been said now that chemotherapy has an important role? And, adding on to that, what is your… from this standpoint now, in a couple of weeks we have the big ASCO meeting, what is the data that you are looking forward to to be presented at ASCO and what might this change throughout the next months for the patients with CRPC?
PMa: Yes. I am a medical oncologist, docetaxel prolongs survival, that’s definitely something we have to take into account. Docetaxel has beaten a lot of new drugs and has been compared to new drugs and always been successful. So it has a role in the management of the patients with castrate resistant prostate cancer besides, of course, always patients and doctors we prefer the less toxic drug to start with. So I think that’s the point. But, again, docetaxel has the role for a few patients, maybe 20% of the patients, it is still my preferred first line.
AM: In all patients? Asymptomatic, minimal disease or…?
PMa: Sorry, castrate resistant disease, visceral metastases.
AM: So this has changed?
PMa: And probably moderately symptomatic.
AM: So this has changed throughout the years with the novel substances that you, as a medical oncologist, do not start with chemo up front but that you use hormonal treatment as first line?
PMa: Sure, yes. It has been a change in the later years, yes.
AM: OK, so it also… And we have a lot of discussion in Germany, and we had this at this meeting, with the role of ADT treatment. Should we continue, when we initiate chemotherapy and those novel treatments should we continue ADT or can this be omitted?
PMa: Again, looking to the clinical trials we always maintained ADT. So if we want to reproduce the results of clinical trials we have to maintain ADT
AM: And this combination obviously doesn’t harm, safety-wise.
PMa: Exactly.
AM: Is there…
PI: To some extent it’s an academic question because many of these patients will be castrated either surgically, irreversible of course, and then pharmacological where there is a certain entity with very low testosterone. So effectively these patients will be castrated for a very long time during chemotherapy.
PMu: So we had the castrate resistant prostate cancer patient population where these new hormonal therapies showed activity. So by definition you need castration levels. We will gain from the future when these new hormonal agents will be tested in an earlier phase and that will happen, the trials are designed already, and we will have that answer in a couple of years’ time. But so far the indication for these new hormonal therapies is in castration level patients.
AM: OK, so a lot of excitement, a lot of development and research we have discussed. Basic research-wise, predictive markers there has been this publication on AR-V7. Your personal view – will this come into clinic and when will this be? Because we get a lot of requests from patients, do you offer this test, can we be included in a clinical trial where it’s offered? Do you have CTCs available at your centre? So what is your view, Pablo?
PMa: The paper in the New England of the AR-V7, it’s amazing, I recommend to read it because it’s the translation of something new, it could be the translation of something new to daily practice. The problem is to reproduce those results in the clinical practice. CTC are available in hospital and available in a lot of hospitals but we don’t know what they perform, if the technique can be easily reproduced in the CTCs we can get in the patients. And also we don’t know about the role of the CTCs as a response for each of the therapies. As you know in some trials CTC has been a predictor of survival and changes in CTC have been predictors of survival, in other trials they didn’t. So to your question, yes, AR-V7 is promising but we need other drugs that work in those patients with AR-V7 positive to be translated into clinical practice. And I don’t see it easily reproducible in all the hospitals.
AM: So future-wise, time-wise when would you suspect to have it readily available throughout Europe? Just a guess. Peter?
PMu: I don’t think…
PI: I think we have started in university institutions, maybe within a year or two. I’m as enthused as everybody else about the initial data but it’s a relatively small series, it has to be confirmed. Even though I’m not a lab technician I know that there are problems with isolating circulating tumour cells so I guess we have to be a little sceptical.
AM: Handing the question over to Peter, knowing that he has a huge laboratory for basic research in urology, so what is your opinion?
PMu: Yes, it will come quicker than we think because the data will be accumulated very fast. A lot of centres are doing it. This splice variant is very promising, it needs to be validated but there are more factors involved there. The striking thing is, to me, that if you’ve seen the retrospective data that if you give abiraterone in castration resistant prostate cancer then afterwards enzalutamide, or enzalutamide and then abi, the results are quite frustrating. There is really a role then for chemotherapy. That was also a little bit of consensus of what we had here. But the reason for that should be followed not only by the clinical symptoms, the radiological parameters and the lab values but also very soon the implementation of these new splice variants. If it is AR-V7 as a sole, if it is in circulating tumour cells or even in biopsies we do more and more biopsies to detect really what is the best sequence of these patients and how abi and enza and chemotherapy should have its place.
PMa: In any case we have identified the first variant but there are a lot of variants out there and we don’t have the technique to identify those variants yet. So we are just starting to work on it.
AM: Very exciting times. I’m looking forward to meeting you gentlemen again at ASCO in a couple of weeks and I thank you very much for educating me for this lovely discussion. I would like to thank the audience for listening to us at ecancer. Thank you very much and goodbye.
