Prof Nicholas Mottet – University Hospital of Saint-Etienne, St Etienne, France
Dr Philipp Mandel – University Hospital Frankfurt, Frankfurt, Germany
Prof Amit Bahl – University Hospitals Bristol, Bristol, UK
NM: Hello everybody, we are here in Frankfurt for the PROSCA meeting which tried to summarise the new data and the evidence base we have on treating prostate cancer nowadays. Especially today we will discuss a little bit about castrate resistant prostate cancer. Let’s start with you immediately about CRPC. We all know the definition of CRPC and recently two papers were published on m0 CRPC, the second one was just published yesterday in New England. So there are two questions for you, the first one is does this stage exist in 2018? And the second question is are you convinced by postponing the mets in the M0 CRPC?
PM: Yes, very good questions. To come to the first question, first of all it’s a matter of how you do the staging. When you use conventional staging – bone scans or CT scans – we do know that the risk of detecting metastases is much lower than, for example, using new imaging modalities like the PSMA PET scan which we do have available in Germany in many, many hospitals. That’s why sometimes clinicians or patients do this out of clinical trials just because they’re available and we all know if the patient wants something very hard that sometimes we just do it. In very, very rare cases it might be that the stage of M0 CRPC does exist but in the majority of the cases I’m quite convinced that there occur metastases somewhere. The good thing about the new studies and the new medications is that we are moving away from the scenario where we say we have to wait until we can see metastases in whatever imaging modality we are using. So we move away from this quite frustrating scenario for us as treating physicians and for the patients to say, well, we have to wait until we see metastasis even though we are quite convinced that there are somewhere metastases but we just can’t prove them because the licensing trials for enzalutamide, abiraterone and the other substances always said it’s metastatic castration resistant prostate cancer. So, to come to your second question, first of all this is, apart from the oncologic data, it’s a good psychological effect for the patients to know that we can do something apart from just waiting for metastasis to occur. If I’m convinced from the primary endpoint, metastasis free survival, as I said, from a psychological point of view this is a very valid endpoint. But if you look at the secondary endpoint, symptomatic progression, this was statistically significant as well so this is an even more valid endpoint, and if we see, for us the most important secondary endpoint, the overall survival, which is not statistically significant yet but it was only an interim analysis where only round about one quarter of the patients needed in the prior calculation already had an event – they died. So these data also on overall survival are very promising and within the next one or two years, as you’ve already said in the session today, I’m quite convinced that this endpoint, which is the most valid one, will also be significant.
NM: Amit, if I got the point correctly, M1 disease is just a matter of definition of which tool you use so M0, M1 are almost the same if it’s CRPC?
AB: Yes, and if you talk to all the radiologists who are specialising in all these new technologies, the word that is coming out, which I say it but it’s not a joke, it’s like M0.5 – it’s what do you want to detect and what is your policy? In some ways this will make us think what are we trying to investigate, why are we trying to investigate it, what will it make us do? Let’s say SPARTAN with apalutamide and PROSPER with enzalutamide, you have a patient who is progressing, there is no evidence on CT and bone scan and you believe the data. I agree that the overall survival might mature and come out. But at this juncture, you’re absolutely right, the symptomatic progression was important and metastasis free survival, in my opinion, is very important. But psychologically I would rather my patient was in a metastasis free state, whatever way we define it, than actually develop a metastasis. It’s a changing situation for the patient’s acceptance. So if I want to do that I will stick with CT and bone scan and give them one of those drugs. But in the past when you didn’t have that option then maybe you were keener to do all the newer investigations to be able to show that you’re dealing with M1 CRPC to be able to give them the abiraterone and enzalutamide.
One very interesting thing which, whilst we consider SPARTAN and PROSPER to be very equivalent studies, they are for the start of it, but SPARTAN actually had the option after apalutamide of being given abiraterone or another drug but the majority got abiraterone. It’s almost like understanding that do these drugs actually work after apalutamide because the question that will always come now is that the earlier we bring enzalutamide or apalutamide, does it leave us only with chemotherapy after that in the real world, or radium-223. So are we taking out those options? That I would like to see in the update of these trials as they come along because I’d really like to see, even though we saw the composite PFS but you didn’t really understand the exact benefit that was coming from the abiraterone in that setting. That’s something, because how do you decide which drug you will give? There is a different side effect profile but the efficacy seems quite similar. So you need the data not just from side effect and efficacy but also sequencing.
NM: That’s correct. Do we agree that the evidence so far that abiraterone after apalutamide, it’s not there? It’s not there yet.
AB: I don’t think so, it’s not there. I don’t think you’ve got the evidence to make a statement, put it in a guideline or recommend it.
NM: The second point to both of you – are all M0 CRPC equal? Are they all the same or are we just discussing here a subgroup of M0 CRPC?
AB: They are not all the same. Everyone who has treated prostate cancer knows that they are not all the same. You have a patient who is M0 CRPC, you keep on scanning them, keep on scanning them and nothing happens over months, even a couple of years. Then there are some patients who within the space of three months actually develop such frankly metastatic disease that you look back and go back and check the previous scan and you see there wasn’t disease there. So they are not all the same. You almost look at these studies and the point is you see the drug worked in M1 CRPC, was it a surprise that enzalutamide would work in M0 CRPC? Absolutely not. So it’s almost the drug to be given to the patient who would otherwise have progressed quite rapidly. Where you can afford to wait I would still potentially wait and see what happens to the disease trajectory at that time point.
NM: What I wanted to highlight, and that’s a question for you, that they’re not equal, not all M0 CRPC are equal, but the data we have are there only for those with a doubling time of less than ten months and most of them had a median PSA doubling time around four months. What the hell[?] with those with a longer PSA doubling time?
PM: Well, probably we just don’t know. We do know that it works for patients with a high risk of metastasis. We do know that a PSA doubling time below ten months is one of the strongest risk factors for the development of metastasis within the next month. Especially these are the patients who have a need for treatment because, as we discussed before, we don’t know, these are maybe the patients who are already M CRPC but we just don’t know. So that’s why it’s quite obvious that these are the patients who need the treatment. Patients with a very slowly rising PSA, we do know that they will not develop metastases so early; we do know that they have a better quality of life. So it’s similar to other debates – we should treat patient risk [??] and patients with a high PSA doubling time are the ones who profit most.
NM: The message is very important but I want to highlight something: it’s absolutely true that the benefit seems to be there for those with rapidly progressing PSA, so individualised treatment. I’d just remind everyone that salvage ADT, salvage ADT, is probably only useful for those with a rapidly progressing PSA. That’s not the case, that’s not how it’s used worldwide. So we have to reinforce, it’s probably correct for a subgroup of M0 CRPC.
The next step will be M1. Let’s say we have M1 based on bone scan and CT scan. We are facing a question of which people. We have a lot of drugs, million dollars for you, Amit, how do we select?
AB: You see, this question gets asked so many times. Unfortunately we don’t have level 1 evidence to say the sequence of docetaxel followed by abiraterone followed by cabazitaxel is better than abiraterone followed by docetaxel, whichever way. So the important message here is that we need to make sure that patients can avail life-prolonging therapies when they are fit enough to get those treatments. So it doesn’t matter what you give to them as long as you’ve explained to the patient that I need to monitor you. The question is not only about whether you get just oral therapy or chemotherapy, the question is whether you get oral therapy and get monitored and when you progress you get chemotherapy or if you get chemotherapy then you get monitored and when you progress you get oral therapy and keeping a close eye on that so that their performance status doesn’t deteriorate to the point that they cannot avail the next treatment. Nobody should be able to question that at all. As long as people do that then you will see that survival is improved. People question whether we’ve improved survival by sequencing. Well, you have to look at the trial results for TAX 327 where median overall survival was 18.9 months in the original publication, became 19.2 in the updated, but there are trials of enzalutamide and abiraterone all going in the 30 month plus range. So clearly with cabazitaxel also if you look at from date of start of first docetaxel chemotherapy median overall survival is 29 months plus. So you have improved survival by sequencing. We will know a bit more when the other trials, like PEACE, report but by the time we get to know that we will be dealing with the situation of the patients having apalutamide or enzalutamide in the earlier setting. Then we would say we have no knowledge of what to do after that.
PM: Yes, I just want to add maybe one or two points but I completely agree. What is always very important as well, which might be even more important in the hormone sensitive metastatic setting but also in the castration resistant setting, is that you also have a look at the life circumstances of your patient at the moment. For example, if you have a younger patient who still wants to run his own business and maybe he doesn’t want all of his workers to see that he has a metastatic prostate carcinoma, maybe for this patient, for example, it would be better to start with abiraterone or enzalutamide because then he can more or less, with some side effects, continue his work. As you already mentioned, windows of opportunity are a very important thing – if you have someone, you think well now he might be fit for chemotherapy but in maybe one year or two years he might be not then you should start with chemotherapy. But the same thing applies to radium-223 – if you have a patient and you think, well, he might progress within the next two years to visceral mets maybe then you should go with radium earlier. But as we have only very, very weak data we can’t really put up the optimal sequence but the most important thing is that patients get as many therapy sequences as possible. Of course this implies a regular staging as well because you have to know when to switch your treatment options.
NM: You both raised a very, very important point – we need to involve the patient in the decision making process. It’s by no means a black and white situation where there is a very, very clear answer for everyone. The patient must be involved in the decision making. Both of you also said we have to follow – could you clarify how to follow and when to decide to switch?
PM: That’s a difficult but very crucial question. We all know that from time to time the follow-up is not sufficient enough. So we all know patients who come back to our outpatient clinics with the last imaging modalities run maybe one or one and a half years ago. They’re showing up with symptomatic bone pain or whatever. So in the CRPC setting it is even more important to do regular bone scans and CT scans compared to the hormone sensitive sector because in the hormone sensitive setting we do have the PSA value still as a quite good parameter for progression. But we know that in the CRPC setting around half of the patients do progress to visceral mets without rising PSA. So the first, very important, statement is you should not do the follow-up alone by clinical examination or PSA, you do have to do CT scan and bone scan on a regular basis. If this is every three months or every six months this is something, or if the patient is doing well maybe nine months. But this is something you have to discus with the patient – you have to decide if you’d rather think that really he will progress within the next 3-6 months or not. It is also very important to do a complete staging, so not say, ‘Well, the last time I did a CT scan, this time I do a bone scan and in six months I’m doing a CT scan again, or maybe a PSMA PET in between,’ because then you just can’t really compare if there’s progress on that. So, to make the point, it is very important to do conventional staging on a regular basis, maybe every six months, and to do a complete staging so you can really compare to the other time points.
NM: When do you switch?
AB: When you switch is always the most difficult decision to make. One has to realise that the guidelines say that two out of three criteria, the St Gallen consensus etc., so biochemical progression, radiological progression and clinical, or symptomatic, progression. But actually two out of three seems quite straightforward but unequivocal radiological progression which is clinically meaningful warrants a change. You cannot sit back and say a patient is not in pain, a patient’s PSA is stable; in fact, probably the patient is developing the most aggressive variant of the disease. So you have to be very mindful of this. I fully agree with the concept of monitoring the patient. I always emphasise one point: first and foremost, if you have established your goals of treatment with the patient your monitoring comes with it. Because if you know that this patient has got other two lines of treatment available, then I should be monitoring this patient on a regular basis, then there is no excuse. What is the excuse of not doing those scans as per the guidelines if you know that there is another line of treatment available for the patient? But if there is no other line of treatment available then you do the scans based on symptoms because you are then managing it in that sense. So if your goal of treatment, your discussion with the patient and your options guide you to proper monitoring then you use the monitoring tools radiologically which you have, or your department has, the expertise of reporting. There is no point in ordering a whole body MRI if you don’t have a radiologist who can read it. So just go with your CT scan and a bone scan. Personally I would be very happy with CT scan with bone windows, actually, and you can do it on a three monthly basis, basically. If you have the facility of doing whole body MRI or doing PET scans, fine but don’t mix and match. It is better to be with one investigation which you are comfortable with, which your unit can report properly and do it that way rather than mixing and matching.
NM: Probably you heard a very important message because both of you said the same thing – do medicine. That means discuss with the patient, interact with the patients. There is no magic button where you press and you have the answer, it’s always an interaction with the patient. So probably that’s the most important message of all the sessions of today. So thank both of you and hopefully you enjoyed the session.
