Prof Nicholas Mottet – University Hospital of Saint-Etienne, St Etienne, France
Prof Amit Bahl – University Hospitals Bristol, Bristol, UK
Prof Piet Ost – Ghent University Hospital, Ghent, Belgium
Dr Inge Van Oort – Radboud University Medical Center, Nijmegen, Holland
NM: Hello everyone, we’re here in Frankfurt for the prostate cancer meeting called PROSCA and I’m very happy to share with you some new things and new interpretation of data with some friends. As you are probably aware, there were a lot of new data and very provocative data presented this year. I will start with Inge because she is interested in castrate resistant. We had two provocative presentations and I just heard one is fully published, the second was published yesterday about M0 in the New England. So now we have two published papers, are you convinced, is this really practice changing now?
IVO: I think it’s depending on the country because what we have seen, it’s about the M0 and we don’t have a lot of those patients because we, in the Netherlands, will wait a long time before even starting ADT. So we don’t have those M0s. Probably for a lot of countries where they start really early with ADT that this will be somewhat changing, at least we have to think about it, about adding the apalutamide or the enzalutamide. But, for me in my practice, probably it won’t change that much but I don’t know if it will change in the UK.
AB: No, I think what you are saying is absolutely relevant because we talk about M0 CRPC as though it is a very distinct subset of population. It’s not that. We’ve heard today about M0.5, so there is M0, there’s M1 and it’s only a matter of time how you detect it and what technology you use to detect it. So if you’re going to base it on CT and bone scan you’ll probably have a higher proportion of M0 CRPC cases but as you get more savvy with your investigations and if you’ve got gallium and the PSMA PET scans and everything else to hand then it’s likely that you’ll get less M0 CRPC. It was never in doubt that the drugs which work in M1 CRPC will work in M0 CRPC, that’s not rocket science really. It’s almost a question of getting the drug licensed in that setting to enable clinicians to use it. One thing which I was pleased to hear you say is I think people should not just rush in with the ADT; we have to use it in a very sensible manner and the same should apply to the stage after that when the ADT starts failing.
IVO: Yes, it’s like when starting ADT sometimes it’s just the easy way out. You don’t have to talk, you don’t have to convince your patient that not starting a treatment with having a prostate cancer will add to their quality of life. So that is a difficult discussion, it takes time. I always say, well, if I just give you an injection or the pills then you will be out of here within two minutes; convincing or talking about the possibility of not starting will take me a long time because it’s difficult.
AB: Yes, and I think that’s a very important message for all our trainees, that it’s education of the patient but before education of the patient it’s education of the clinician.
NM: And the second important message is discuss with the patient; the patient has to be involved with the decision.
IVO: That need that information and every patient is different, has to know the options to know that, for me, this treatment will be the right treatment. But if you don’t give those options they don’t have them.
NM: That was the first point, the second is for Piet. We heard from retrospective data, a large database, that probably treating the primary might play a role. Suddenly we have a randomised trial presented at AUA, a negative one, what the hell is there? Positive, negative, where are we?
PO: One of the main things was that all of the retrospective evidence, different papers were actually published on the same datasets. The majority of them were CR datasets or other large registries and inherently they’re biased. Although statistically they try to manipulate, maybe that’s a strong word, the data but actually these data should be used to generate hypotheses. This hypothesis is that has to translate in a trial. The HORRAD trial, which you just alluded to, was at that time a very innovative concept. They said, well, does a local therapy, in this case radiotherapy, is that able to change the disease course? There’s a lot of rationale that you would say, yes, it probably will but, on the other hand, there’s also a big rationale why it wouldn’t. For example, we’ve seen data now that not only the primary can give rise to new metastases but also metastases themselves can give rise to new metastases. So why, all of a sudden, if you have a patient with not only a local tumour and different spots and they can all see it to give rise to new metastases, why would only treating one spot locally, why would that make a difference? That is something why I believe, or potentially believe, that the HORRAD trial was negative – they were all patients with a quite high volume of disease. So in this subset it is clearly shown now that a local treatment is not the way to go. I know that there are urologists who will claim that, okay, radiotherapy doesn’t work probably surgery will. So now we have evidence that for patients with more than five bone mets on conventional imaging and you want to treat them locally that’s something that you shouldn’t do unless, of course, you have some symptoms to palliate.
NM: But that’s a different question.
PO: That’s a different question. But if you want to look for a harder endpoint there appears to be no benefit whatsoever to do that at this time. But luckily there are a lot of clinical trials still running so you can include your patients there or, what I now do with my patients, I say, well, wait until September and in September during ESMO the STAMPEDE data will be presented and maybe then we will have an answer, maybe then we will offer you a local treatment or no treatment whatsoever.
IVO: I don’t think that will make any difference if you treat your prostate with radiotherapy or you just do the prostatectomy. It’s the same thing, it does the same thing, so probably the endpoint will be nothing else than the HORRAD study and it was a good study, it took forever but we now know that it doesn’t work for those kinds of people, those kinds of patients and probably the amount of metastasis will have something to do with it. I’m really awaiting September.
NM: Do we all agree that it should not be done outside a trial?
IVO: Yes.
AB: I think at this juncture you will have to say, and Piet made a very important point, that unless the patient is highly symptomatic, which is just so that people don’t take the message that it should never, ever be done. But if you are doing it in a patient with the concept that that might improve their long-term outcomes we don’t have that data so we can’t promote that activity on that. I’ll just say that remember the up-front chemotherapy first trial, the GETUG trial, was negative and then STAMPEDE and CHAARTED changed that. So I’m hoping that the first trial being negative might just be only the first and then we gather the evidence.
NM: Correct but also remember the kidney story – remove the primary, remove the primary, remove the primary where there are mets and suddenly, plenary ASCO, negative CARMINA trial.
PO: But it has already been proven also in breast cancer.
NM: Exactly the same thing.
PO: So there are other tumour types where it appears not to work. So we’re lagging a bit behind with prostate cancer but the HORRAD trial is already showing we might end up in the same…
NM: It might not be the answer for everyone. Amit, a very simple question to you – we have two standards of care now for newly diagnosed M1 disease, docetaxel or abiraterone on top of castration. Practically, the repeated question, how do we choose?
AB: Isn’t it good to actually have a choice? First of all, I always say that making a choice can be difficult but being in a position to make choice is actually better than being in a position not to be able to make a choice. Unfortunately, as currently things stand in my practice, guided by NICE guidelines, I can only give them up front docetaxel if they’re eligible. We’re awaiting NICE, the initial document has come out for consultation which initially is negative but we are waiting, there can be appeals and then they may reconsider it. Now, assuming that you have the reimbursement and you have the right patient who is willing, it’s paramount that we discuss with the patient both these options. Like we’ve seen, the core specific survival is exactly the same, there’s no difference. The difference is in failure free or progression free survival but that’s because chemo is given for six cycles whereas abiraterone is continued until progression. So if it wasn’t different I would have actually questioned it likely. Whilst chemotherapy might seem something that no patient really wants chemotherapy but it is upon us to be able to give them the support to get them through their treatment. Quality of life data has actually shown that a year down the line their quality of life in the CHAARTED study was no worse than the group who didn’t have chemotherapy. So we can reassure our patients on that. Equally there is data from LATITUDE with the abiraterone quality of life showing that quality of life is better. So we’ve now got two treatments with improved survival, improved quality of life. I think it’s down to the discussions with the patient – some may like to have tablets but they need to realise that it will require regular blood tests. There are issues regarding managing toxicity like hypokalemia, so one has to be cautious on that front. Equally with chemotherapy, whilst it might be a daunting approach, but it is a limited six cycle approach and actually after that your visits to the hospital are less compared to abiraterone. So it’s having that full discussion but whichever choice they make I’ll be fully supportive of that.
IVO: Yes, for me too. It’s just a choice, having a choice. Again, talking to your patient and asking them what is important for you. Is it important for you to be out of this treatment within a few months, then you can choose the docetaxel? Or is it important not to get chemo because chemo, really, every patient doesn’t want to have chemo? But, just like you said, if you tell them they will get chemo anyway during the course of their disease and then having a choice – do I do it now feeling rather well or do I do it within a few years, maybe not as well as now, that’s also a choice that you can discuss. The option of tablets always seems better but knowing abiraterone, knowing that you have to take that without any food, having regular blood tests, it’s not like having just a tablet, it is a treatment.
PO: And daily steroids.
IVO: Yes, and daily steroids also. Having it lifelong or until progression or two years, maybe even if you say we’ll do it for two years, maybe then it’s also a little bit more clear for the patient. They have so many choices now.
NM: The second question regarding these two things, and it’s jumping from what you just said, that probably treating the primary is not correct for every patient. For the M1 disease we have the LATITUDE where they are only pure, newly diagnosed M1, disease never treated; in STAMPEDE with a mixture of newly diagnosed, progressing etc. Are those metastatic patients different or are they the same?
AB: We have enough data out there to tell us that de novo metastatic disease has a worse prognosis. So there has to be some difference. We haven’t been able to tease out that difference but we know that they are different. So I would be very strongly recommending one of these treatments for de novo metastatic disease which fulfils the criteria of the risk factors, say, for the LATITUDE study with abiraterone. But the bottom line is even if it is not de novo, and obviously my patients have gone into STAMPEDE and contributed to the data, I would say that every clinician can have a feel whether the patient’s disease is aggressive enough, risky enough, for the patient to die of metastatic prostate cancer. Now, let’s say a patient didn’t have de novo metastatic disease but had a radical prostatectomy, radical radiotherapy, two years ago and he’s come back and his PSA is rising and you scanned him and you found two bone spots, are you worried? Well, you’re worried that the radical treatment failed but you’re not worried that the patient will die and you know that you can manage this patient quite well. But say if you scanned that patient and actually got a super-scan on a bone scan without the patient being symptomatic, you and I have seen those patients, you’d be really worried. I would treat that patient with this idea.
IVO: Yes. I think also within this year we see that we create different kinds of patients than the years before. We see different kinds of patients because of all the new imaging modalities and we have to rethink everything again and again with all this new evidence to see which patient is the one that was the patient for that study so that treatment will be the right one. Last year it’s all new kinds of things and we have to be more at these kinds of meetings and just talk about it so that we get used to the new kinds of treatments.
NM: And a very last question for Piet, a provocative one, you probably expect that one. M1 disease with one spot – treating the spot without ADT, is it useful? Without ADT, just to postpone ADT.
PO: In the recurrent setting, for example what we did, all these patients in the STORM trial all got fancy imaging. So they were all conventional imaging negative but you put on your different glasses which are more sensitive and all of a sudden you see a spot. So actually you have a patient, according to the guidelines, who has biochemical recurrence, conventional imaging not metastatic. If you look at the guidelines those patients should get deferred ADT so that’s why in that study that was one of our arms. We were wondering are we able to defer that ADT for a longer period if we give them, for example SBRT only to that lesion? It appeared to be that we were able to defer that for a longer time. The question, of course, is does that matter in the long run, we do not know. Do I believe that it is the best solution only to give SBRT? When I look at our own data we see that half of our patients will relapse with a PSA increase or radiological progression within one year, that’s quite a lot. If you look at all the data, what we do with radiotherapy in the primary setting, even in the salvage setting we always combine with temporary systemic drugs, ADT. So for me it makes sense now to go in that same direction. So if we see metastatic disease with novel imaging we should probably go for, or we could go for, SBRT with systemic drugs, trying to indeed postpone progression, improve survival. But that should be part of new trials. So do I believe that we should go in the direction by combining metastasis directed therapy with systemic drugs? Yes I do believe so. I don’t think that metastasis directed therapy only in metastatic patients is the way to go. I think we should evolve now and take the lessons we learn from primary tumours and also what we know from full-blown metastatic and systemic drugs are the mainstay or the backbone of the treatment. But if you want to really change the thing, I think adding local treatment in specific patient groups might have a benefit.
NM: We have a lot of new data coming, most of them are coming from randomised trials but randomised trials are the only way to clearly show a benefit. All these new things should probably not be done outside trials. It’s not because you have a phase II trial, even very attractive, that you have to jump on it and treat the patient like if it was approved. It has to be done in a trial. So thank you all very much for this discussion and good luck with your patients.
