EE: Hello from Chicago. We’re back, right? Back in action at the ASCO Annual Meeting. It’s been a while but I actually saw a lot of people walking around the corridors today so I’m enthusiastic that we’re back to live meeting and fully live meetings. And we’re here with colleagues that do not need any introduction and I’ll let them speak a little bit about themselves because we need to discuss today, in this round table, an unmet need and where we are with that – high risk localised prostate cancer. So I’ll go first to the urologist to introduce himself and then us oncologists.
KM: That’s good, that’s normally the other way round. I’m Kurt Miller, I’m an oncologist… I’m a urologist from Berlin…
EE: No, that’s what I said! You’re not an oncologist.
KM: No, no, no. No, no, it’s good. I’m a urologist from Berlin, Germany. Thank you.
KF: I’m not a urologist, I’m a medical oncologist from Gustave Roussy in Villejuif in France.
OS: And I’m Oliver Sartor, medical oncology from the southern United States in New Orleans, Louisiana.
EE: So I’m Eleni Efstathiou, I’m a medical oncologist focussing in prostate cancer and I live in the South but I’m also Greek. So we’ve got 2½ Europeans and 1½ Southerners with the Southern gentleman here, I can attest to that. It’s great to be back again but we’re missing out on one member that should be in this round table, a radiation oncologist, we acknowledge that and potentially a pathologist and a radiologist. We’re going to talk about that in a minute. So I’m going to start with you, Karim. You’ve done a lot, as the rest on the panel, a lot of research in prostate cancer and more recently hormone naïve prostate cancer. But where do we stand, do you think, when it comes to high risk localised disease? Have we made progress and what would you call the most progress we have made in the past three years?
KM: Actually I think a very important progress that was made was basically twenty years ago with a demonstration that ADT can help radiation to perhaps cure more patients and definitely prolong time to metastasis. But, again, this was twenty years ago and for twenty years, to be honest, we haven’t seen much for these men with high risk localised disease. Very recently we saw fantastic data in the STAMPEDE phase III trial with abiraterone, indicating that when you add abiraterone in men with very high risk disease, so those with even nodal disease in the pelvis or those with at least two high risk criteria amongst T3 disease, high Gleason score or PSA greater than 40, not 20, then abiraterone not only postponed metastasis but also significantly and clinically meaningfully decreased the risk of death which is, again, a first within the last two decades or so. Because it’s a generally well-tolerated agent that was used for two years in the trial and also because it’s now a generic drug in almost all countries, I think we should use it in this indication and actually I do use it in this indication.
EE: Do you require a tumour board meeting to do that or have you agreed to move forward?
KF: Actually both. We have actually all agreed within the team that we should do this but we decided also that we should validate all our indications in the tumour board, mostly because it’s not an approved drug in this indication. So we thought it was better to officially show to the board that we actually agree that this particular patient should get it.
EE: So you made a great point about how this trial actually within follow-up, I believe it was a median six year follow-up, showed already an overall survival benefit to favour the combinatorial strategy, pointing to your comment that this is very high risk localised disease. In your practice, Oliver, have you gone to the extent of actually extending to all high risk?
OS: I’m not quite comfortable. If we look at the node positive, yes, meeting the STAMPEDE criteria – two out of three, T3/T4, Gleason 8-10, PSA >40 – so two out of three, very comfortable. As we move it down into the high risk category I’m not so sure. And what we’re doing right now is using decipher, and that’s a genomic classifier, to be able to put people into various risk classifications, so genomic risk classification, for the very high risk and the less high risk. Actually we have an ongoing trial, NRG009, where the high risk individuals by decipher are going to get intensification and the lower risk by decipher are going to get de-intensification, actually less treatment – hormones for only one year instead of the two that are standard. So we’re trying to adopt this clinical trial as being a new standard within those categories of patients that STAMPEDE excluded. So that’s a little bit of a nuanced answer but that’s the way we’re trying to approach it now.
EE: But you’re a big academic centre so that doesn’t apply to community practices. I’m going to ask you something, since you are a US-based oncologist, would you extrapolate this data to apply to the other three available agents for hormone naïve prostate cancer? Meaning enzalutamide, apalutamide, darolutamide?
OS: I think on the surface, yes, because we’ve seen over and over and over again that these agents all perform very well in their settings. Now, as the academic in me, I’ll say no but the practicality is apalutamide, enzalutamide, darolutamide, abiraterone, all terrifically active agents and all have their place. We have unequivocal, grade A, level 1 evidence to show that each is active in prolonging survival.
EE: So I agree completely with you, though, of course, the problem I’m going to go to Kurt. Kurt, these patients come to you first and in high risk localised disease we had a standard of care, as you described, a three years that we are trying to curtail of ADT plus radiation. But more and more we see these men undergoing radical prostatectomies, and this is in no way a criticism. Would you be extrapolating this data and doing tumour boards where you would do that or how do you proceed?
KM: No, having those men that are undergoing radical prostatectomy, putting them on three years ADT plus/minus abiraterone, we don’t do this because there is no data whatsoever supporting it. The good thing, ‘the good thing’, after radical prostatectomy is with the PSA you can see where the road goes. If it’s going back to zero you don’t need to do anything immediately and then you can decide is that once you might have a PSA progression what you can do – imaging, SRT, SRT combining with ADT and so on. So that’s a completely different situation. In association with RT there’s now very solid data really showing what you can do and the good next step is, as Oliver has said, to try to personalise it a little bit better, to see where you intensify and where you de-intensify. So that’s probably the future.
OS: If you don’t mind, Eleni, one of the things that was a deficiency in the STAMPEDE and, of course, in current practice is no PSMA PET. If that guy walks into my clinic today and he’s got a Gleason 9, PSA 41, guess what I’m doing? I’m getting a PSMA PET.
EE: Well that was my next question.
OS: Okay, I didn’t mean to jump ahead. So that’s a caveat that I think is very important.
EE: Well, let’s discuss this because I like Kurt… Kurt, you’re saying right now this man who is young and will come in the door, 55 year-old, and he has high risk localised, I’m not talking about the extreme, you’re going to go for surgery potentially. If there’s going to be a tumour board…
KM: Here I will discuss it with him, definitely, and there’s no head-to-head RT plus whatever hormones versus surgery, you have no comparison. So, yes, we would discuss both options.
EE: And let’s say you do a PSMA PET?
KM: Yes, we definitely would also, as Oliver has said, if PSA is 40+ so we would definitely recommend to do a PSMA PET to have a better idea of what’s going on here.
EE: So we just saw this data here at ASCO suggesting that there’s a change in practice when you see that PSMA. How do we know if we’re doing this right? That’s what I want to hear from all three of you. What do you do?
KM: We don’t. We don’t, because almost all the studies are based on conventional imaging, we’ve seen so far. And now the only thing is, it’s all just the way I’m talking to the patient. If he has a bone met in the PSMA PET and we’re talking about surgery or local treatment, that’s a different story. We still can do it but we’re not sure what the outcome will be, actually, in that situation. So I would definitely have a different counselling for the patient if he is metastasis rather than if…
EE: So we’ve got an answer, I’m going to go to Karim, back to Karim. We’ve got an answer from STAMPEDE again, interestingly, for the oligometastatic, conventional not PSMA.
KM: Again, conventional.
EE: Conventional, you’re right. But if you see 4 or 5 on PSMA you can ascribe that conventional criteria, the 5-10 becomes a problem. Do you apply the STAMPEDE approach of treating the primary at least, plus… what?
KM: We do. And I was about to say that indeed we have some guidance, some evidence, to help us for decision making. One comes, indeed, from the STAMPEDE metastatic radiation trial which showed clearly that patients with oligometastatic disease should be treated locally with radiation. In that scenario you can indirectly think that local treatment should be given, even if the PSMA PET shows minimal extra-prostatic disease. And on top of that we now have many trials testing the next generation hormonal agents indicating that the benefit is also seen in men with oligometastatic disease, not only in men with 100 bony metastases but also in those with just a few. So indirectly if, in your scenario of a man with Gleason 8 or T3 or whatever, PSA 41, the imaging shows oligometastatic disease I think we have good reason to consider local treatment combined with ADT and with any other next generation hormonal agents. The question is the duration – should that be forever, should that be for two years? And, of course, that’s difficult to answer.
EE: So I’m going to come to you and I know you’re going to want to rebuttal that but I also want to ask you… So, just not to confuse you, we are still discussing high risk localised by conventional criteria and if PSMA PET is negative we can go ahead with whether we’re going for surgery or STAMPEDE-style radiation plus ADT plus abiraterone or what have you. But if it’s PSMA positive then you’ve upstaged it but you probably should treat your primary. What do you do with the two or three lesions after you treat?
OS: Well, that’s where I was going to go because, see, that’s sort of the next question. I agree completely with everything Karim said but now I want to add if we’ve got two or three oligometastatic lesions should we be SBRT treating those lesions? Does it make a difference? I hate to say it, in our practice maybe we’re doing things that are not well supported but the SBRT to the lesions, the treatment to the primary, the hormonal treatment with intensification, maybe we ought to do them all. Now, that’s not proven. The SBRT is the unproven part and there are ongoing trials but seeing a lesion that is easily treated with SBRT and ignoring it? That’s a little bit hard to do sometimes.
EE: Well, what do you think, Kurt?
KM: Yeah, we would probably do the same as Oliver has said. There are only a few data like the ORIOLE trial or something that supports giving SBRT in addition to ADT and that’s the question here. The good thing with the SBRT is if it’s bony lesions you almost have no toxicity whatsoever. So it’s an easy step and the patients like it usually if you treat their metastases. So, yes, we don’t have much evidence but in most of the patients we do it.
EE: You do?
EE: So it’s always important to have a tumour board and everyone be on the same page, obviously.
KM: Absolutely, yes.
KF: But still I would recommend to keep randomising. We are randomising the question so if people are listening to us, make sure it’s possible.
EE: Referring to academic centres.
EE: But if it’s a remote community practice that has everything in place and there is a tumour board, it would be something, especially for young men, to discuss.
KF: Yes, it is reasonable.
OS: There’s maybe a small caveat here. So we’re talking about metastatic disease, the standard of care for typical metastatic disease is hormones forever. I think there’s a separate discussion that can be had about the truncation of hormones at x interval. Now, I don’t know what x is, I don’t think anybody knows what x is, but if you treat all the known sites of disease with definitive therapy, whether it be radiation, surgery, SBRT, whatever, do you really need to continue hormones forever? I think the answer is likely no but then I would be the first to say I don’t really know.
EE: We don’t and, in fact, because I have been more and more using the oral LHRH antagonist which is not yet available I know in Europe, some of the criticism is that we know that the leuprolide depot stays longer in the patient so we’re truncating but the trials, essentially, were longer because the castration effect is longer. A lot of things that we will have to test and understand better. So, as you understand, this is still totally uncharted waters; we’re starting to just scratch the surface. So I want to go to these tools. We know that this is a heterogeneous disease; we know, for instance, that in the United States we do have guidelines that would recommend germline testing in high risk localised. I do it in everyone who walks in the door and if positive go for genetic testing and discussion. What is your practice and where does Europe stand with that?
OS: Same as yours. Let’s go to Europe.
KF: You mean in terms of testing?
EE: High risk localised.
OS: Germline. High risk localised.
EE: Germline. You or in Germany?
KF: We do germline testing in all men with metastatic disease. For patients with high risk we’re on the fence because the data is scarce. I guess in a young man, especially if there is family history, we would do. In an older man without, maybe not.
KM: Not immediately, as you said, not if the patient walks in to my door and has high risk localised disease. We would do it at a later stage if we see but not at the beginning. It’s not mainstream yet.
EE: But is it in your guidelines or not?
KM: It’s not in the guidelines.
EE: It’s not in the guidelines, that’s my understanding. So let’s talk about the future – heterogeneous disease. We know that while we’re developing phase III trials that are looking agnostically to all patients and doing enhanced androgen signalling inhibition, Kurt will comment in a minute that that’s not leading to a very big success. Do you want to talk a little bit about the phase II data out there? Guilty. Go ahead, tell us what you think about the neoadjuvant data in the phase II setting.
KM: Well, we’ve done this. I remember since twenty years we’ve tried to do neoadjuvant testing, see what does prostate cancer within the prostate when you take it out. So far we’ve never seen a real breakthrough. I just mentioned that trial looking at abiraterone or abiraterone plus apalutamide and what you see is when you put it together between 3-7% complete pathological responses plus minimal residual disease. So probably you can’t cure these patients by giving them hormones, that’s what I take from that. So it’s probably an interesting thing where you look at what’s going to go in the prostate for very early phase studies but it’s not a concept where you can really say we can avoid radiating or taking the prostate out.
EE: Karim, what do you think? If you’d like to comment on the phase III trials that are ongoing in the field and give your thoughts – do you agree with Kurt? Should we be looking for at least some predictors early on because these phase III trials are all comers?
KF: All comers. Yes, I fully agree. It’s quite likely that the ongoing phase III trials testing the second generation AR antagonists apalutamide, enzalutamide, darolutamide will end up with similar results as compared to what we just saw in STAMPEDE abiraterone in very high risk disease. Of course we’re waiting for the evidence and this evidence will be welcome to help us. But it’s very likely, to be honest. But this disease, as you rightly said, is heterogeneous and we hate as oncologists, to be honest, giving drugs to all comers not knowing whether the patient will benefit. Even more, of course, when it’s about chemotherapy or more toxic treatments. I loved the presentation at ASCO GU a couple of months ago about artificial intelligence based on pathologic slides from the RTOG group showing that not only the machine is able to better identify who are the men with bad cancers as opposed to a classical T, Gleason score and PSA classification, so that’s already a plus, but, most importantly, they were able to identify who are the men who need ADT adjuvantly to radiation and who are the men who just don’t benefit from additional ADT. So basically we can de-escalate again the treatment for some high risk patients just not to get ADT because they just don’t benefit from that. This is quite robust data, I have to say, and the beauty here is that it’s quite cheap – you just scan a slide, send it to the machine, get your answer a minute after that and then you can apply the data. So that’s quite beautiful science.
EE: I’m going to make a comment, I would like the organisers of this video to not show it to pathologists because you’re trying to put them out of business. I’m joking. It’s actually something the pathologists are working on, in fact, and that’s why it’s great. Do you want to run us down, because I know it’s part of your passion as well, which trials you feel are going to help us understand better? That we’re expecting to report in the coming 2-3 years. Fully report.
OS: So one of the trials that is quite mature right now is the ATLAS trial. This is an intensification trial, it’s within the conventional high risk criteria where PSA more than 20, Gleason 8, 9, 10, T3, one of the above not two of the above and not PSA 40 like STAMPEDE. The ATLAS trial has been ongoing for a long time, it has yet to report but it could report sometime in the next couple of years, I don’t know exactly, of course I don’t have that crystal ball, but it’s important. Another important trial is the ENZARAD trial looking with enzalutamide in a similar situation and I look forward to learning more about that when it’s reported. Those are the two big ones right now that I’m aware of. I’m looking at Kurt – are there other ones out there in this space?
EE: What is urology doing?
KM: When you said I just thought about this, I’m not sure what the name is, enza cell self trial which is enzalutamide as monotherapy, which is unusual, in combination with salvage radiotherapy for biochemical recurrence following radical prostatectomy. You know there has been quite some uncertainty when and how should we combine hormones plus salvage radiation therapy. There have been two trials – GETUG, I think it was 16, was the one – half a year of ADT plus salvage – and the other was the RTOG trial – two years of bicalutamide. Pretty old trials actually. Too high a PSA at baseline when they started SRT. So that’s an interesting trial probably answering some of these questions of when and how should we combine hormones plus salvage radiation therapy in that setting.
EE: There are also trials of neoadjuvant followed by surgery, combining enhanced androgen signalling inhibition such as the Protas trial that we’re probably going to have to wait for a few years as well. I think that 2-3 years from now we’re probably going to be sitting here and not hypothesising but understanding whether we should be using neoadjuvant approaches, not just for radiation, which we’ve established, we just need confirmation, but also for surgical approaches. This is an unsolved puzzle, gentlemen.
OS: We look forward to more data.
EE: Absolutely. Thank you all for joining.