ASCO GU 2023
Latest in hormone sensitive prostate cancer
Prof Eleni Efstathiou – Houston Methodist Cancer Center, Houston, USA
Prof Boris Hadaschik – University of Duisburg-Essen, Essen, Germany
Prof Gerhardt Attard – University College London: Cancer Institute, London, UK
Prof Heather Payne – University College Hospital, London, UK
EE: Hello, I’m Eleni Efstathiou, a GU medical oncologist, and we just wrapped up prostate cancer updates at GU ASCO in San Francisco. I’m joined by three of my colleagues, Dr Boris Hadaschik, Dr Heather Payne and Dr Gerhardt Attard, everyone from Europe apart from me, I’m Greek but from Texas. So we have a good representation today – two GU medical oncologists, a urologist and a person who can actually not just be a medical oncologist but also the radiation oncologist, Dr Heather Payne is a clinical oncologist, I really envy you for that.
HP: We’ve got it all.
EE: You do. We’re here to discuss what are the take home messages from hormone naïve disease updates. We didn’t hear anything earth-shattering practice changing but I think we got some new tips on how to handle our patients, some updates. I will turn with that first to Dr Attard to provide us his thoughts on the two updates we got for major phase III setting metastatic hormone naïve, ARASENS and PEACE-1. Your thoughts?
GA: ARASENS was presented, I guess, a year ago and published concurrently in The New England Journal of Medicine. ARASENS is a trial metastatic hormone naïve. ADT plus docetaxel was the backbone standard of care and patients were randomised to darolutamide versus placebo and that was a positive study so there’s a survival advantage of adding darolutamide. That initial report did not provide the breakdown by metastatic volume; that information was not a stratification factor. In fact, the trial started recruitment before CHAARTED had read out the long-term outcome data, before LATITUDE presented. So that’s why that was not incorporated in the trial. Here at GU ASCO Maha Hussein presented a post hoc analysis of the outcomes split by CHAARTED volume criteria and LATITUDE risk criteria. I think LATITUDE risk criteria is probably less relevant; it was used to select patients for the LATITUDE trial and it’s not really in use. So let’s focus on volume. As we expected, the majority of patients, 77%, were high volume. That is the group with the largest number of patients, the largest number of events because, of course, they’re the ones at worst prognosis. There’s a clear benefit for darolutamide in that population. In the low volume patients, similar to what we saw in PEACE-1 about a year and a half ago now, there is insufficient data to be certain of adding darolutamide to ADT docetaxel. So I guess we haven’t learned anything new but we’ve confirmed our expectations that ARASENS was a study in high volume patients, bad prognosis disease, that that advantage is there. Does it change what we’ve been doing to date? Probably not and the question remains what is the advantage provided by adding docetaxel to that backbone ADT/ARSI? We’re not going to get the answer any time soon, in fact, what was exciting was there was a debate in the panel discussion about future trials that may answer this. I think it was Mike Morris who said he has a proposal application for funding under consideration so that’s a trial that may start but, of course, read out many years from now. So until that data comes we’re in the situation that we’re going to have to use clinical pragmatism and choose patients for addition of docetaxel without level 1 evidence. To wrap this up, Eleni, there was a poster at ASCO which was an individual patient data analysis, so main ASCO last year, from the STOPCAP analysis that across more than 2,000 patients from STAMPEDE, GETUG-15 and CHAARTED looked for differences in outcome by timing of diagnosis of metastatic disease, by disease volume and by T-stage. What was interesting was, firstly, it confirmed prior hypotheses that low volume metachronous don’t get benefit but the greatest benefit appears to be in the synchronous high volume who have bulky primary tumours, so those T4 disease. So that’s information we should use in making our decisions for whom to use triplet therapy. So if we’re going to add docetaxel to ADT plus darolutamide or ADT abiraterone, it’s primarily for those patients that we should be considering it.
EE: That’s a great overview, actually, that you just provided. You made a comment that I want to turn to Heather for thoughts. They did an update where they looked and showed us that more than two-thirds of their population was what we would define as high volume. The numbers, both on the control arm, ADT plus docetaxel, versus the triplet that was not reached in that subset, I believe, are pretty impressive, suggesting that over time we’re getting better outcomes for our patients. Does looking at specifically those numbers, as compared to what we reported almost ten years ago with CHAARTED, shift your mind towards using more the triplet in your practice or not?
HP: I think it’s still difficult, to be honest, and certainly in England only 36% of men are ever suitable for docetaxel. I think we have to bear that in mind when we’re thinking about triplet therapy, that even if we’re looking at the high volume a lot of men are either unsuitable or unwilling to have chemotherapy. So I think they are a smaller group than the all comers that we see. I think that the low volume data was immature and I don’t think we can make any conclusions from that. The high volume ones, I think it’s always a shame that we don’t include nodes when we talk about high volume because we know that those men with bone and metastatic nodal disease are going to do so much worse. They are perhaps a group where we should be considering escalation. To me it would be the men that I would have given docetaxel to that I would add in darolutamide or abiraterone but the ones who I would have previously given ADT and an ARTA, I don’t think there’s a need to add in the docetaxel. Of course, the big elephant in the room was that we wanted that other arm, didn’t we? We wanted ADT and darolutamide.
EE: No, you’re 100% right but we need to keep in mind, and I think that applied to PEACE-1 that we’re going to get to, that that was the standard of care when they were starting. They were looking into the future and not seeing it as being… they could not. That was, of course, unlike PEACE-1, a study sponsored by pharma so they had to follow specific guidelines. So it’s still great data, I think we need the update.
HP: Oh, absolutely.
EE: I want to turn to you. Germany is a little bit of a different beast, let’s call it, when it comes to the involvement of urologists in actually providing also chemotherapy, still to this day. So I wanted to get your thoughts, it’s not like you’re going to be biased against it, so what are your thoughts? Is there still value in triplet?
BH: Yes, as a urologist in Germany I do apply chemotherapy. What we learned over the recent past is that ADT plus an ARTA is an excellent choice and it’s the novel standard of care. I’m absolutely with Heather – if there is a patient that is younger and high volume and fit and a patient that I would have offered docetaxel, now I offer triple therapy. I think in reality that’s 20% of men with de novo mHSPC I do see so we offer it right now. It’s darolutamide though so it’s not yet available, it will come at the end of March. So if they fulfil LATITUDE criteria and Abi is reimbursed we hand him docetaxel. But what we don’t do anymore is a doublet with ADT plus docetaxel, so the standard of care here in ARASENS has shifted, that’s even falling out of the guidelines of the EAU this year – ADT plus docetaxel will not anymore be considered a standard of care. Coming back to the point of Heather, I do think that we will learn more and more by applying more modern imaging about the CHAARTED criteria and then putting in really volume of disease, looking at lymph nodes and maybe even some visceral disease. So I think it’s really an area where we can prognosticate our patients better but right now my take home is an ARTA/ADT doublet is the novel standard of care and in some men we triple therapy with the addition of docetaxel.
EE: Very well, very elegantly summarised. Just to add on, in the US the use of docetaxel has shrunk down to 4% in hormone naïve disease.
HP: Really?
EE: CRPC is not doing that great either, that’s a different discussion, that is a concern. But back to you, Gerhardt, the trailblazers in the triplet have been the PEACE study, right? They presented the first data. We got a little bit of an update and I wanted your thoughts on what they just presented.
GA: So it was an analysis of…
EE: I feel the same way with the PEACE-1 update, yes, I was like…
GA: There’s so much great data from PEACE-1. In fact, going back to your earlier point about improving survival and I think Karim is such an excellent presenter and trialist. I guess he is the first one to show the different outcomes over time. But we do need to be careful because patients are getting better treatments in CRPC and despite the relatively smaller absolute benefit, there are true improvements in life expectancy with PSMA-Lutetium, earlier use of ARSIs etc. So there’s a number of confounders. Anyway, back to the new data which was looking at outcomes by age and by fitness. I think we can really summarise this that the most important thing is fitness, not biological age. So an unfit older patient does not do well but if the patient is fit enough then his outcomes are equivalent.
EE: And I think we live through that in the clinic – I have patients who are octogenarians that are much fitter than me – so I think we would all agree that we experience it every day. But we need tips as to who performs well when we start treatment for metastatic hormone naïve prostate cancer and we need that for, of course, our own guidance in the clinic but also to reassure our patients. So there was a presentation regarding PSA response in this – what are your thoughts on that, Heather?
HP: I think that’s quite useful because we’ve seen this over a number of studies, haven’t we? A deep PSA nadir, 0.1, 0.2, those men have a better overall survival. What does that mean? So if somebody doesn’t have a deep nadir do you stop the treatment? Well, no, but I think that you do need to monitor those men a little more carefully and be aware that perhaps they’re not going to do so well and have a threshold for changing treatment and perhaps imaging them slightly more regularly.
EE: Great segue to you, don’t be scared, I can see it in your eyes. Do you think there’s a reason to start considering more enhanced imaging for these or just stay with conventional? I know because you’re a champion I’m asking you of advanced imaging, but where we draw the line.
BH: I’m a firm believer in more advanced imaging because it provides more accurate information. There are less false positives, you do see more but you have to balance cost. Does it make a difference in that disease state? So if I have a patient who is responding, deep PSA response, there is nothing going to happen so why should I image him regularly with a PET, that’s not cost efficient right now. On the other hand, I think we can learn more by modern imaging to be able to prognosticate but we always have to reflect that all the phase III data that we are discussing are based on conventional imaging. So you have to be careful making decisions based on modern imaging especially with regards to primary therapy of the prostate. So only because you see something on PSMA-PET STAMPEDE is still valid and we should not withhold local treatment. So it’s really a balance, you have to be careful. If you have access embrace modern imaging, it is helpful, but you have to reflect.
EE: Now I’m going to challenge you. You’re a urologist, we know where your heart is, but there was data presented comparing in the earlier disease setting, intermediate disease setting, surgery versus radiation and, in fact, a more appealing radiation scheme. Do you want to talk to us about that, I then want to get Heather’s opinion.
BH: Certainly. So I’m a surgeon, I do robotic surgery, I do open surgery and I love doing surgery besides all the imaging and the rest. So surgery is great but we have to be aware of patient outcomes and patient reported outcomes. So the study that was presented here is by Nicholas van As from London, the PACE-A trial. In PACE-A it is a randomised trial, so they have to be really congratulated, between SBRT, so five fractions of radiotherapy to the prostate over one or two weeks without the addition of ADT, against minimally invasive prostatectomy. Most of those were done robotically by a high volume surgeon, some of them laparoscopically. Since they treated men with intermediate risk disease and some low risk disease so we are not talking about oncologically dangerous cancers, it’s like, yes, we consider therapy but we are not afraid of outcome. So the primary endpoint of the study was to test if men undergoing radiotherapy have less incontinence than men undergoing surgery at two years, so not six weeks after surgery but two years after local treatment, is the one point so incontinence. The other one is bowel bother, so if you have this ultra hyperfractionated radiotherapy how much does that affect your bowel? The study had problems with recruitment during COVID times, it was powered to see a 9% difference for pad use, that was the primary endpoint, and then the IDMC looked at the data after recruitment of 120 patients instead of the planned 230 and they said, ‘We do see a difference so you stop recruitment,’ and now this is the first presentation. There will be upcoming presentations looking at longer term toxicity and oncologic outcome but the primary data is out here and the primary endpoint was positive for SBRT, so negative for surgery. It showed that men reported pad use, so any pad, after two years in 47% of the time. So nearly every second patient that underwent prostatectomy had at least a safety pad and this is something we have to appreciate. We can argue against it and say, ‘Well, in my clinical practice this is unheard of and they’re all dry from the beginning,’ but, no, this is patient reported outcomes and we have to acknowledge that incontinence as pad use is a little bit more prevalent than maybe thought of. On the other hand, surgery was better for the bowel bother, that’s clear, but surgery again was worse for sexuality looking at the two-year time-point. So the data is out there, we can argue with it. I think the most important part is that we have to congratulate the UK for doing such a study and testing a novel regime and this regime of five times ultra-hyperfractionation is in PACE-B as a non-inferiority trial tested against a more standard fractionation scheme. So this is something that will probably come longer and it was as good as surgery.
EE: Very well said and coming from a surgeon. And I know you have shared with me also your preference for the SBRT regime, are you now convinced or is it too early that we should apply it?
HP: I think we need to see PACE-B results but one of the really great things about this study was that there were no hormones. Traditionally we would have used six months of ADT with intermediate risk. So that’s going to be a very important outcome of the study because we heard, and as we were discussing, the number of men, especially the older men, who never recover testosterone even with six months of ADT. So I think that was good. The bowel toxicity was slightly early to report at two years because obviously late toxicity from radiotherapy is going to increase.
EE: I do appreciate that you put that in perspective.
HP: And there were no spaces whereas in the modern radiotherapy… so that may make bowel toxicity better.
EE: So let’s move on a little bit to the presentation by Dr Nguyen from the Farber. The very, very sensational titled FORMULA-509. I wanted to wrap this up by getting your thoughts on that and a couple of words from you two gentlemen.
HP: This was a study looking at salvage radiotherapy and the premise of it was that standard of care we would use two years of hormones with salvage radiotherapy. It was looking to see if an escalated six months in this situation with ADT, apalutamide and abiraterone would be better, easier for patients because they’d have these hormones for a shorter period of time. It only really reached the endpoint with those men with a PSA of above 0.5 which I would argue is probably slightly high. At home we would treat between 0.1 and 0.2 and we’d look at PSA kinetics and risk factors of the initial prostatectomy. Obviously we’ve then seen ACIS coming through and we’ve seen abiraterone/enzalutamide in STAMPEDE and so we’re not looking at combining ARTAs in this setting anymore. Personally, I’d have loved to have seen apalutamide monotherapy because we have bicalutamide, we have the Shipley data which we’ve based a lot of our salvage hormone radiotherapy on. I think the anti-androgens have got quite a big role to play in this and the side effects wear off more quickly, you don’t get castrate levels of testosterone.
EE: That’s actually an excellent point. Now, I wanted to just summarise briefly. We didn’t get anything that will change our practice going home. We got some refinement points, we understand, we think, a little better the disease. But just, Gerhardt from you, what do you expect to hear more from this year in the hormone naïve setting? Are we expecting something that will come through and may change our practice from a study prospective report?
GA: Not that I’m aware of. There are some really exciting trials we are all looking out for including, for example, the trials of AR antagonists in M0 disease. ENZARAD studied enzalutamide, as the name says, in a very similar population to the STAMPEDE high risk localised patients we presented a couple of years ago.
EE: And published wonderfully and I think should change, probably, our standard of care across the world.
GA: I think it has, I think it has. Of course the question is can we extrapolate that data to enzalutamide, to apalutamide, to other treatments. There’s no biological reason why we couldn’t but we need that level 1 data. So there’s ENZARAD, there’s also ATLAS which has studied apalutamide but included lower risk patients so it may take a bit longer to report there. And PROTEUS because the other question is can we extrapolate to men receiving surgery who receive ADT or ADT/apalutamide? So I do not have a crystal ball but I think we may be looking at not this year but the next couple of years.
EE: So high risk localised is our next biggest unmet need, we’re going to reach it, you tackled it first, you showed us the way. I’d like to thank everyone for attending and we hope to get more data very soon out to you. Thank you.
