Episode 515: PROTEUS - A Reflection on the Data and Controversies with Neha Vapiwala

(upbeat music) - Hey everyone, welcome to another Your Amigos podcast, Tom and I are here with Neha Vapuwala, who is a radiation oncologist at Penn. And we're gonna talk about the Proteus trial. We've covered this topic before, actually, with Mary Ellen Taplin around the time of her ASCO presentation. There's been a subsequent New England Journal publication with more detail. And there's been a lot of controversy online about all facets of this trial, including patients that are included, a lot of discussion around endpoints, et cetera, et cetera, the control arm. And we're gonna dive into all of that. Before we do that, I'm gonna give a very brief summary of the trial just to catch us all up to speed. So this was a phase three trial over 2,100 patients with high-risk prostate cancer, who were randomized to ADT monotherapy or ADT plus apolutamide for six months. Patients then underwent radical prostatectomy and lived no deception. And then got an adjuvant period of six months of that same single or dual hormonal therapy. There were co-primary endpoints. One was a pathologic endpoint of a mound of residual tumor in the primary specimen. And the other was metastas free survival, which initially started off with conventional imaging and then changed to incorporate PSMA pad that I'm sure we'll talk about. And real briefly, the pathology response rates favored the ADT plus ARPI arm, 9% versus 1%. So both will numbers, but clearly a big increase in the dual therapy arm. And the metastas free survival was an absolute difference of about 5% at five years. Hazard ratio is 0.8. Upper bound of the confidence interval was 0.96 and P value was 0.02. There's a bunch of secondary endpoints, including MFS by conventional imaging alone that we're gonna get into. And then the last thing I'll mention is the added toxicity was about an 8% increase in grade three or four adverse events in patients getting dual therapy as opposed to monotherapy. So now with that as a background, we wanted to start actually with the standard of care, putting this trial to the side for a second. Before these data were available, what is the standard of care? How did we get to the standard of care in high-risk forensic cancer for both surgery and radiation? - Well, thanks Brian and Tom, first of all, for having me and for having the radiation oncologist perspective on this important trial. So like you said, I think standard of care is where we have to start. And I think is really honestly one of the key criticisms of what the produce trial has added to the literatures. We generally consider surgery as an acceptable treatment for patients with high-risk or localized prostate cancer. You see it in the guidelines. This is ultimately based on where there's not randomized clinical trial data, at least multi-institutional data and series that say you can perform surgery safely on these patients in the era of robotic assisted prostatectomy. You can do this with hopefully acceptable side effect profile. And then we have a plethora of data that in those patients that are followed, these days often with ultra-sensitive PSA, you can reserve additional post-operative therapy for those patients who demonstrate evidence of recurrence. And you can deliver early salvage radiotherapy with or without antigen-depression therapy. And these days, that is often driven by genomic testing. We have now biomarkers that are available that might help guide that decision about the added role of antigen-depression therapy in that specific setting. - Now, what do you call patients? Sorry to interrupt, what do you call patients? High-risk patient comes in. Let's say for surgery, cure rates with surgery alone. Is there an accepted number? - Well, I will say that overall, it's about a third of patients that will need additional treatment after surgery. That's all-comers. If you start to look at, you know, node positive on pre-op imaging, really bulky T3, T4, MRI suggesting or demonstrating EC or SVI, you can pretty much, you know, guarantee that they're gonna need post-operative treatment. So that's one paradigm, right? And that's what we're used to. And the idea there is, okay, we're not treating everybody adjuvantly for high-risk features. We can monitor them and be selective in who we treat. And thereby spare those patients who hopefully will never be destined to have a clinically significant recurrence. And then on the flip side for those patients that are interested in non-invasive therapy or maybe they're not eligible for surgery medically or more importantly, they have, you know, really locally advanced disease historically. All the trial data has demonstrated, first of all, radiotherapy is sort of the backbone of local treatment. And I know Tom's wondering, you know, well, is that just because that's what people got at the time? And I would say historically, in the '80s, '90s, yeah, that's pretty much those old RTOG trials. It's because that's super bulky disease. You know, surgeons weren't operating on those patients. Yes, they went to the radiation oncologist. But we have multiple randomized clinical trials demonstrating that the combination of radiotherapy and long-term antigen-deparation therapy achieves excellent outcomes in a population that otherwise, you know, I think historically was felt to be potentially not curable. And now with PSMA PET, you know, we do even better. And for those patients, again, I usually quote about 80% chance of, you know, long-term disease control with that standard. And so it sounds like historically, a lot of the obviously patients were probably presenting with bulkier disease. I assume historically, they were not as much candidates for surgeries so they kind of drifted towards, if you will, radiation. And so that became perhaps more of a standard of care. Is that the first statement? I think that's fair, historically, both in the US and in, you know, a lot of countries with, you know, earlier access to screening and other tools. But I would say in many parts of the world to this day, you will hear from practitioners who will tell you they still do digital rectal exams and find, you know, T4 disease. So sadly, you know, it does still happen in various parts of the world that we see these bulky patients. OK, OK, so now here you go. So look, you've got radiation therapy and you've got surgery. You've got this Harris population. History has said that as we go back in time, there's been a group of patients, the surgeons haven't been terribly interested in because they're worried they won't be able to cut it all out. Radiation oncologists came in. They still are doing radiation to those patients. And at the time, because they were bulky and there was lots of disease, they started doing antideprobation therapy. And that meant that there was two choices, either pure surgery alone or radiation with antideprobation. But there were some surgical trials with antideprobation in the past. Is that correct? And what was the outcome of those trials? And how is that different from the radiation trials? And when you do cross-trial comparisons of the two, is it actually that surgery is just so much better than radiation therapy that all that antideprobation, or does it just catch us up with where the surgery would have been anyway? Yeah, that's a great question. And the answer, as always, is patient selection, right? So it is really difficult to make those types of cross-trial comparisons, although it's tempting to. It's not really valid to do so. But what I will say is we have all sorts of mechanistic data, everything from the idea of radio sensitization and vitro that we see with hormone therapy when it's used in concert with radiation. There's people that postulate about the effect of hormone therapy in reducing hypoxia, which can be sometimes a form of radio resistance. And so there's a lot of reasons why those two in combination work well. And with radiation, historically, we have been able to, and now with modern techniques, really achieve the types of doses and address the volume, including the lymph nodes, to a greater extent and perhaps potentially to a safer extent, than what has been seen in the surgical literature. And there, if you look at extended pelvic lymph node dissection, again, we're still in areas of controversies to why that is that the physical removal is not necessarily directly comparable to what radio therapy achieves. But I will say, to answer your question, all of the trials that have been done thus far with this sort of new adjuvant hormone therapy surgery approach have been negative to date. And that doesn't mean the surgery didn't work. It just means the hormone didn't help. That's right. And again, depending on who you picked, before that trial. If you're a patient, the hormone's mind will be helping because the patients are a much lower risk than you pitch higher risk patients with radiation therapy, then, of course, they're going to have micrometastatic disease. And basically, you're treating more patients with earlier, with early M1 disease. Exactly. And so it lends itself to a positive trial, where the surgeon said, no, I'm picking this patient, picking that patient. Many of those patients have it. And so your numbers at risk of minimal residual disease and those surgical trials are smaller, is that not why, is it that the reason why hormone therapy, rather than some synergistic magic between the two, a radiation therapy and hormone therapy? I don't know if we can say that. Because if you look at the Paxiar, the residual burden, which was a composite end point, one of the primary endpoints of proteus, and you look, OK, yes, there was this improvement. improvement, you know, almost tenfold improvement, but when you try to translate that into what that actually meant for MFS, and whether you look at MFS by conventional imaging or MFS by PSMA PET, regardless, it just wasn't as impressive as you would think, as you would expect. And what we see in bladder cancer, what we see in breast cancer, in terms of PATCR translating into or being a reliable surrogate for MFS or OS, we're not seeing that in prostate cancer. So there's obviously more going on biologically than, you know, sort of simply saying, okay, well, we're not addressing all the disease. And I will say, you know, the four-year, you know, rates of patients free of disease on both arms of proteas were surprisingly low. And I don't know how much of that is, you know, that portion, almost one in five patients I think had a PSA over 40. So were some of these patients, like you said, already micrometastatic and, you know, already doomed to have the cancer return. I don't know, but those seem like very low failure-free survival, you know, rates on both arms. So something about patient selection there that we need to tease out. I have a question. So we're kind of leaking into the trial discussion here. So the control arm of this trial has been scrutinized. As we just said, previous trials of hormones and surgery have not been positive. It's not a standard of care. Control arm in this trial was ADT monotherapy. Presumably, had it been surgery alone, the differences would have been greater. Is that a fair presumption? Well, I think maybe, maybe not. Maybe, maybe not. Exactly. And there is this sub-study where they're going to prepare surgery alone to the, you know, surgery plus combined systemic therapy approach, but the primary endpoint for that is a vent-free survival, which is a PSA-driven endpoint. And so you really kind of need to look at, again, MFS, to have that pure discussion if we're going to use, you know, what the ice cap and others have established as an acceptable surrogate. When you look at that sub-study, which everyone's really excited about and have an EFS primary endpoint, I think we should all, you know, keep that in mind when we interpret those results. But I don't know, is the short answer? I think all we know so far is if you're going to use a perioperative systemic therapy approach, it appears that this combination offers certain advantages, specifically reducing the positive surgical margin rate, increasing PCR and decreasing minimal residual disease. But with an MFS improvement, that if you were to look at just conventional imaging is non-impressive, and if you just look at PSA-maid-driven, which is more than half of the events, then are you actually capturing anything that's going to translate into OAS? I mean, that's not a show that I'm going to take it. I was going to ask that. Maybe it's for us as medical oncologists more, I mean, delaying PSA-maid pet events, right? That's what we're talking about, because the conventional wasn't positive, and the PSA-maid pet endpoint was. I know it was composite. I mean, there's no correct me if I'm wrong. There's no data that improvements in that endpoint leads to some distant outcome. Some better distant, more distant outcome, like survival, et cetera. That's right. We don't know that yet. I know Chris Sweeney and others have posited this idea of freedom from clinical detriment, and so I don't want to undermine or underestimate, you know, the importance to the patient of avoiding additional stressful scans or additional, you know, disease that comes back and additional therapy. But it's hard to say that this is a good thing in this population just yet, because we have a standard approach, which is if you just do surgery, you can very efficiently and effectively identify the people that will need early salvage and do very limited radiotherapy with or without hormone therapy and treat the patients that need it. And now this approach could, you know, muddy the waters because how are you going to know who needs that? And certainly in the protocol, it wasn't mandated, so it was very much dealer's choice. So we are left with more questions. I would say at the moment. You know, then I can design it with the neoageven part of the, what, why, you know, it sounds to me like you, what you're saying is that they could unsurgery alone. It would have been more interesting. It would have been cleaner. It was possible because the neoageven radiome, a neoageven hormone therapy took part in the control arm. It might be that they had higher risk patients take part because everyone was going to get hormone therapy. Many patients might have come back and said, look, the standard of the care is just to have the surgery alone. You can do that. But in this trial, you've got a bit worse disease. We can give you a bit of hormones first and then, you know, is that a conversation that would happen and is that why the outcome was less good? Why would they do the trial this way? Well, my understanding is they did the trial this way because of the issue of blinding and wanting to, you know, sort of be able to have that type of echo poison, both arms. But honestly, Tom, I would think that argument would be very hard to have to a patient because usually the appeal of surgery, one of the appeals of surgery, is avoiding systemic therapy. It's avoiding the need for that. Oh, you're telling me I have to have radiation with, you know, how many months or years of hormone therapy and what it does to my testosterone? No, thank you. I'm going to take my chances on surgery. And then if during follow-up, I need radiation or hormone therapy or both, you know, I'll take my chances. So, it seems a little unlikely to me, anyway, at least the population I see, and many of us see in the US, they generally, you know, like the avoidance of hormone therapy. So I'm not sure that that was a selling point. And the only other question on this section is, what's the benefit, what is the additional benefit of, of NHRH and RP in the perioptive setting compared to radiation alone? We know in protease we talked about, has ratio of 0.81, and what, what, what sort of date, what's the benefit of, of, of perioperative hormone therapy on top of radiation therapy? So post-operative, you mean, in the setting of recurrence? Yeah. And some of our best data among the trials we have, for example, is the sport trial or RTOG O534, and in that population, you know, we saw failure-free survival benefits in patients that had generally PSAs of over 0.35 in the recurrence setting, which again, you know, that's a population that was, you know, initially enrolled before the pet era. Now, these days, most patients present, even at much lower PSAs than that. There's a recent meta-analysis, the Poseidon meta-analysis that suggests actually, many of these patients with these lower PSAs, you can get away with just radiotherapy to the bed alone. You really don't need the hormone therapy at this point. And I think now, all of the studies we're doing, including mine, which is the ECAGACRA and 81, 91, indicate trial, it's actively enrolling, it's almost done, and one of the randomizations is post-operative radiotherapy with ADT as the standard of care for patients with clear biochemical recurrence post-operatively with or without six months of apolutamide intensification. So I hope to have an answer for you as far as the intensification piece goes. But the benefit has generally been that biochemical recurrence rates in patients that demonstrate, you know, biochemical recurrence, but then go through this treatment, radiotherapy and ADT. Second biochemical recurrence, you know, thankfully, happens in about 15 to 20% of patients, if you, you know, select well and if you monitor them closely. So we are effective with that approach. Question, I mean, is one of, I totally agree, that appeal of surgery is to avoid hormone therapy, which I think most men want to do, is it possible that even though there's effective salvage therapy in a good biomarker, i.e. ultra-sensitive PSA, that you're missing a window for care? I don't think there's data, but it is part of the rationale, like we do in a lot of malignancies. Well, let's, let's be more intense up front because we're going to cure more patients, even if we're over-treating some of them, right? We do that all the time. Sure. Well, we have, it's a great point. We have quite a bit of data on early salvage versus adjuvant radiotherapy in the post-upsetting, and really, you know, early salvage has shown fairly consistently, you know, there was a time where, of course, the comparator arm was not early salvage, it was more just as you wish kind of thing. But, you know, in the studies that are more, sort of modern and had specified thresholds, you know, we're not seeing it as overtreatment in the journey of patients because, again, these trials have helped us to say, okay, this is the point at which you do intervene and you haven't missed the window, and you haven't. It is different for hormones. I mean, I think that toxicity-- It is different for hormones. Early salvage RT, and I don't know, X number of months or years or hormones to me would be wildly different. It is. It absolutely is. And what we currently have is enough data in the PSA PET era about does the ADT really, you know, need to be added. But I think many people are using PSA velocity appropriately, and, you know, PSA thresholds that they feel might warrant a discussion for ADT, but it's not a given that everyone has to get it. So you can have a lot of high risk patients locally advanced, what have you? They want surgery, they want to avoid systemic therapy, they have the surgery, they do well for a number of years, they can get radiotherapy, if and as something shows up on PSA. PSA or PET or both. I do quite well and potentially avoid systemic therapy altogether, which again when you look at the potential side effect profile, especially when you intensify with the RPI, you know, that's that's important to a lot of these usually younger men. Yeah, I feel it's time to move on before we do. I want one more question for me, and I don't know the answer to it, which is important. Look, I don't want radiation therapy, cures patients with prostate cancer, surgery, cures patients with prostate cancer, does the hormone therapies that we currently use? Are they curing lots of patients with prostate cancer? Or is all they're doing is creating stasis, which means in the end, the cancer will eventually come back, but it can delay that by very, very long periods of time by which time many of those patients have developed other problems because of the nature to some extent of the disease. What evidence do you have that the addition of hormone therapy is actually curing patients? So I will say on the surgical literature side, I don't think we have that yet, and we haven't had it historically with that sort of new adjuvant periop approach, like we said, and we don't have it yet. The proteus, again, given the percentage of patients with recurrent disease at four years, given even despite the MFS benefit, the fact that the majority of that was based on PSMA PET, we're not seeing, oh yeah, look at this through line of patients that are now clearly cured. We do have, you know, literally 20, 25 year data, where these patients, and, you know, again, with anything ranging from 18 to 24 months up to 36 months in the classic Bola trial, that these patients, there are those that have, you know, long term disease control, we're talking 10, 15, 20 years out. So the answer is yes, some, some of them do appear to be cured with hormone therapy. The trick is, of course, always knowing who, and this is where I think we're getting better and better using biomarkers and trying to stratify these patients in further prospective trials to just deescalate wherever we can. I would be loathe to any time we have tried to reduce the amount of hormone therapy duration or to omitted altogether in unselected populations, it generally doesn't go well, so I think it's doing something. That's how you that, and it is curing some helping. I have a question, there are a number of secondary endpoints presented, and some of those has issues, I think we're more impressive. Do you, do you put much stock in that? Is it just part of the overall discussion like we've talked about, you know, obviously their secondary endpoints and the powering, et cetera, you know, can be called into question. But is there anything there that says boy, this really, this is actually maybe even more impressive than delaying psimate positivity, you know, EFS was one of those and like I said, you know, it was actually to me, concerningly low event free survival in both arms. I think from a safety signal standpoint, the idea that, you know, there's no new safety signals, but honestly, you know, the grade three and four A's were 40 versus 30% 39 versus 31 is the exact. And, you know, even if that was predominantly rash, about one in five of the men enrolled on the study did not recover testosterone to over 200, a level of over 200. So again, I think some of these secondary endpoints, I'm not sure that there's anything there that would make me, you know, say this needs to be immediately incorporated into practice. If anything, it's the primary endpoints that raise a lot of questions and require, I think, ongoing follow up and some additional analysis and I'll just add, you know, as far as the. Secondary endpoints of patient quality of life and all that we are waiting for those data, but if you look at the rates of incontinence, you know, just things that you might see after surgery alone, the combination there be armed did have some higher rates. As well as you just having ADT on board, compared to historically what you might expect with surgery alone, so we can't ignore that either or have to see how that shakes out over time. So, cause will encourage urologists to do more surgery for high risk patients that they might have otherwise said, hey, go see my radiation oncologist, you think this kind of opens the door back up for for them operating, I'm not saying inappropriately, but just are they a little more encouraged now to keep patients as opposed to refer them. The last thing is however many urologists you speak to, you'll get that many different, you know, answers and viewpoints and I'm talking really globally, you do have your logic surgeons who are understandably excited about this, I think it is really important for the field and for prostate cancer, you know, drug development for us to be able to have tissue, there are ways to get tissue in radio therapy patients as well, obviously not the entire specimen. I think, you know, the opportunity for us to have some correlation with path response, with imaging, with radio therapy, hormone therapy, surgery, all these combinations is important for us to really better understand the value of some of the newer treatments that that we may introduce having said this, you know, I think for the surgeons that are interested in doing this, taking on the management of even just the patients with ADT alone, even if you're not. It's fine with the RPI is something that, you know, I think they have to consider as part of their workflow and their practice and what they're comfortable managing, who is going to take care of some of those AEs and again very low rates less than 1%, but there was an increased rate is 0.7 versus 0.1 of AEs leading to death. So, again, I think thinking about what is the added bang for the buck until you see that there's better refinement, and I know you said we'll just talk about that, but it would be hard to imagine that everybody that comes through high risk locally advanced, you're going to take this approach. I think those are your logic surgeons that are interested will hopefully, you know, try to decide and refine who might be appropriate and add greatest risk for micro-medicine disease such that they might benefit from this. And then you have plenty of surgeons who worldwide, again, who are, you know, concerned or at least, you know, inquisitive about some of the questions raised by this study, but not ready to, you know, call this practice changing. And I think that's, you know, appropriate. I think it's important for us to await additional data and see what we can get answered. Aside from the surgery alone arm, are there other big trials going on around surgery that are going to help? Or is this, I don't think so. I don't know. No, so it's kind of that surgery alone arm, which I'm sure will raise more controversy, and then we're kind of stuck, right? I mean, it's kind of. Yeah, that sub-study, you know, again, we'll have to see the selection for ADTAPA will need to be specified. Again, we don't have validated predicted biomarkers. It's still a pet-based MFS. And then, you know, while it's still not comparing to non-surgical treatment. So there's going to be a lot that still remains to be answered. So last question for me is about you alluded to this biomarkers. I know there is data at ASCO about using the decipher scores. Is it genoma classifier? It's not the only one, but it's the one I hear about most. Sure. And where are we in terms of either intensifying or de-intensifying based on a selection tool like a genoma classifier and high-risk prostate cancer? I mean, I'll tell you, in the rate of therapy world, we are quite accustomed to doing this, you know, thinking about when we treat lymph nodes, when we don't, and incorporating, of course, pet imaging with that, but also, you know, for making that hormone therapy decision, and both in the, you know, newly diagnosed intact setting and in the post-op setting, quite accustomed to incorporating these tools. I would say, you know, for surgery, it makes sense that, you know, we utilize some of these tools or at least study and try to validate them. Because right now, there's no sort of individualized periop approach that you could offer. I mean, uniform escalation, I just don't think these data are compelling enough to offer that. I think kind of made that point clear. So, you know, whether, and then you introduced the cost effective piece of it, you know, cost effective analysis, you know, then you really have to question it. But yeah, that's where we're at is, you know, really figuring out, you know, if you look at, there's some interesting work, there was even sort of a recent publication, Daria Tulkies on it, and others were surgeons looked at their own patient population, and they looked at patients who would have been eligible for proteas, and, you know, how they would have done with surgery. So, yeah, there might be some, again, ways in which we can do some correlative work, not just with the proteas data set, but hopefully others that might be able to contribute to figuring this out. But, you know, for now, these data are really consistent with what we saw in the recent Enzerrad trial, which again, we're MFS by conventional imaging. The addition of an ARPI did not add to radiotherapy and ADT, and you could argue technically in proteas, the addition of an ARPI did not improve MFS by conventional imaging in proteas either compared to surgery and ADT. So, in that sense, it actually seems fairly consistent. But biomarkers, absolutely. And then, you know, let's not forget there's obviously alterations, you know, patients that will have, you know, specific findings that may make them either more or less likely, right? To respond to an ARPI strategy. So, you know, thinking about those broader questions, right? It's gonna be next step. - Yeah. I mean, why is the end met, sorry, sorry, why is the end of rad discussion relevant in this space? Is it because it's a similar patient population, but they were using radiation therapy in both alums instead and added the RP? And one of the populations similar enough, and where the outcomes of the populations and the control of similar enough to make cross-trial comparisons. - So, again, always with the caveats of cross-trial comparisons that you can't, you know, put too much talk in them. But the reason that often might come up in conversation is it's certainly the answer-ad population better, I would say correlates with the proteus group, certainly more than, say, stampede, M zero. So, you know, when you're looking to other data, it's kind of like, which population is at least, you know, somewhat similar? And also with answer-ad, you know, again, really it was testing the question, local therapy, antigen-depression therapy. In this case, the local therapy was radiation rather than surgery. And the addition of an ARPI, but in that study, again, it was MFS by conventional imaging and they kept it as such. And so, those MFS, you know, by conventional imaging or lack benefit, lack thereof, is essentially what you see if you just look at MFS by conventional imaging in proteus. It's not dissimilar. Again, a lot ahead of originating still, even when I say the populations are comparable, and like I say, we don't have, you know, all the data on, again, molecular stratification and, sort of, biologically distinct populations that we'd have to be looking at, but in general, lineage, necessity, basal, like, you know, differentiation, all that still needs to be evaluated. - And, yeah, my guess to my next question, you've mentioned three or four. You clearly have quite a big concern around this endpoint and changing from conventional imaging to pet imaging. But why, you know, I realized it's unorthodox, a little bit, change your endpoint in a trial. But it moved with the times and they probably would have had to close the trial down if that wasn't the case. It wasn't, you know, and why would it be, why would it be so different? And, and, you know, you said, "I mean, it was negative, this was negative, conventional, this, you know, it was the new imaging that dragged it over the line and, and, and, you know, just explain that to me because it's, I guess it's possible that you could look at it a different way and say, actually, because the trial is bigger or more robust, the confidence will become narrower and the hazard ratios are about, you know, it's just the way that stats work. You need to do big trials for them to be positive and it would have been, of course, it would have been positive because it would have been underpowered and it wouldn't have been the just trial design." So it was a self-fulfilling prophecy to say, "Yes, the subgroup was negative and therefore it didn't work and end the meta-negative, this is negative and therefore it's negative trial." And they kind of didn't budge it but they had to change it, they budged it a bit. And so the way in those two populations is so different. - So let me say this, you know, first of all, as I started by saying, I congratulate the, you know, investigators, I think the patients, you know, really it's important to acknowledge all of the work. And of course, all the patients and their contributions to this trial and I get that there has been so much emphasis on incorporating PSMA PET, right? I mean, it's an integrated biomarker in my own study. So I understand, you know, the pressure and the importance of modernizing trials. It's just that, you know, there's just some fundamental truths that complicate the picture. One is, you know, we know from the threshold effect, the surrogate threshold effect, from the ice cup consortium, that MFS by conventional imaging improvements, those reliably predict future overall survival benefit. As of now, we cannot say that MFS by PSMA PET is a surrogate endpoint of OS, okay, fine. But then when you introduce it mid trial, which again, I get, I understand the pressures, I get what it was done. You know, when you incorporate it midway, now you're looking at, you know, over 50% in both arms, you know, whenever there was, you know, a PSA signal, patients who are getting PET understandably, right? 'Cause that's pragmatic and that's with the practice. But the reality is that, you know, now you're seeing things earlier. And so how do you know how much of this is, you know, again, reflecting a bias, early time bias towards, you know, earlier detection of biochemical and PET detected progression, rather than actually what you are asking about, Tom, which is, are we actually eradicating micrometallic disease early, actually curing these patients? So now I'm not saying there was a right or wrong, but you know, the reality is this complicates the understanding. And then the third thing that muddies the water is how do we then, as radiation oncologists, when we see these patients who are now, some of them testosterone suppressed for longer than you would like, even if a lot of them do recover, there's still a decent percentage of that zone, as I said, just under 20%. How do we understand which ones might be having disease? That is brewing that we, you know, need to radiate. When do we do so? How do we understand biochemical recurrence in this sort of post neo-adjuvant ADT-ARPI population? And when do you act, do you wait for the PET to show something and ignore the PSA? 'Cause it's, I don't know if we know that. So I think that's part of some of the angst that you might be hearing about the study is sort of like, okay, this is great for clinical trials. This is raising a lot of important questions. I commend the investigators for doing it, but like, where does this leave us in clinic? And that, you know, 55-year-old who's looking at you like, now what, you know, and again, a lot of them were just high risk by grade only. Clinical T1C, okay, fine. But some of them had, you know, PSAs in the 50s, 60s higher, some, you know, have these potential biologic variants that were aggressive and just don't know. - So two questions to finish for me. Number one, which patients would it be reasonable to use the Proteus approach? And then number two, symbol one, to start is, is what do you need to see next to change your mind and increase that? - I mean, the event, again, the low rates of event free survival at four years concern me. I don't know how to walk that back. Because now you have a population that has seen hormone therapy, some of them have now seen ARPI, significant percentage, like 80, are not free of disease. And we don't know what to do with that. So I don't know how we're gonna pick who this is right for unless you have a population that, again, wants to take this approach in the hopes of avoiding radiotherapy, maybe altogether, but that's not usually as much of an incentive as avoiding ADT and ARPI. - Not to say there aren't patients who are very much happy to not have radiation and don't want it. Of course they're out there, but it's a lot to go through for something that you might still end up getting. And frankly, the percentages that were in this trial, although lower than you might expect, considering it wasn't protocol mandated, there's still a significant portion that got ADT within five years, which is, you know, if you're gonna have reduced surgical margins and an improved PCR rate, you'd want that to translate into not needing, not needing savage therapy, right? So if we haven't spared them that, you've now truly intensified therapy and thrown the kitchen sink at them and it's not clear what the long-term cure will be. So I think that's a long-winded way of me saying, I literally have no idea who you should offer this to. At this time. - It was a very nice way to say that. - It was beautifully put, very, very important. What would some an advocate for this approach? What would the advocate, because you said you've spoken to many etologists, you've heard different opinions, give me the other, the glass half full approach. And what you've heard from some of your oncologists who they would treat and the justification for that. - Yeah, I think there are patients who absolutely want surgery. They are, you know, very much in that mindset and it's appropriate. And listen, I always say to my mentees, you know, the most important person to convince a patient to have a prostatectomy is often, if they see one, is often the radiation oncologist because we are able to provide this sort of unbiased endorsement of, you know, saying, yeah, I think sir, three is absolutely perfect. - Are the medical oncologist? - Of course, of course, of course. But in our dichotomy of local therapies right now, yes. - Gotcha. - Correct. But absolutely, you guys are often, often, often I go to. (laughing) - Most of our guests are actually much rude than you are. - Oh, I'm not done yet. - Oh, no, just. But what I was going to say is, you know, I think if you have that patient and you say, okay, they absolutely want surgery for all the right reasons. And they have a disease where I am genuinely concerned about metastatic disease. I'm genuinely concerned they are at high risk for needing postoperative everything under the sun. I think that's a patient that you talk to and you say, here are the side effects of this approach. If I'm going to do this, the data suggests that I should give you an ADT plus six months of this, you know, apolutimide, an ARPI. Here's what the added, you know, impact is on your quality of life and how we're going to manage your grade three, grade four rash. We are potentially seeing more of a signal towards urinary incontinence or some other local side effects. If that pans out to be true, have that conversation and then offer it to that patient. But again, I don't think we can say to them though that they will have an overall survival benefit. We definitely can't say that. And I don't think we can say that they will be free of additional treatments beyond, I guess, really, you know, the four year mark at this point. And even then the savagery of therapy, as you saw, was needed. So even if I'm legalized. I mean, it's, you know, great trials sometimes raise more questions and answers. I think this might be one of those kind of trials. So it's important not because it was a slam dunk positive result for everyone. But because it's really intensified the discussion around who needs what and the intensification intensification, biomarkers, et cetera. So, you know, if for no other reason, it moves the field forward because it's basically reinvigorated this, this high-risk prostate cancer discussion, especially in regards to surgery. Absolutely. And maybe the extent of surgery, you know, what's needed there. Yeah. And like I said earlier, I think the opportunity for, you know, sort of understanding drug effect for collecting that tissue. I mean, I think, you know, it sets up a very nice platform for these types of trials. And again, I think both radiotherapy and surgery as local treatments where you can then get tissue after drug exposure would be great. But without understanding some of the molecular classifications of some of these patients, it's just, it's just such a heterogeneous group that it's hard to make individual decisions based on this. Thank you so much for joining us. Really appreciate your level headed expertise. Thank you for having me on Twitter and such about this lot of strong emotions. I think, I think this was perfect. Thank you for having me and I assume Tom has some, some football he needs to go watch and cheer for. Yeah, it's only my coming home apparently. Oh, right. Yes. Probably air after that final. So hopefully. Yes. Yes. We never wouldn't end. Ain't nobody struggles in the end. Oh. I know. A euphemism for life. I know.