Episode 525: ESMO 2026 - PEACE-1 and CAPItello-281

(upbeat music) - Your Amigo's podcast, Karim Fizzazi. Karim, welcome. I'm never allowed to do the introduction normally, Karim, because I'm so bad at it. But Karim, 'cause this year you're one of us, a really special guest for your, 'cause you've got two presentations at Esmo, and we're gonna talk about both those presentations in this prostate cancer pathway. Our podcast, the first thing we're gonna talk about is peace. And that's not a global peace. That is the clinical trial piece one. We're supportive of both. We're very supportive of peace to one of us. - Of course, I don't let you do the intro's time, 'cause you're wondering. - Well, we're not talking about world peace today. Karim, we're talking about your trial. And Karim, while I'd like you to start, I've obviously congratulations, because these are investigation initiated trials. They're really hard to do. We could talk maybe at the end about the peace consortium and how successful it's been. But what I'd like to start at the moment is to know where you are in terms of triplet therapy, and a little bit about the design of this trial, and what influence it's had so far on global practice in a knowledge that there are other trials, stampede, Enzermet, Arasand in this space as well. There's low volume, there's high volume, et cetera. Where are we now, and what was designed for the peaceful original trial? - Absolutely, and thank you, Tom and Brian, for the opportunity. So, we're speaking about patients with denervo, metacetic prostate cancer. So, other roles say about 10% of the patients who are diners with disease in the Western world, but that can be up to 60%, 70% in other countries, colleagues from China are telling me that this is approximately the proportion of men with evidence of metaces, this is a diagnosis, and this also apply to many men across the world. So, it's quite big, and obviously, those men mostly die from the disease as opposed to those with localized disease who are either cure or at least don't die from the disease. So, it's clinically super important, of course. You may remember that, it sounds crazy, but just 10 years ago, we were tweeting this man, we've only on the gene deprivation therapy, and we were waiting for progression, for castration resistant, before we would start some other treatments, already at this time, the STAC cell, the gene receptor pathway inhibitors, and some others. Things have changed dramatically in the last decade. We could show that two drugs are better than one, three drugs are better than two, and piece one, that's academic European trial, was a cremator in this second demonstration, it was really the first trial that showed that combining ADT, those STAC cell and a baratron was better when compared versus ADT and STAC cell, and this was also confirmed just a couple of months later by a former trial, Colorescence, showing the same benefit with Vestime with Darutomide in state of other ratron, and somehow Anzamat, which was conducted mostly in Australia, by Chris Swini, partly confirmed the same findings with Vestime, a subgroup of men who actually received a triplet. So, I think the data are quite robust, we know that. Question is how keen patients are to receive the triplet, including the STAC cell, and also the communications we may have with all the patients, it also obviously depends how we present things. When we presented the data back five years ago, now, DSMO and then in the publication, we had approximately three and a half years of follow-up already, we knew that radiographic progression, free survival, and overall survival were improved in the trial significantly. But of course, the follow-up was quite short for overall survival, the medians were not reached at this time. And when you had a look at the capital mayor covers, they took their time before the separate because patients don't die immediately. So, I could understand that some of our colleagues were not completely convinced by the data, and they were perhaps waiting for longer follow-up before making their decision towards a more triplet versus doublet. So, this is why it's so important to have long-term data. It's actually rare to get those long-term datas in pharma trials, typically I know, of course, that clinical research has a cost and pharma trial when they have their primary analysis and that allows them to go to the market. They typically stop the follow-up, they close the trials, which, of course, makes financial sense. But scientifically and medically, I'm happy that all the academic trials ends I'm at again led by Chris and peace one that we've been conducting here in Europe could continue the follow-up and eventually, without with follow-up of eight years, which is exactly what we have here in this one. So, this is pretty much what we are now before ESMO and I'm glad that the ESMO committee selected all the related analysis. It's a room quick question from me. So, one of the controversies on this trial and other trials in this space, including Stampede, has been that the control arm had dose-etaxal and LHRH agonists rather than an RP. And so, many people said that, and I think Matt Syed and others have done some retrospective data on this and most people feel that an RP would have beaten dose-etaxal and therefore, because the control arm, it was the right control arm at the time, as you said, the original positive data was dose-etaxal, but because the evolt, the field evolved, that created uncertainty about whether the triplet was better than the RP doublet. What's your position on that? - Well, I think it's a fair comment. Having said that, well, basically, as I said before, we showed that two drugs are better than one and thus was first established with ADT plus dose-etaxal back in 2015. And then, two, three years later, the RP showed the same benefit when I added to ADT. So, yes, you're right, and when we conducted piece one, the standard of care was either ADT alone at the beginning of a trial or ADT plus dose-etaxal starting, say, in 2015. And we could complete the actual back in 2018, when actually the RPs were not already approved and reimbursed. It couldn't have been a control arm in all a trial, just because the demonstration was not there at this time. - No, it just because. - I totally get it, couldn't it be? And I think you picked the right control arm at the time. There's no criticism around that. The issue is whether, in the current trials we're doing, amplitude, vision, capitolo, we're talking about that in a minute. It wasn't chemotherapy, it was the RP that was chosen as the control arm. It wasn't the triplet that was chosen either. It was the doublet. And so I guess it pruned us back to this complicated issue about, you know, is it the RP doublet that's the triplet? And what does that mean for the triplet moving forward? And I know that there are people, for example, who believe in lower risk patients for all sorts of different or lower volume disease, those patients should probably be avoiding triplet therapy. They should be getting the doublet, but not with those attacks or with the RP. Do you agree with those people or do you push back? - So, so far as to, let's speak about facts. And then when, maybe. - We love facts, we love facts on the show. - Absolutely. (all laughing) Well, I'm gonna speak about facts coming from your country, Tom. - Not all of the truth, for example. We're not very good at our facts, right? We're not very good at those, particularly recently. - Very good. - Far away. I'm looking forward to it. - So, Sue, this is Tampede. As you both know, and probably all of the people who are listening to us know, Tampede is a multi-arm, multi-quations trial. And actually, at a time, back by 10 years ago, patients who are randomized to receive either ADT or STACCEL, so those STACCEL doublet, or ADT or RATRA. So, be a hormonal therapy. Approximately 500 men were directly randomized between those two doublets. And the data were analyzed between those two arms of all survival is exactly the same. it's, you know, the other way. is really one. There was no difference in OS. PFS was in favor of a baratron, but always was exactly the same. So this makes me quite confident thinking. And of course, I don't have direct evidence for what I'm going to say, that if the control arm in piece one, Arasens and Enzamet, has been a hormonal doublet, quite likely the triplet should have been still the best pick. Of course, we don't have direct evidence, we don't know. And that's criticism that remains. But I think that the doubt should benefit all our patients. And this is really the conversation I'm having of my patients. I'm telling them that in my opinion, the main standard is a triplet in men with the nerve metastatic disease. Now, of course, if as a contraindication for the staxel, if a patient doesn't want the staxel, of course, another conversation. But I think we should start the conversation with a triplet. And indeed, with this updated analysis of piece one, the benefit we reported five years ago, not only remain, it's actually greater. For the graphic progression for survival, it's more than a two years absolute difference in median. So we're providing two years of additional good life, if you will, to patients. If you look at the rates at seven years, only 15% of the patients in the control arm have not progressed or died versus 37% in the experimental arm with a triplet. So it's really twice more, more than twice more actually. For overall survival, it's also almost a two years absolute difference in median with a hazard ratio of 0.68. And at seven years, 31% of patients are still alive in the control arm with a doublet versus almost 50% in the experimental arm with a triplet. So it's quite big. And coming back finally to your question, Tom, about the volume question, you're right. Some people felt initially based on charted that we should use the staxel and hence the triplet only for patients with higher volume disease. But actually, this was not confirmed again by Stumpede with the same question and more patients actually. And if I look at piece one by volume, we see a benefit not only for patients with high volume with a triplet with more than one year of overall survival benefit moving from 3.5 to more than 4.5. And again, a hazard ratio of 0.67. But also for patients with low volume disease, you see actually even more benefit with a difference in median of overall survival of 1.6 years moving from 6.2 to 7.8. And the hazard ratio is pretty much the same around 0.7. So you see the volume thing doesn't really play its role. And I think to be fair with you, I think we should stop counting metastasis. This is not something we're doing in many other cancers. I think it's very misleading, especially on a bone scan, which measure a bone making, not direct cancer. And I think we should go more for biomarkers rather than counting metastasis. Just to follow up on the volume discussion, I mean, you're pretty clearly advocating that volume should not be considered a decision making in that triplet's the standard of care. But how do you count for those other data sets? Is it a matter of how they counted or the definition of high volume low volume? It certainly makes more sense intuitively that somebody with more disease i.e. high volume has a better chance of benefiting from the triplet, but the data that you just quoted from your asthma presentation doesn't really support that, right? It's a pretty consistent benefit across volume, so to speak. So how do you reconcile that? I don't necessarily disagree, we should stop counting volume, but I still kind of go back to those original data sets that did show a difference based on volume of disease. You know what? What happened, Brian? In the first three trials of distaxile, stampede charted, and G2G15. I think there was a myth understanding by all of us by the way. I'm not blaming anyone here. Between the number of metastasis of a volume and the timing of metastasis. And indeed, both charted and G2G15 included both patients with the nervous metastasis disease and men with relapsing prostate, metastasis, prostate cancer, post-local treatment. Why stampede? Included only the nerve. And hence the disagreement or discordance between the findings, charted and G2G15 saying, "Well, the staxile works in men with high volume disease, but not in low volume." While stampede at this time said, "Well, no, the staxile works in both." And what the metastasis was conducted, best time using four subgroups, including low volume, high volume, but also the nervous versus metacranus, if you will. It became much clearer that patients with the nervous benefit from those staxile, regardless of the volume, a bit more for high volume, but really it's the continuum. So you will see a benefit in patients with one, two, three burn metastasis. On the other hand, patients who relapse from localized disease just don't benefit at all from those staxile. Most of these men actually do have low volume disease when very labs. So this is why it was confusing. So the simple message, I think, to me and hopefully to colleagues, should be, if you see a patient relapsing with metastasis, homoincentive metastasis disease, post-prostatectomy or radiation therapy, don't use the staxile, simple message. And if you see a patient with the nervous metastasis disease, yes, please integrate the staxile, at least in the discussion with the patient. Statistically, you'll have these men. Karim, you were a bit dismissive of volume of disease in that you said, look, we should stop counting metastasis. And I think Brian and I probably would agree with that. It sounds crude. But you seem to be brought into this synchronous and metacronist story much more strongly. Are you picking rules that you like and dismissing the ones you don't like? Or is there something different between those two rules in your opinion? Well, I think we need to dig more in the biology of those two scenarios. And maybe if I could, I'd like you to push you on the same conversation on the decipher data and the P10 data looking at those, the staxile response. So if you could just address that issue around timing, and then bring in the decipher biomarker work and give me your opinion on those two issues, please. Very happy to do so. So first regarding the timing, Chris Winnie did a beautiful work pulling together data. Even before all these trials, showing that even at the time, we were using ADTO alone for metastasis-commoncentive disease, patients with metacronis metastatic disease live much longer as compared to those with denervo. It's really doubled. Even at this time, the life expectancy was approximately eight years after the diagnosis of the first metastasis when it comes to metacronis patients. And again, those are typically metacronis loud volume. This is the typical way the cancer relapses. As opposed to approximately four years for patients with denervo disease, and actually if you split them between loud and high volume, it was say 3.5 years versus 4.5 years for loud or high volume. So yes, of course, high volume is a little worse, but not very different as compared to denervo loud volume. Again, the big difference in outcomes is between denervo and metacronis. So yes, clinically, and based also on the metanalyzes of the distaxal role, I think we should pay more attention to that simple, of course, parameter. You just need to figure out whether your patient was diagnosed with prostate cancer yesterday or five years or ten years ago, so not very difficult. To help for your decision-making, as to whether you should advise triplet therapy, yes or no. Now coming back to your second question, Tom, I think really the work the Stanford group has been doing with decipher is beautiful. I really hope we all see validation for that. And basically what they suggest is that, number one, if you have a decipher high test, you're much more likely to benefit from the staxal, while if you have a decipher low, you're very unlikely. I'd love to see validation. It's not easy, of course, because the samples are quite old now, and ideally, of course, you need a randomized trial to test vesipostasis, or at least to validate it. They were also able to suggest that a P10-deficient signature is predictive for benefit of the staxel. Again, I'd love to see validation for that. That would be more than biomarker, and much more relevant to me, as compared to simply counting metastasis, and saying, "If I see two or three burn metastasis on a planar burn scan, I'll do ves," and I see, "If I see four or five burn metastasis, I'll do that." Honestly, that really doesn't make sense to me. For toxicity to problem, we haven't talked, they're told about toxicity. The chemotherapy tox is obviously in both farms of this trial, but there's no toxic, or there's no chemotox associated, sorry, let me get abscited, there's no chemotox, of course there's toxic with RP, but there's no chemotox with RP. So it's difficult in this trial to define toxicity, because both farms have chemotherapy in it, and that most people be using RP as the control. In your opinion, what is the price patients pay from chemotherapy toxic compared to RP? So, well, first, basically, when you look at long-term toxicity in piece one, the good news is that we couldn't find additional toxicity in the long term. The only difference, basically, between the two arms is, as expected, for hypotension and hypokalemia, and it's not that big, 21% versus 14% for hypertension, and 4% versus 1% for hypokalemia, so not honestly, not a big, big deal. Now, you're right, the stock cell was used in both arms, so we do see chemotox as it in both arms, but again, I don't think, I don't know why, and tell me what your opinion is, we see 5% nitropinic fever events, 5% in the triplet arm versus 6% by the way in the end tablet arm, and nitropinic in general is a great 3 and 4 is 10%. So, in terms of, let's call it terrible or life-threatening toxicity, I don't think this is crazy. I think, you know, for example, in colorectal cancer, maybe also in breast cancer, in other cancers, with similar age, similar populations, I think we accept much more toxicity for all patients, for benefit that is not necessarily exactly the same. Again, here we were speaking about one, two years of additional life in medians, in the overall triplet population, it was really two years, it's really big, so not, I really believe that for prostate cancer, we are, you know, maybe kind of chicken, with a toxicity we are about, we are happy to speak with all our patients. So, yes, again, in terms of toxicity, reassuring data in the long term, we're in peace one, and no excess in those tags are related toxicity, and about 5% of nitropinic fever. So, Kareem, in 2026, which patients are getting dose of taxal chemotherapy? Which I was going to ask just to add on before your answer is of all the patients in this scenario that walk into your clinic, what percent are actually getting the triplet you offer it to everybody, but, you know, not everybody gets it. So, is it half the patients, three quarters, what percent actually get it? Well, it really varies depending on who starts the conversation, it's really oncologists related, think, which I think is very unfair to patients. I think we should do a better job. Honestly, in my experience, for the nerve patients, I would say probably three out of four patients receive a triplet. Of course, it may vary according to whether you see patients with lots of comorbidities, some colleagues are telling me where I work, I see very elderly patients, very old patients with lots of comorbidities, malcardioline fraction here, etc., so really hard to use the triplet even if I'm convinced. And I say, well, yes, of course, it don't make sense. Patients I'm seeing are, I guess, a probably fitter, so there might be a bias. But I really think that we should really start the conversation, telling patients, the main standard of care is the triplet. And then you start the conversation and you adapt depending on patient's preferences and, obviously, age comorbidities. Karim, last one for me on this topic, lutishium, parpinhibition, lots of opportunities now beyond chemotherapy. I think it's probably true that the global community is not using as much chemotherapy as you are. Do you feel that these results, because, as you say, they're broadly impressive, do you think that more chemotherapy will be given, and do you think chemotherapy should be sequenced with parpinhibition and lutishium, or actually, is it a different patient group? Right. So first, you know, two important, you know, subject also, dostaxel, anabiratron, are generic drugs, meaning that they're cheap. And that, I think, is also key, of course, depending on who pays and how much it costs where you work. But with all the treatments, we may, you were mentioning, Tom, parpinhibitors, lutishium, parpinhibition, have a significant cost, either to patients, insurance, or healthcare, or health environment. So that is also something to take into consideration. Also, at least until now, they haven't shown the same degree of benefit that the dostaxel based triplet have shown in either piece one, aracense, and indirectly, also in enzymatic. So that's also important to remember, and I think, to tell patients. Now, to be fair with the other drugs, their follow-up is shorter. We still need more data, with lutishium, psa, with the parpinhibitors. I'm quite convinced that the parpinhibitors will demonstrate significant, and not only statistically significant, but clinically significant, and quite dramatic to be clear, benefit in overall survival. To all the patients, I may be wrong, of course, the future will tell, but it's very likely, even also what we know with these agents in the CRPC setting. An important question with these agents, the parpinhibitors, will be, should we use them continuously, as we are doing with RPs, or should we cap? Should we try to reduce the onset of the incidence of mild displeasure or the chemia? That, I think, remains to be addressed. But I think they are very promising. I think you're right, also, that some colleagues will begin to use ADT, the Staxxel and an RP, and then start their parpinhibitors right after the Staxxel is done. It's just for months, not very long. Even if we don't have data at the moment, so we will need, ideally, to do this in a context of a trial. But I'm hearing colleagues telling me that this is what they will be doing if the parpinhibitors are being approved. For PSMA, for Lutitium PSMA, I think we need updated analysis of the PSMA edition trial. It's positive by RPFS, as shown in our last year, but maybe not as good, let's say, as I would frankly, expecting. So we need longer term data with a trial. I think it's coming. And we will be better in a better situation to understand whether it can really help these patients at the stage, again, and to be put in to be balanced. We've accost the side effects, but generally speaking, it's a quite well-treated drug. So, Kreme, I want to move on to Capitolo, but I think just to wrap up this space, I think it's fair to say there's a lot of potential triplets out there, including with new drugs, old drugs, et cetera. It seems like the next several years are going to hopefully, in the context of a trial, sort that out a bit, which patients should get which triplet, if you will, can some get sequential triplets where they get chemo up front and then apartment it there later as you alluded to, but it seems like there's a lot of work to do in that area, including I would say some de-escalation trials that are ongoing now that we have multiple active drugs in whom do we escalate and in whom do we de-escalate. Do you agree with that? Is that that seem where the next I don't know three to five years is going to bring us? I completely agree. I've you know coming to be de-escalation, I think we need to be very cautious avoid doing it outside the trial. I would hate just, you know, waking up a morning or in evening, whatever in three, four, five years time and with trials showing us that actually it is detrimental to patients to de-escalate. Again, in the context of a trial, I think it's a fair deal, but outside that trial, I try to avoid de-escalating, of course, in situations where toxicity does not mandate de-escalating. But I know it's quite popular in general and I would hate, you know, to see that. I think again, we should pay more attention to synchronous, so the nerve o versus metacranus, and I think that for metacranus, de-escalation makes a lot of sense. These patients live probably ten years after the diagnosis of metacranus, and they may indeed benefit from de-escalation. They really do well. For patients with denover disease, I'm still more on the fence, and I think we should be very cautious with de-escalation. Fair. So let's move on in the last ten minutes to the capital of data, which you also updated. If you don't mind, I will summarize quickly sort of where we were up to this point and then turn it over to you. So the biology is that there's about 10 percent, as I understand, or some subset of patients with prostate cancer at P10 deficiency, that drives this proliferation pathway, which includes upregulation of AKT. Capificertib is inhibits AKT. That's the basis for its use in this subpopulation. And there have been prior data with this in a similar drug, prostate cancer showing some activity, but to my knowledge, this was the first large trial in the hormones sensitive setting. So this was 1000 patients randomized, ADT, abby, and both arms, and then half the patients get pivoted, half get placebo. And the initial data, and I was privileged to be part of an ODAC. I think about six months ago, they talked in depth about these data showed an RPFS benefit. The OS was fairly immature at the time. There wasn't benefit, but it was fairly immature. There were, you know, I think it was brought to ODAC, because there was concerns around two things, one around the toxicity of the drug, and the other around the biomarker. So this is just in P10 deficiency. Patients greater than 90% by immunohistochemistry, and some evidence of a gradation where more degrees of P10 deficiency, if you will, led to greater benefit in some conversations around that. It was ultimately ODAC ultimately endorsed it. It was ultimately FDA approved a couple months ago, maybe or so. And on that, with that as a background, then you presented the update. This is Kapatella 281 term update. I think of both RPFS and OS importantly. If you want to just walk us through, and then I have a bunch of questions. Sure. And thank you for summarizing this so nicely. Depending on how we select this man, the incidence is actually, or maybe a bit higher, probably more 25% of patients with the neventastic disease. At least with the cutoff we used in the Kapatella trial, we chose more than 90% of the cells without any P10. But again, we made debate about number one, the actual incidence, and number two, the best biomarker to use. So when we reported the data year ago, the demographic progression for survival to the primary endpoint was significantly improved with the average of approximately 0.8 moving from about 26 month to 43. So an absolute delta of more than seven months. But obviously, the rest was completely mature with a median follow-up of approximately year and a half when we first analyzed the data. We now have almost three years of median follow-up. This analysis was actually done in conjections with the agencies who really wanted to know more before making their decisions. And the maturity for overall survival is of course greater. Unfortunately, these men with P10 loss tend to die sooner than later, they have bad disease. And this is why now the medians have been reached. The other ratio for overall survival is 0.82 to the P value of 0.044. And this is descriptive at this time, we cannot claim complete victory. But it's still, it's an it's a novel survival difference in millions of 11 months moving from approximately 46 months to approximately 57 months. And the curve super rate very, very nice, so Lee and the Kaplan may, Kaplan may have features. So that's great. And as you said, Brian, with as updated analysis, it appears that patients with more P10 deficiency tend to benefit even more. If you set the curve for greater than 95 percent, deficient P10 deficient cells, the hazard ratio is now 0.76. And of course, the higher the P10 loss, the greater the benefit in overall survival. So we may debate regarding what is the ideal cutoff to use in all the clinic. If the drug is approved, I know that in the US, it's already approved. And of course, it's probably subjective. It's hard to say what is the ideal cutoff to that justify use to be balanced with with toxicity. You're right. The treatment comes with increased risk of diarrhea, hyperblicemia, rash anemia. So and of course, the financial cost. Chris, sorry for interrupting. So look, I mean, we just heard about your piece one trial. You had, you know, really beautiful hazard ratios there, 0.5, 0.6. You looked at subsets there, which because the overall trial was positive, it's very fair to then look at subsets. But if overall, you're not statistically positive, you know, then trying to find other subsets where there's enrichment, you know, there'll always be enrichment of some description in a forest plot. And you know, we are, you know, there's always a danger of overinterpretation in trials that are not yet positive that you find a subset you like. When you look at these data, and I agree that hazard ratio has gone from 0.9, it's gone down to 0.8, 2 for OS, but it's not yet significant. And you were, you know, you were a bit negative about the Lutishium data also not having OS. Why are you not also negative about this in the context of the other data that you've shown us? You know, thank you and very, very come and come. So this, I mean, VES updated analysis of capital O281 shows that the hazard ratio for overall survival has improved 0.82. P value is 0.04, but it is dressed as cryptive at this time because this is again an internalizes for overall survival. And to claim victory for OS, we should have had a P value of point or whatever. So right now it remains as cryptive, but and we will need to wait for the final analysis to to confirm this data. But I think it remains a good news for us for patients. And I'm saying that because the, the delta we saw year ago for PFS actually translates almost exactly to overall survival now. And the absolute difference in median for overall survival is 11 months. I'm moving from 46 months in VADT Abaradran arm to 57 in VES particular triplet, including capacitive. So that, that's quite big. Regarding PSMA editions of the Lutishium PSMA trial, we as we're speaking, we don't have the same follow up and we don't have the same data for overall survival. PFS is significantly different, which is, which is great, of course, but it as we are speaking, it comes by its own. We don't have overall survival being improved, but even not a real trend, if you will, as compared to if I'm making in the reconparation then with KAPI 281. And also we don't have another clinical benefit, if you will, Tom, in the PSMA edition trial, say, "Screted with events, time to quote your flight iteration, time to pain." You're speaking about screted rated events. In KAPI TELO, we also see a benefit. We have a ratio is, again, approximately 0.8, same P value, and the median time to screted rated events is a Approximately 36 months versus 44 months. So, we're starting to get. - Let me package. - I get the package, I can see you're brought into it. The other issue is, these were mainly, these were quite a high risk patient population. A lot of de novo patients. In the first part of our podcast, you talked to me about, you're treating all of these patients with chemotherapy triplets, almost all of the patients. The control arm of this was just the RP arm. Is this the wrong control arm for these patients? And would capi certab have. Would it have beaten triplet chemotherapy, almost certainly not, I would guess, is that right? - You know, I think your comment actually applies to all vest generation of trials. That's true for the capital of trial. I would have honestly prefer having the staxial spot of the control arm and the experimental arm combined or immediately sequential. That also applies to the PSM edition trial. It also applies to the pop inhibitor trial that we spoke about early on today. It's not been the case, it is as it is, but it really applies to all of them. You're also right, Tom, because as we said before, patients with P10 loss may actually be the one who benefit most from the staxial. So we'd love to treat them with the staxial as right, as well, sorry. And we are actually currently considering developing a quadruplet regimen of ADTB, Raju and the staxial incapacity for these men with P10 loss, which biologically make a lot of sense to me. And again, given that with the staxial can be provided in just four month time, you can, I think, easily treat your patients with the staxial, stop it, and then start the capacity without wasting time. So that I think would you do that in practice now? You know, and so that trial that reads out which is obviously years from now, how would you integrate it now if you had capacitive assertive available? Would you do just as you said, give him chemo upfront and sequence or. - You know, in general, I don't really like to do this thing outside trials. And even more, yes, and to be frank, even more after we saw in the prostate world, the era to 2/3 trial, in just to refresh your memory, this was a trial combining at a Raju and plus radium to 2/3. People who are doing this outside trial, because these are generally saved drugs in the 2010, we had evidence that radium improves of all survival, we had evidence that other radium improved survival in castration resistant disease. So people were saying, well, we're not combining. And when the trial read out, we figured out that this is a toxic combination, with clear access in fractures, and nobody had fought about it before the trial was conducted. So to me, this was a strong lesson. Don't do these things outside of trial. You never know. - So how would you do, if you have a P10 deficient patient who walks into clinic, and I know this is hypothetical, I mean, how do you choose that, and how do you choose one of the other, if you had to choose, if you're not going to sequence outside of trial? - Well, right now, you're basically going to choose, but you've got to choose between your children, Kareem. - I mean, they're both your trials. This is a difficult one, isn't it? I mean, how do you pick, how do you pick your child Kareem? Here we go, folks. - Well, actually my system makes me choice to be choose, sorry, to be honest. Right now, capacity is not approved, so I have to use the back cell. If it is approved, hopefully, I'll have this trial ongoing, and I can propose a patient the credit plate, but now it's nicely done for me. - It was nicely done for me. - The answer is, don't choose between your children, have another one. - Well, that's a good answer. - Kareem, last question for me on the biomarker, right? You chose 90% as the cut off in this trial, perfectly reasonable. It seems to me that data suggests a bit of a gradient effect, right, with more deficiency, if you will, leading to a greater effect, then I totally understand it's subsets. But talk about the reliability of the biomarker is my pathologist doing IHC, going to come up with the same percentages yours, and do you think there's something there, with the greater degrees of p10 deficiency and greater benefit? - Well, I think it's a key question, Brian, and you know, when you're trying to think about it, how do we assess the biomarker? It's human eyes. That's, as you said, it's holopathologists who will tell us it's 92% lost, or 94, 98, or whatever. And it could well be indeed that this reflects a different body, say, 90% to 95%, so it's almost 10% of cells. It might, you know, indicate that a significant part of a cancer still has p10, while between 95% and 100%, a significant proportion of these men with more than 95%, actually are 100% lost, so it's zero. That might be a different body. I'm trying just to simplify, of course, and I'm not sure what I'm saying is right, but it might be that the good segregation is really more than 95-ish percent. And of course, nobody's gonna be exact about 95 versus 96, or whatever, but I think if your pathologist telling you well, I can see cells with p10 staining, or it's super rare, that might be a good patience for capacitive simply. But of course, I'd love to see more and scientific data to support what I'm saying, to make sure I'm right or I'm wrong, actually. Karim, this has been fabulous. Thank you very much for your time today, and congratulations on your two presentations. Links nicely to each other at the meeting. Thank you very much, we'd appreciate it. Thanks, Karim. We appreciate all your time.