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- [00:08]
A
Our next session is on the evolving landscape of metastatic hormone sensitive disease. In essence broadening the discussion we just had about radioligand. I'm gonna have the panel introduce themselves. And Chuck, let's start with you.
- [00:19]
B
Hi, I am Chuck Ryan. I'm from Morris Sloan Kettering Cancer center and I'm a medical oncologist.
- [00:24]
C
Neera Jagarwal, medical oncologist, Huntsman Cancer Institute.
- [00:28]
D
Michael Morris, medical oncologist for Memorial Sloan Kennedy Cancer Center.
- [00:33]
E
Chris Sweeney, University of Adelaide without a microphone.
- [00:38]
F
Tanya Dorf from City of Hope in California.
- [00:42]
A
Apologies to Mike for not having his picture. I'm not sure what happened. And note, Neeraj is running for the ASCO nominating committee. He's not allowed to self promote, but if you're so inclined, Vote early and vote often. Okay, so we're going to take a little different spin on this than we've done with other things. I've basically asked each of them to sort of talk briefly about sort of the third agent that they might add to an ADT ARPI backbone. The graphics got a little screwed up there. I don't remember the order, but Michael's going to do Lutetian. We just got through with that. Neeraj will talk about PARP inhibition. Tanya Docetaxel, Chris AKT inhibition. And then Chuck's going to say that we really shouldn't be giving a third agent to anybody. That's what the first do no harm is. So they'll each sort of just present. I think we have two or three slides just sort of what's the state of the field, what's the data supporting, etc. And then we'll discuss and debate a little bit. And then at the end, actually we have cases. So we have sort of. It's a fabricated case that I've changed the features throughout the case and stuff. And then we'll talk about. Actually, Petros, see those whiteboards? Did you bring them up? Just put them on the side of the stage. We're going to have each. We're going to present a case. Have each of them sort of write down what they do for that particular patient and then we'll talk about that. Yes, this is high technology. High technology. Passing around just as a. As a place to start. Yeah, pass them out if you could. Just as a place to start. This is from the apccc. Our friend and colleague, Silky Gillison, who we will one day get to Nashville, runs this great conference in Lugano, Switzerland every other year about sort of the state of prostate cancer and consensus across various Aspects and I think I'm not going to go through this, but I think it just lays out adt, ARPI backbone for all patients except perhaps frail or limited life expectancy. And then based on synchron, timing of disease, synchronous versus metacronous and volume of disease, I. E. Number of bone mets, you know, what's the intensification approach and you can see sort of the consensus based on the, the number in favor. So I think this was in May. So this is before a lot of the data we heard about with psma, addition and amplitude and other things that we'll talk about, but sort of the state of the field at that time and what we're going to talk about is, all right, now if we want to add more things to it, how do we do that? All right, if you see your picture on a slide, then that's your cue to start talking.
- [02:59]
F
So I remember when charted first came out and we were really shocked that using docetaxel early versus later made such a huge impact in survival. Right. So we know that docetaxel, as much as we don't love to use chemotherapy and prostate cancer really has, can have some profound effects. And we probably all still have patients in our clinic who got that regimen and are in remission, still on their adt. Right. But of course the AR pathway inhibitors also provide profound advantages in the metastatic hormone sensitive setting. And so it came out through the doublet and triplet sort of experience that volume of disease and synchronous versus metachronous actually do make a big difference. So this is a meta analysis of these trials where you can see that for high volume the triplets come out on top, whereas for low volume probably the doublet is perfectly adequate. Can we go to the next slide?
- [04:03]
A
Yeah, yeah, just, just say when you want to go.
- [04:05]
F
But of course, wouldn't we rather use molecular features, biology and not only the clinical features? It was really exciting last year at ESMO to see the work using Decipher in the charted and stampede datasets. Essentially, if you have a high or a low decipher score, you benefit from the abiraterone, but if you have a low decipher score, you didn't benefit from docetaxel. Really, could we use Decipher as a way to pick who needs the triplet, who needs the docetaxel and then moving on to the next. I'm so apologetic that we don't have the authors on this. Emily Grist is the first author and GERT Attard is the senior author. This is a beautiful, beautiful, deep scientific paper looking at a number of different signatures including PAM 50 luminal basal Arkansas Pten decipher in the data set from charted. And one of the things that stood out was pten deletion seemed to also be very predictive for who benefits from docetaxel. And that's what these curves are showing that if you have active pten maybe you don't benefit as much from the docetaxel.
- [05:18]
A
So let's pause there. I'll ask others to comment and my specific question would be is, are we ready? How do we use these in practice? Do we need prospective data? Where does decipher or PTEN or whatever biomarker goes from here? Chuck, do you want to start?
- [05:31]
B
Well, I think it just also begins to put tumor biology ahead of counting lesions on a bone scan as a major driver of decision making, which I think is a good thing. And this won't be the end of such tests. Are we ready to make all of our decisions based on this? No. Do we need a prospective trial? I think we have better places to put our resources in terms of validating docetaxel by deciphering.
- [05:57]
A
So you wouldn't do a prospector trial.
- [05:59]
B
Based on this in hormone sensitive prostate cancer? Are we going to get that done? You know, this would be pragmatic about it.
- [06:05]
A
So if you don't do that prospective trial, I guess how do you move it forward? Maybe that would be.
- [06:10]
B
Yeah, some data. I mean it's a good question. So some data comes out and it basically is, this is why we have studies like Charted and Stampede which have been so influential is because the studies were done, samples were collected and we continue to study them. So this is as much a testament to the decipher predictability as it is to our ability to do these big hard tests, hard studies and keep pounding away at the data. So I'm just going to make that point. But the other thing is that decipher itself is an iterating test and there are new versions coming out and they keep integrating new biology, et cetera, et cetera. So we may see further and further analyses, outcomes of this particular data set with newer iterations of the decipher test. And you know, I don't, I just, I just am thinking realistically here, are we going to really do another MHS PC study where we're going to use the cipher, we're going to integrate a new marker? As much as we'd love to do it I just don't think it's going to.
- [07:07]
A
Fair enough. Other comments weigh in on that.
- [07:11]
E
So the challenge is. And for the record, Tom, thanks for the microphone. The question is this is adt docet hexel vs adt testosterone suppression doesn't have the ARPA question. So hopefully by ASCO next year annual meeting, we'll actually look at ADT Dosey Enzo vs ADT Enza to answer the question.
- [07:35]
B
Yeah.
- [07:36]
E
Now the challenge that is that for some reason patients got docetaxel on Enzalutamide based on physician intuition. And it turns out physicians are really good at choosing who does poorly versus not. And the patients who got docetactal had a poor prognosis in enzyme. So hopefully we'll be able to account for that in the biomarker analysis and ask does this hold up in the ADTRP versus ADTRP docetaxel setting? So at this stage it's great and. But your point is absolutely correct. There is a lot of love between the cooperative groups and getting together between Chartered Stampede enzymet to answer these questions because we can do this as a cooperative group and actually dig deep. So I just want to shout out to the cooperative groups we can ask bigger questions beyond industry based studies because we have a longer time frame.
- [08:34]
B
These are our tax dollars at work, by the way. Honestly, seriously, like, you know, cooperative group studies, nih look at where we are. We're learning so much from them.
- [08:41]
A
I think Chuck should be a politician, don't you? He's really very, very poised, Michael.
- [08:45]
D
Yeah, I just want to separate the effort to create better prognostic criteria versus those that are treatment selection criteria. So pten, for example, we know can segregate well performing from poorly performing characteristics, but that overlaps with a number of other different biomarkers. And so the real challenge there is sorting out which is really the driving biomarker and which are the others that follow downstream from that. But for something like P10 where you could use it as treatment selection criteria for an actionable alteration that leads to a better outcome clinically, the same thing with PARP or PSMA or whatever, those represent really remarkable opportunities to intervene in a patient's otherwise natural history. Those of course can be tested because you can just if it's druggable, you give the drug or you don't. What Chuck I think is alluding to is just developing and seeing which are the dominant prognostic factors. Not even sure that that's something that we would invest money in, as Chuck was saying, to do prospectively but this is a different effort. This leads to an actual drug, a trial and a patient who may do better as a result of being identified with the marker.
- [10:16]
C
Neeraj, my approach, you said, what is your take on these data? I like to start every patient on ADT plus ARPI and then build up from there. If we can do that for most of our patients, that will be a big win. Even now 30% of our patients are not getting ADT plus ARPI. So all these tests are great studies are fantastic, but I think we need to implement them in our real world patient population.
- [10:42]
A
So just to summarize, we'll move on. Is docetaxel obviously a clearly established role right now, selected by timing and volume of mets, but hopefully better biomarkers moving forward. But we're not quite there to implement them in practice. Okay, good. I see shaking heads. I like that. All right Niraj, you're up.
- [10:59]
C
So this is the amplitude trial data presented by Gert Attard a few months ago and then just published. So this is MHSPC setting. Patients had to have these predefined pre specified HRR mutations. So you can see here BRCA1, BRCA2, BRIP1, CDK12 and so on. And key eligibility criteria were they had to have hormone sensitive disease, hormone knife disease and they were not allowed to have any PARP inhibitor or chemo or any of that prior to a diagnosis. But they were allowed to get chemotherapy in the metastatic hormone sensitive prostate cancer. This is a different trial from what we have just discussed that chemotherapy was allowed despite the fact that 80% of these patients had high volume disease. 90% of these patients had de novo disease. Only 16% of these patients actually received docetaxel chemotherapy. Thus reflecting that chemotherapy use is very low in the real world setting or even in trial setting. Now coming to the randomized portion. Patients were randomized to add ADT plus abiratin versus AGT plus abidatin plus naparib. Primary endpoint was radiographic progression free survival. It was met. There was a statistically significant improvement in BRAA1 and DRAA2 patient population. You can see here the HR is 52.50percent reduction in risk of progression or death in those patients who had BRA1 and BRAA2 mutations. Please note that ATM positive patients were not included in this trial. So BRA1 and BRAA2 mutation positive patients. What? 50% of total patients in this trial. I would also like to bring your attention to the control arm PFS 26 months. We expect 39, 40 months in these patients so that it tells us that these patients have poor prognosis and they need something better. If you look at all HRR mutation patients, it was 0.63 as far as hazard ratio is concerned and there's a 40% reduction in risk of progression or death. If you look at the table on the right side, upper right corner, that shows you the breakdown of RPFs benefit by individual gene types. And my take on this is trial is not powered to look for these individual gene subsets. So I look at them and this is for your information. Next slide. Do we have a slide again?
- [13:30]
A
We do.
- [13:31]
C
We have one more, yeah. So this is a secondary endpoint. Overall survival very important. Secondary endpoint is not mature yet. If you look at the side effects, no new signals from the efficacy perspective. Anemia is common side effect with PARP inhibitors and we know and many other anti cancer drug and we know that anemia happens in first three, four months and timely reduction of dose of these patients who develop grade three for anemia can allow these patients to receive PARP inhibitors for a long time. So timely identification of these side effects. Cardiovascular side effect is unique for niraparib. Hypertension is quite common but this is also common with abiraterone so timely recognition of hypertension and treatment is necessary. So what is my take on the amplitude trial? Abiraterone plus niraparib should be considered as a standard of care for patients with MHSPC with BRCA1 and BRCA2 mutations and an option for patients with MHS PC with HRR mutations. For these patients who are starting this treatment, I monitor them very closely for blood pressure and liver function, test for abiraterone and CBC for PARP inhibitor and ultimately timely symptomatic management is the key to allow these patients to continue treatment for a long time.
- [14:54]
A
Thanks, Neeraj. All right, comments on the data, questions, nuances. It's available tomorrow using it and who are you using it in, Michael?
- [15:03]
D
I think it's a great study. First of all, it's a contemporary control arm of ADT and an arpi. Second, the trial was selected for the patients most likely to benefit and they did the sub analysis to see within those that group of patients who's most likely of the most likely to benefit. And I think that if most people seeing this data had a patient walk in with a BRCA mutation to their clinic, Neeraj was being very magnanimous and saying well it should be considered but who among us would not give that.
- [15:40]
A
Therapy or the BRCA mutant.
- [15:42]
B
Yep, it's the least controversial of all the MHSBCs.
- [15:46]
E
Yes, that's right.
- [15:46]
A
Yeah. Did you want to say something?
- [15:48]
E
Yeah. Curmudgeon. My name is Chris. Number two. Number one, this didn't allow docetaxel as a front loading therapy.
- [15:59]
A
No, it did allow patients could get docetaxel.
- [16:02]
E
They didn't get it.
- [16:03]
A
So I guess that's a question. It's really high risk, but only 16% got it. Is that just because people don't want it or.
- [16:09]
F
I think it's because you had a biomarker. Right. You knew this patient had HR and was gonna go onto a trial where they might get a highly effective therapy. I don't think this reflects how we would treat a non HR or especially non brca. High volume de novo metastatic.
- [16:25]
E
And so the other thing just. I'm just pushing the issues. I'm pushing buttons Saturday morning as I do. So HR mutant. That includes the BRCA patients in it. What is the data without the BRCA patients in that group?
- [16:39]
A
Yeah, we don't know. They didn't present the hr. BRCA or did they? I don't have it on the slide.
- [16:45]
B
No. Hr. Okay.
- [16:46]
A
HR not. And take out the brca.
- [16:49]
E
Why did they not do that?
- [16:51]
C
I. I just want to make a comment on docetaxel. With due respect to fantastic work Chris has done for the field. This patient had this patient population and 90%, 90% of these had de novo disease. 80% of these patients had high volume disease. Docetaxel was allowed for these patients prior to enrollment on the trial and 16% of these patients received docetaxel. These are trial eligible patients. ECOG performance status 01. And it is very consistent with real world data that less than 10% of patients in the US receive docetaxel chemotherapy in the MHSPC setting.
- [17:34]
A
I mean, I think Tanya's point's a good one though. If I'm the doc, I might be like, oh, I got this great targeted therapy. I don't get chemo. I don't. You know, even if they need it by other criteria, I don't know that's the case.
- [17:42]
E
But there's a 50% chance they won't get it.
- [17:46]
A
Fair enough.
- [17:47]
B
But I.
- [17:47]
A
We don't know why. I'm just saying.
- [17:49]
E
I'm just saying the data keeps coming out. Docetaxel. The old dog still works. I'm not a dot Taxel defender. I'm a data defender. And that's what I'm going to say right now. But we talk down docetaxel I don't think.
- [18:05]
A
We're not talking down dotax.
- [18:07]
E
No, no. As patient, we talk about there's chemophobia in the world and we do not, we do not talk it up. We talk it down.
- [18:15]
A
Michael, last word on this. We're have to move on for time unless you want to.
- [18:18]
D
We don't know that docetaxel would have been appropriate in addition to an AAP in this patient population or any other. It's never been shown. So to criticize this trial because it doesn't use docetaxel is silly, I agree.
- [18:31]
E
No, it's not silly. It's the question. I mean it's, it is a question actually. So I actually have data from chartered suggesting the patients who did have a germline graph mutation and we're trying to follow up on this, did actually trouble. Did actually worse and they didn't benefit from docetaxel. There's actually biological reason why they may actually benefit from docetaxel. I'm just saying there is an alternative agent. If you can't get this, that may be benefit and we need to ask the question.
- [19:03]
D
But this trial wasn't sent to answer that question.
- [19:05]
E
No, it's not sent to ask the question. It's set to ask the question about the new drug, the new therapy, the.
- [19:10]
D
Expensive one, the control arm is not a new drug.
- [19:14]
E
No, but I'm just saying.
- [19:15]
A
Comment to Chuck.
- [19:16]
B
I'm going to make, I think what am I, the first do no harm guy for this panel?
- [19:20]
C
Yes.
- [19:20]
A
You're the elder statesman.
- [19:21]
B
Yeah, the elder statesman. Right. And so one of the questions that we should be asking of this trial is does this help us with the ARPI plus PARP question at all? And are there BRCA patients, for example, who are so exquisitely sensitive to PARP inhibition, then Maybe the abiraterone, etc. Is something that we could consider pulling out. So I'm just taking, I'm just taking the. I don't. I didn't mean to.
- [19:45]
A
You don't have a dog in the fight.
- [19:46]
B
But. Yeah, but, but what I'm saying is that it does. Does it suggest to some that there are, there's an opportunity to use PARP inhibitors in a de escalation strategy in hormone sensitive.
- [19:58]
A
De escalation. I love it. So, last comment for me and then we're going to move on in time is I think what we're bumping up against is we have a lot of new third agents we could give. That's what this whole session's about and we can't give them all at one time. Right. So you're going to have to select whatever your criteria are. And I think as we get to the cases, I've made some that are intentionally doing that. All right, Michael, we just got done with the session but maybe like a quick one sentence summary and then some who weren't on that panel can comment.
- [20:23]
D
Sure thing. Quick one sentence summary is we already have approval of the use of lutetium across the spectrum of metastatic CrPC. And so this was the first randomized study to look at lutetium for CSPC. Did I say CrPC before? We have approval on CrPC. This was the first in CSPC. The trial was ADT, the ARPI of physician's choice, plus or minus lutetium. They got six doses every six weeks per convention. The primary endpoint was RPFS and there was a crossover. So OS was a secondary endpoint. RPFS looked like it was positive with a hazard ratio of 0.72 in favor of the lutetium. Triplet os, which is quite immature, revealed a preliminary hazard ratio 0.84. For neither of the arms do we have a median overall survival to report. That's in both cases actually for RPFs as well. So it's. The data are early and from a tox standpoint there were more adverse events in the lutetium containing arm, particularly in relationship to xerostomia and there wasn't a statistically significant difference in quality of life between the two arms.
- [21:48]
A
We just lost 10 minutes on our timer somehow. Comments on the data. Chuck, you weren't in the other session on the panel, so.
- [21:53]
B
Yeah, so I mean, getting back this obviously offers an opportunity for integrating a new therapy into mhspc, which is great. We'll see where, where we go with longer term outcome and approvals and things like that. There's been a lot of debate that I can't, I don't, I can't really add to, on, on the potential toxicity, et cetera, of this approach in early stage disease, earlier stage disease. I would ask the question of whether we're going to see a tox signal from a late, a late effect tox signal from lutetium, which is different from docetaxel. For example, the docetaxel toxicity stops at the end of docetaxel pretty much. And the quality of life data suggested that, you know, you pay a cost in quality of life and you get it back. We don't know that Quite so. Quite so. Quite so. Yet we don't know that yet with lutetium and I wonder will there be problems with patients who are surviving four, five, six years platelets and things like that. So we'll wait and see.
- [22:48]
A
Niraj, any comment?
- [22:49]
C
Yeah, so first of all, congratulations to the alliance team and the PSM Edition team. This took I think seven years to complete this trial and I love to have a see a positive trial in prostate cancer and have an I haven't have this option in the clinic now. Next step is to learn how to do it, how to how many dose we should give and how to manage toxicities long term. But I do want to make a comment from the previous session. We were talking about CCTG PR21 200 patient trial, phase 2 trial comparing docetaxel with lutetium and docetaxel was Superior in a 200 patient trial and then PSMA 4 trial, Lutetium was superior to ARPI. And what is the comparison? What is better, what is worse? And my take on this is very different patient population. If you look at the overall survival of patients in the lutetium therapy arm in the phase 2 trial that was 14 months. If you look at the overall survival of PSMA4 patient in the Lutetium mom, that's 24 months, that's 10 months difference. These are very different patient population. So my personal take is both are great therapy and docetaxel is a viable treatment which we already know.
- [24:04]
A
All right, I'm going to thank you for that comment.
- [24:07]
D
Can I just say one thing about the dositaxel dot just had?
- [24:10]
A
Sure.
- [24:11]
D
The issue that keeps coming up and that Chris aptly raised was is the use of docetaxel which is the implicit control arm that has never been tested in these triplets. But I would just give a plug to the Aspire trial which is now approved by an opening through the cooperative groups which is adt, ARPI plus or minus docetaxel. And there's also a SWAG study that is also a multi group study that is looking at intensification for poor responders with docetaxel, for those who don't completely respond to ADT and an arpi. So I do think that Chris's concerns will actually come into the contemporary era through trials that are up and running. And I'm sure that those trials aren't going to meet whatever level of perfection that some are demanding. But those are the trials that we'll have. And congratulations for the people for doing the right study to address Chris's concerns.
- [25:12]
E
Chris, we're going to move the cooperative.
- [25:13]
A
Groups, we're going to move to AKT.
- [25:15]
B
And tax dollars at work.
- [25:17]
A
Yeah, we're going to move to AKT inhibition. If you just want to give us a summary.
- [25:21]
E
So AKT inhibition, it's a great idea. It's a biologic therapy. We have a target. The problem is we don't know the right target. So here is the top showing eye potential abiraterone plus minus apaticertib in patients with first line castration resistant prostate cancer. RPFS benefit, 0.77 os, nothing disappointing. As part of the from the beginning, my day in the sun faded. Now, sorry, reminiscing. No, that's not about me. But you look down at Capitello, we look there. IHC greater than 90% RPFS benefit, no clear OS benefit. Now, about 6,000 patients were screened to get on the study by IHC. And if you go down to 100% P10 negativity, you get a stronger signal. Now the question is, is there a better biomarker? And the answer is. Well, when we looked at a P10 loss in the eye potential study, yes, there was an OS benefit. But if you look at the whole pathway, AKT mutation, PIK3C mutation, P10 loss, the signal gets stronger. So I think the study was not the best study because it didn't have the best biomarker. Yes, P10 IHC is a lot easier than NGS. Why they didn't push forward with the NGS is unclear to me because then you now look at capevercity with Fulvestran in a very similar disease, breast cancer, ER driven estrogen receptor driven disease. They did use the NGS and look at that whopping overall survival of 0.69.
- [27:17]
A
So let me ask, sort of you and the panel, is there any future for, given everything we're talking about and all the activity, et cetera, is there any future for AKT inhibition in prostate cancer?
- [27:26]
E
Can I just point out the toxicity profile, please? Aberdeen Prednisone and AKT inhibition did result in a lot of hyperglycemic hyperosmolarcoma and some deaths. This is not without its toxicity profile. The death rate from this is greater than the death rate from docetaxel. Oh, sorry, I said that word again.
- [27:50]
A
Anybody else comments? I mean, it seems to me, I think it's a.
- [27:54]
B
Your question, is there a future? Yes, there is. I mean, we have, as it's been said a few times now, there's a duality of issues here. Two variables, the drug and the test. And we know that pten loss is a big driver of morbidity and mortality in prostate cancer. So it is a very appropriate target. And we now have a signal on a drug with a positive study. That's a good thing. This is the beginning of a conversation that started 30 years ago, but now it's the beginning of a clinically validated conversation.
- [28:29]
A
Fair enough.
- [28:29]
F
But I would say, you know, given the negative trial in CrPC and given that we may learn that the same biomarker actually predicts for benefit from some of the other agents in the first line setting, it's a little unclear to me how much of a role there will be. I mean, I hope this a positive trial. Of course I want it to translate into practice. But as we're learning more about this particular biomarker, it may not only apply to this drug.
- [28:56]
E
Now what drug might apply to you, do you infer? Docetaxel.
- [29:03]
D
There's also the hepatocertib and the capivercab. Studies are different populations, so different drugs, different biomarker, different population. To answer your question, is there a future? There is a future, but we have to use the right triad there in selecting where to pursue the pathway.
- [29:23]
E
Agree.
- [29:24]
C
So how much time? 20 seconds?
- [29:26]
E
15.
- [29:27]
A
Okay.
- [29:28]
C
So anytime I see a positive phase three trial, it makes me very happy. I know the years of work which has gone into this. So yes, there is a future. If you look at the cutoff P10 loss by IHC cutoff, 90% was the predefined. But if you look at the 100% cutoff, the magnitude of difference for benefit favoring capiva serdip goes up in the MHSBC setting. So ultimately I hope we have this option available and we can decide in the clinic who is the right candidate for this drug.
- [29:59]
B
That's a really good point. I mean the positive trials, you know, hopefully we'll get a drug out there available for us to use in appropriate settings. And it's our job as thought leaders, as academics, as researchers to optimize the use over time. And I think we, we need to, you know, embrace that a little bit more.
- [30:17]
A
I'm hit this more optimism than I thought. So I'm hearing like not quite there maybe, but, but optimism for the future. Fair enough. All right, Chuck's going to take us home on the do no harm de escalation.
- [30:26]
B
Yeah. So I get to present a case as a patient of mine, 58 year old gentleman who had in 2022 had a Gleason 7 and he underwent Brachytherapy for that. He had a decipher score done back then, which was 0.66. So he then had a rising PSA, which was watched for a while. And then when I met him last fall when I started at MSK, he had had the rising PSAs done. And he had this October of 2024 gallium PSMA PET scan, which you're seeing here. And there were four lesions. At this time his PSA was 14 and four lesions. And what struck me was that there were two extremely bright lesions, T8 and T10 with the SUVs of 42 and 57, and two that were less bright. None of them were symptomatic. This was a patient now with metachronous oligometastatic prostate cancer. So I started him on Rolugalix and Darolutamide and his PSA promptly dropped to zero. And then we completed SBRT to the four metastases in February, PSA has remained zero. You can flip this, move the slide. And so it's for me a very thought provoking case because this is a young guy with a lot of life ahead of him. We now have a lot of clinical trial to support various therapy choices in this patient. And we have some gaps in our knowledge for patients such as this. But he does sort of follow into this the box here, red box, metachronous or recurrent, where the NCCN guidelines recommend doublet therapy, which could be considered in the high volume or triplet for the high volume and doublet therapy for the low volume. It does not quite answer the question of who should get SBRT and who should not and go on to the next slide. And so I bring this case up for a few reasons, of course, that we'll discuss. But one of the things, and I guess I'm the. What am I? The do no harm, do no harm, but I'm also the glass is half full kind of guy here today because many of our patients, most of our patients, and when we look at all of these phase three trials, we'll have deep and durable responses again when we consider PSA as the marker, which may not be the end of the story there, and that patients who have deep and durable PSA responses, that's associated with a favorable long term os. So the box, the columns, the bar graph on the far upper right is from the darolutomide experience and demonstrating that at any point during therapy, about two thirds of patients will experience a PSA of 0 or undetectable. And the bottom graph are basically the outcomes based on who has a low undetectable PSA versus not. And I think all of us are experienced clinicians enough to know that a good response by PSA early on as this patient experienced is a favorable thing. And so now we've been talking about all these trials of adding this drug, adding docetaxel, et cetera. And the implication of all these results is that we're going to continue to treat patients forever with these drugs, or at least I should say until the particular therapy fails. But now go on to the next slide. Here I am with this young, healthy, vigorous patient whose PSA dropped promptly to zero. We've completed the sbrt and I told him from day one that I plan to give him a finite duration of therapy. I couldn't predict the future. Of course, I can't predict the future. But this to me just seemed like a case where if we go at it aggressively and we ablate the treatments that we can see, this is a patient where we can drive his tumor burden to zero. It's about as good a case as we're going to get. So when I bring up the issue where I was assigned the notion of first do no harm, I guess I would say first do a little bit of harm and then back off on your harm or back off on your therapy. And that's the point I'm trying to make is can we be having more and more of these conversations about even curing metastatic prostate cancer or at least driving a situation to having a long term treatment free interval? And of course, I'm not the only one out there making this case.
- [34:43]
A
Excellent, Chuck. Thank you, Tanya.
- [34:44]
F
So I just want to point out that when NCCN makes that recommendation for doublet, it's not based on PET detected metastasis. Right. It's using conventional imaging. And I think we need to figure out, I mean, obviously metastasis is metastasis, but when we are seeing it so early, that really is a different patient than when we're seeing on conventional imaging. Second, in terms of do no harm, I do worry about radiating everything we see on a PET scan when we know there can be false positives. And I think we have the luxury being at academic institutions that we have tumor boards and we look at these with our radiation oncologists and our nuclear medicine physicians, and we make a nuanced judgment about what to radiate. But doing no harm also includes not radiating things that shouldn't be radiated.
- [35:36]
B
So doing more harm also includes giving seven years of ADT to a patient who only might need 18 months. Right.
- [35:42]
F
And so I completely agree with your practice backing off.
- [35:45]
A
What duration, Mr. Doolittle? Harm. What duration of therapy?
- [35:47]
B
Dr. Doolittle.
- [35:48]
A
Dr. Sorry, Dr. Doolittle.
- [35:52]
E
That's.
- [35:52]
A
What duration of hormone therapy would you give? Do you have a set standard or you kind of.
- [35:57]
B
So I, I'm. I have to see him in April and I. I sort of planted the seed at 18 months of treatment.
- [36:02]
A
18 months.
- [36:03]
E
Okay.
- [36:03]
A
Arbitrary but reasonable.
- [36:04]
C
So I'd like to highlight a beautiful paper. David Einstein is here. And then Ravi Haddon was the senior author in JCO on defining PSR recurrence with PSMA PET positive disease conventional scan negative disease. And they have proposed a new terminology. PSMA PET positive BCR and PSMA PET positive negative bcr. And I love that David so wanted to give the shout out. And in this case this is a PSMA PET positive bcr. Not to me. Mhspc. I'm gonna. We can define it mhspc. And I agree with Chuck that this patient requires definitive duration of AGT plus crpi, not indefinite.
- [36:50]
E
Can I weigh in there? I suspect looking those PSMA PET images there was probably sclerotic lesions that would make him conventional positive so. But not always. You're right. Embark study with the overall survival would suggest that this patient is not too dissimilar to the metacritous low volume on conventional imaging with an over survival presto earlier yet with median PSA of 1.0. But I'm going to go and I'm going to say this. Wait for it. Wait for it. Dr. Doolittle. Dr. Do not do little Dr. Do not.
- [37:26]
B
What?
- [37:26]
D
Yeah.
- [37:27]
E
Do no dose attacks.
- [37:30]
D
All right.
- [37:30]
A
I want to get to the case.
- [37:31]
B
He shouldn't get.
- [37:32]
E
He should not get docetaxel.
- [37:34]
A
I. I just put out this poll about will have the biggest clinical impact and the greatest number of patients. Don't criticize the question but that's what I came up with. And it was sort of interesting that docetaxel and lutetium, you know, sort of were clear winners AKT maybe not surprising given the limitations. I don't know Michael, if you had a comment on this but. And obviously PARP's at a disadvantage because it's, you know, either BRCA or even at HRR. Right. So I think that's probably why that didn't score as well. Let's get on to the cases. You all have little whiteboards. So as soon as I finish the case you're going to write down what you would do all the relevant data is in the chart. The image is representative. So if I say there's three bonets and you think there's four in the image, they were just pulled off the web. These are made up cases for purposes. So don't pay attention to the image too much. It's just there. So I have something to show on the right side. 68 year old ECoG1 radiation and short course hormones. A while ago had an appropriate nadir but then lost the follow up. Shows up with a PSA of 126 and multifocal bone mets on a bone scan. No visceral disease on ct. Does not have a PSMA PET at this time, has an ATM mutation and pten status is unknown.
- [38:48]
F
Is he symptomatic?
- [38:49]
A
Patient is mildly symptomatic. That's what the ECoG one is meant to. It's normal.
- [38:55]
C
It's hormone sensitive or CrPC.
- [38:58]
A
Hormone sensitive.
- [38:59]
B
Okay. Yeah. Writing down what we would do, what would you.
- [39:02]
A
What drug or drugs would you give this patient? Just high level. And then I'll ask you to reveal it and give sort of a short rationale. Chuck, I'm going to start with you. Unless you want me to end with you because you seem. Yeah, no, take your time.
- [39:29]
E
I'm done with you.
- [39:30]
C
I'm ready whenever you want.
- [39:31]
B
I'm going to do eight.
- [39:33]
D
Yeah, sure.
- [39:33]
B
Oh yeah. I'm going to do 80. Hi. I'm going to do ADT plus and Arpi and the reason I'm not adding docetaxel here is it's seven. It's five years. It's a metachronous disease. He was lost to follow up. This could suggest a slightly slower biology than somebody who had a normal PSA two years ago and shows up in the ER with bone meds.
- [39:56]
A
Yeah, fair enough.
- [39:56]
C
Niraj, ADT plus arpi. I have nothing else to add to what Chuck said.
- [40:02]
A
Awesome.
- [40:05]
D
I would at least discuss DOSI with him even though it's metachronous.
- [40:11]
A
Because of the volume of disease.
- [40:12]
D
Because of the volume. He's young. He has a PSA126.
- [40:18]
B
I would.
- [40:19]
D
I would consider intensification.
- [40:21]
A
Any reason to do a PSMA pet?
- [40:25]
D
No, actually.
- [40:25]
A
Okay. You wouldn't do it because you want to give him lutetium.
- [40:29]
D
He's right. Now I don't think the data are. Are mature enough in addition for me to add lutetium, so I would not do it right now.
- [40:37]
A
Fair enough.
- [40:38]
B
Chris, Docetaxel.
- [40:47]
E
Metacritus. High volume is a very heterogeneous disease. So I agree 100%. Not all Metagoras, but the point estimate of 0.7 in the looks similar. So if he presented with a bone scan like that, I would be more inclined. If he had five metastases and he presented the way he described, I would not give it, but I would probably lean towards. Yes, but there are patients with protections, high volume who are lean towards. No.
- [41:16]
B
Is the ATM figure in it. Nobody's met.
- [41:20]
A
Tanya, who has the neatest handwriting, by the way, by far.
- [41:24]
F
I would definitely use doublet. I would talk about docetaxel. Makes me a little nervous that he disappeared. I would want to make sure he's going to follow through. But I would feel perfectly comfortable putting him on a clinical trial. I'm being told that we cannot use that option because of course, all of us in this room probably would. But just to say I'm not that dogmatic. I would talk about docetaxel. He's symptomatic, high burden. But I would be open to a novel triplet.
- [41:45]
A
So I should have taken clinical trial off the table.
- [41:48]
C
Just a very quick note. The PSA nadir point is very important here. And he had a very nice PSA nadir with the first time when he got the adt. And that's a very good marker, I.
- [41:59]
A
Think for me for being hormone sensitive. Yeah. Yep, fair enough. Yep, fair enough. All right. 68 year old guy now ecog zero, has the same sort of history of somewhat remote radiation and hormones in appropriate nadir. This PSA now is lower. It's 12.5. Has more oligometastatic disease. Four bone mets on a bone scan, no visceral disease. You see rib two spine and a pelvis. That's what the images are supposed to show. These are all PSMA avid, so I guess not terribly dissimilar from your case. Chuck, maybe a little older, has a check 2 mutation and unknown PTEN status. We should add some music while they were writing next year. Write that down.
- [42:51]
E
And this is de novo, isn't it?
- [42:54]
A
Prior radiation. Yeah. How long did it.
- [42:56]
B
Basically the same case, but the recurrence five years ago. Yep.
- [42:59]
A
The recurrence is more oligometer.
- [43:00]
E
Yeah, that's how I'm reading it properly.
- [43:02]
B
Very similar to my case. Yeah.
- [43:03]
A
Yeah, similar to Chuck's case. I think we know, but do what I did.
- [43:08]
E
Metachronous, maybe low volume.
- [43:11]
A
All right. I'm going to start over at Tanya this time. Go ahead.
- [43:16]
F
I would do what Chuck. I would do what Chuck did for his case and give doublet for a defined Course.
- [43:23]
A
And how long would you give Doublet?
- [43:26]
F
I'd say a year.
- [43:27]
A
Just a year. Okay, Chris.
- [43:30]
E
Doublet sbrt. Two years.
- [43:32]
A
You'd give two years?
- [43:33]
D
Okay, Michael, Doublet sbrt. I'm not gonna commit to years.
- [43:40]
A
How do you decide?
- [43:42]
D
That's the problem. Okay, That's.
- [43:45]
A
I have two years completely arbitrarily, just so that I have a number and some patients don't make it, but I don't.
- [43:50]
B
I kind of extrapolate from the 36 month versus 18 month ADT study and radiation treated patients from years ago.
- [43:56]
A
Okay.
- [43:57]
B
Suggesting that 18 months is much better. Quality of life? Not as roughly equivalent. It's an extra.
- [44:06]
C
So this is PSMA PET positive bcr. So I'll give ADT plus ARPI plus SBRT and definitive duration of therapy. About two years.
- [44:17]
A
About two years. Okay.
- [44:19]
B
Chuck, same as everybody else. I drew SBRT discussion because apparently that's what we all talk about in the last. The last case, which we can have a dead discussion. But I don't know where the pelvic lymph nodes are relative to the prior radiation. So that's why it's not a guarantee.
- [44:34]
D
I might add. Just a relation to Tanya's point that she made before, that if this patient had a lesion that was just PSMA positive, I would absolutely irradiate it. In your example, it was four PSMA positive. Four positive. Unconventional imaging. So everything matched up. But we know from Oriole and from Empire one that if you use PSMA PET in the guidance of your treatment, the patient has a better outcome.
- [45:03]
F
I was just alluding to ribs, which we know can be false positives. Right. And you've probably seen some scans where there's like an indeterminate. Right. I agree. You don't have to have a CT correlate or MRI correlate, but you want to be confident that what you're treating is disease.
- [45:19]
A
We have a nuclear medicine doc in our tumor boards, which is super helpful because I didn't realize all the nuances of not having a correlate. And I assume positive was positive, but clearly it's not the case. All right, we're making great Progress. Younger guy, 58 year old, EcoG1, no prior treatment, comes in with the PSA of 412. A lot of bone mets on scan. Also has liver mets on ct. Assume it's all biopsy. Proven multiple PSMA avid lesions, has P53 and RB and P10 altered by NGS. Sorry we don't have things to wipe.
- [45:53]
D
Off the back of the pen. Is an eraser.
- [45:57]
B
Oh, I dropped my pen.
- [46:00]
A
It's a low budget operation.
- [46:04]
D
I'm always mentoring.
- [46:08]
A
All right, who wants to start? Anybody? Neeraj, you ready?
- [46:12]
C
Yeah. This is rather straightforward. P53 RB1 loss. This patient is destined to have, at least not destined, but very likely to have neuroendocrine differentiation down the line. So this is high volume metastatic prostate cancer de novo, young man. I will go with ADT plus ARPI plus docetaxel triplet.
- [46:33]
B
Okay.
- [46:33]
A
Anybody different?
- [46:35]
B
Oh, Chuck, I'm doing a quadruplet here and this is something that.
- [46:40]
A
I thought you were Dr. Do Little.
- [46:42]
B
Huh? Yeah, no, this is.
- [46:45]
E
This is Dr. Dumour.
- [46:46]
B
This is Dr. Dumour and Dr. Doolittle, but. But he's Jimmy as well. Again, don't ask me for phase three data, but you know, I've treated a number of these patients. These patients I had. I had one who just died within a year of diagnosis with this exact profile. And you know, we. We've attempted to integrate carboplatin with cabazitaxel. We did a hormone sensitive study in that. Love to do a phase three, but we can't get that going. Um, so I think this is one where, you know, he's going to be a neuroendocrine patient in about nine months. Yeah, and we want to try to.
- [47:17]
C
And I was sticking to the approved therapies right now, but I agree with you.
- [47:21]
A
Okay, so intense therapy, chemo based, maybe doublet chemo. I think we have maybe two more. One or two more. 68 year old man, ecog zero. This is. This is also somebody who had prior radiation. PSA is 74. Multifocal bone disease, equivocal liver lesions on CT, you see the PSMA PET there? Multiple PSMA, avid bone and lymph node lesions, high SUV. This patient has a BRCA2 mutation and is PTEN deleted. So.
- [47:56]
D
Are we projecting to 2026 when we might have some approval?
- [48:00]
A
So if you have all the drugs, there's no real reimbursement limitations. This is just. Yeah, I don't want that to limit your answer.
- [48:11]
C
It's pretty straightforward actually.
- [48:14]
D
Well, I think that this gets at. This is a good question. I like this because you have to decide between Capitello and amplitude.
- [48:26]
A
And your decision is.
- [48:28]
C
Oh, my decision is ADT plus abiraterone plus niraparib. Because of brca.
- [48:34]
A
The BRCA drives. Does the BRCA drives everyone to use parp. Tanya can see your answers.
- [48:40]
F
Chris's point though is interesting about docetaxel since that was allowed in amplitude.
- [48:46]
B
What did he say?
- [48:47]
A
Okay, so maybe give docetaxel first.
- [48:50]
E
That. To give you time to fight the insurance companies.
- [48:52]
B
Oh, yeah.
- [48:55]
A
Right.
- [48:55]
E
Okay, that's. That's a bad scan. You can't wait.
- [49:00]
A
So you start with chemo, and then when chemo's done, give parp.
- [49:04]
E
Yeah.
- [49:05]
A
Is that right?
- [49:06]
B
But I. Yes, that's. I like that.
- [49:09]
C
That's very appropriate. The only concern, and as I was a part of the amplitude trial, one reason we did not see very high use of docetaxel chemotherapy was the concern that if you give chemo, well, myelosuppression may make them less eligible for PARP inhibitor down the line. But again, there are no data in this regard. And I personally think BRCA2 is such a dominant player in this case that if I can get PARP inhibitors, that.
- [49:36]
A
Trumps everything when you have brca.
- [49:37]
B
Totally agree. Yeah, I agree with you. And I guess the question is, how often do we actually see BRCA2 plus PTEN deletion?
- [49:43]
E
It's rare. It's rare.
- [49:44]
A
It's all made up. Chuck, I know what you're trying to.
- [49:47]
B
Do, but I think that's two drivers.
- [49:50]
A
I was trying to put you.
- [49:50]
B
Yeah, yeah. Okay.
- [49:52]
E
Almost mutually exclusive.
- [49:54]
A
We are out of time. I'd like to thank the panel for your excellent participation. Thank you.