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Oliver Sartor: Thank you to the organizers for the opportunity to be here. And I had a little discussion with Tom about this topic, about the optimal time for PSMA radioligand therapy, and decided after a little bit of thought that maybe I would play the role of the provocateur rather than just simply recite the data that you all know. And so what I'll simply say is, these are my views and probably no one else's, but that's okay.

So, what is the optimal time for any therapy? And I think there are a couple of criteria you're going to say when it's proven effective by criteria that you're confident in. That's probably things like overall survival and quality of life and other parameters. How do you feel? How do you function? How do you survive? And these are the things we have confidence in.

Another way to look at it is when it's proven superior to all the known alternatives. Well, it turns out that we don't really achieve that goal because all the alternatives are rarely used in the control arm. We can look at VISION as a good example of that, and we can look at PSMAfore, SPLASH, or ECLIPSE as a good example of that. So not everything is going to be compared. So we're going to be left almost entirely in the field to talk about, well, what if we'd done this or what if we'd done that?

Now, the way that I kind of think about it in the clinic is a little bit differently. I think about when that particular therapy is preferred over the known and available alternatives. And that's how we assess things in the clinic. It's not against everything that's on the planet because sometimes we don't have access. It's surely we're just trying to make a practical decision for our patient. And that's the way I think when I go to the clinic. And I think that's the way I should think.

Now, we have these proven effectives and we have the overall survival, the rPFS, the ORs, the adverse event profiles, and the things that I think we have a lot of confidence in. I mean, I know that therapy was a phase two trial, but I have confidence in those findings. We could quibble that phase two versus phase three VISION, of course, have confidence in. For PSMAfore and VISION, I have a lot of confidence in the rPFS, overall response rate, objective. This would be using resist criteria, lots of confidence there. And these adverse event profiles, I have a lot of confidence in. But then we have these control arms that are sort of controversial, but that just is restating what everybody already knows.

Now, when is one therapy preferred over another is I think a very interesting question. And I just sort of listed a little bit at the top. Castration, okay, that's everybody's favorite therapy. We have loss of libido, erectile dysfunction, fatigue, cognitive issues, depression, emotional lability, muscle loss, bone loss, lassitude, hot flashes, glucose intolerance, etc. If I happen to ask a man would they like to be castrated, the answer is likely to be no. We've learned how to phrase this in all these very polite terms. We talk about ADT, we talk about hormonal therapy, it's castration. Men don't like it.

Chemotherapy, excuse me. Look, I've been involved with chemotherapy for many years. That was actually one of the co-leads in the Cabazitaxel trial. But fatigue, loss of appetite, nausea, vomiting, diarrhea, hair loss, mouth sores, skin and nail problems, trouble remembering things, chemo brain, nerve damage, increased risk of infection, etc, etc. So these alternatives, which are kind of the big ones, whether it be castration or chemotherapy, is the alternative that we face when we go in the clinic. And so I'm going to say that we ought to be giving radioligand therapy before castration and before chemotherapy, so people don't have to deal with these side effects.

Now, do we have any data? Well, not exactly data that should be convincing. And we have all these varieties of therapies, this complex treatment landscape, which Matt helped review in the beginning. And one of the things that's absolutely true is that these landscapes are dominated by castration and chemotherapy. So, what do we do today in the clinic? We do things that men really don't want to have done.

So, what about castrate-sensitive disease? It turns out that we do have a trial with castration that's going to be looking at PSMA lutetium, and this is the PSMAddition trial, phase three sponsored by Novartis, already completed accrual, 1100 plus patients, a big deal. And the only problem is that's with castration, so it doesn't get us where we want to be.

Now, Mike Sathekge from the University of Pretoria in South Africa, one of my favorite guys, by the way, he's just an absolutely fabulous guy. And he put out this little publication with no hormonal therapy looking at actinium, this PSMA-617 actinium and that's the waterfall plot. Now, we don't really know about the durability. I think there are some issues that need to be followed up. And I'm not trying to push the monotherapy here, but I'm simply going to say that you can get pretty good activity, at least with an alpha. There is some beta data and it was presented at EANM, I think it was four years ago by Richard Baum, but I haven't seen a follow-up. And I texted Richard beforehand. He said, no, he hasn't published any follow-up. So I don't have the follow-up on that data, but it looked pretty good when giving lutetium. It's dominated by lymph node positive disease and relatively non-advanced disease.

Now, I'm not going to cover the LuTectomy trial, but I just want to bring it to your attention because I'm trying to think about giving lutetium beforehand. And Louise is here, and I think Louise, didn't you present this to the EANM? No?

Louise Emmett: [Inaudible].

Oliver Sartor: I'm sorry.

Louise Emmett: [Inaudible].

Oliver Sartor: Okay. But it's out there now published and what you see, the PSA declines are pretty impressive. But remember, the PSA declines don't really get us to where we want to be. There's histologic evidence of effect in 80% of patients and one patient had minimal residual disease in the final pathology, but no patients got a complete pathologic response.

One of the things, and I don't want to be too cynical, but the earlier you come in the treatment paradigm, the FDA approvals become more and more difficult because of the duration of the trials. And currently, you're looking at things like MFS in this particular space, and I'll just simply say, get ready for $400 million, 9-year follow-up type of stuff. And that doesn't make it easy.

Now, what about treating very early metastatic disease? Say the PSMA PET positive conventional imaging negative. There are trials out there, the one that I'm going to highlight is the phase three that you may not know about and it's probably going to open this quarter. This is called PSMA-DC. And so, PSMA-DC looks at all metastatic disease, but PSMA PET are only conventional imaging negative. And it looks at patients all of whom are considered to be amenable to SBRT to all the lesions. Now we're beginning to cheat a little bit by squeezing down on the PSA doubling time because some of these patients have really good prognosis and if they're too good of a prognosis, you're never going to reach the endpoint.

All of these patients have prior treatment with radical prostatectomy radiation, a non-castrate testosterone at baseline, they could have had some prior adjuvant ADT but it had to be more than 12 months ago when they had to have fully recovered their testosterone, randomization between SBRT in both arms and SPRT plus lutetium with an MFS endpoint, that is an FDA-approvable endpoint. This can move the lutetium into the space of castrate-sensitive disease without using hormones if it turns out to be positive.

Now, for those who may have a debate, whereas Tom right there in the front row, he might want to debate, because one of the things we know about beta is that there's a crossfire effect, and that's great. And crossfire works best when you've got something to crossfire within. You have a tumor big enough to get some crossfire effect. But when you start getting into these really small tumors, a lot of the crossfires off into space, so you don't really hit the tumor. And betas once you shrink down to a particularly small level, are not thought to be particularly effective.

So Louis and I have gone back and forth on this a bit and she sent me a beautiful reference and I've lost it, so there's probably a better reference out there but I found this one, which I did like. And the question is, they were beginning to calculate cure probabilities... By the way, this was 1995 I think when this was put together. And I come down to lutetium and I underlined that and what is the optimal diameter to try to cure patients? And they put two millimeters. Okay, two millimeters is pretty small. You don't necessarily going to see that on a PET.

So I surveyed a few of the people I respect coming into the meeting here. I said, okay, well how big a lesion can you see on a PSMA PET? Of course, it depends on how hot it is because some of these things have a lot of PSMA PET uptake. But most people don't really go much below two millimeters. Most people are in the three to four-millimeter type range. It also depends, by the way, on the location because certain locations are easier than others depending on the background effect. But nevertheless, if you begin to back calculate this down, two millimeters can probably go to one and you can get a pretty good effect and maybe even 0.5, but probably below 0.5 millimeters you're not going to have much of an effect.

But the bottom line is I think you can treat something you cannot see. That's a controversial statement. And somebody like Tom may give me a tough time, but that's okay. We're here to give each other tough times. That's what we enjoy. So the other thing is I don't want to necessarily say that lutetium is the end-all and be-all because something like terbium, and we do have some data with terbium in experimental settings where they go into smaller tumors and terbium looks a bit better.

I'm not going to go into the beta emissions of terbium, but they're scrunched down. They're a bunch of low energy betas and it looks like... Plus [Inaudible 00:11:40] are really controversial. Some people believe they're important. I'm still waiting to find out, but some people do believe. But the bottom line is terbium is probably better than lutetium for these small lesions. But why mess around with a beta when you can go to an alpha?

So one of the things I know about alphas is they don't go very far, they have a huge linear energy transfer, and they kill things very readily. And if you want to treat small tumors, I think you want to go with an alpha, not a beta. And so now we have things like lead-212, actinium as we begin to maybe think about salivary sparing, a little bit more safety data. We got to generate data, don't get me wrong. But nevertheless, I think an alpha in this space could be really cool.

So what's the optimal time for PSMA radioligand therapy? Notice I didn't put an isotope. I just said radioligand therapy. I think when you can provide clinically meaningful improvement as compared to standard of care, well that's kind of the obvious statement. But you have to be able to get a regulatory endpoint. I'm going to be slightly dogmatic for a moment, okay? If you don't have an approval, you don't have a gain. You can sit around in a conference and you can talk about how great you are, but you cannot go to the patient and treat them globally without regulatory approval. So if you're designing trials for fun and games, go ahead and do it. But let's change the practice of medicine and really change the regulatory environment so we get to the point where we need to be for the patients.

Can we provide a reasonable alternative to castration and chemotherapy? Our patients abhor those alternatives. Well, I'm saying it's time we need to do better. But we got to do the trials, we have to do them properly, we have to do them in the framework of an FDA approval, and that's going to take some hard work. So let's go to work. That'll be it. Thank you.