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Jeremie Calais: All right. My turn. So I was tasked to give an overview of all the clinical trials using PSMA radiopharmaceutical therapy in 2025. So I look at clinicaltrials.gov, the trial in progress presented at ASCO last year, ESMO, ASCO GU earlier this year. I used a lot of UroToday. They do a really great job extracting slides and data from all the meetings. So Zach, I know you're somewhere looking at the slides. So thank you for all the great work you're doing. I use that a lot.

And then my views, trials I know here and there. When you look at clinicaltrials.gov as of yesterday, if you put “PSMA therapy,” you have 570 studies that pop up. So I tried to filter it out a little bit, phase 2, phase 3. At the end, I chose and selected 70 trials that I found of interest. So how am I going to present 70 trials in eight minutes or less? I found a way. I think I will merge them by groups and thematics, and I will provide some lists. By the way, the slides will not be available, but the recording of the presentation will be available for everybody for four weeks. So we will get access to all the slides and the content.

So this is another way to display the prostate cancer journey, all the trials that were conducted. This is not exhaustive. Many are missing, of course. So let’s go by this stage. As presented earlier, the main phase 3 randomized registration trials for the prechemotherapy setting with PSMAfore this morning, SPLASH, and ECLIPSE represented. So this is really the next big thing, really coming now. I will not expand.

Mike just presented the TheraP trial a few years ago, but I think we need more data comparing lutetium PSMA to chemotherapy. I can see in the community still the reluctance from some med oncs due to the lack of a demonstrated superiority in terms of OS versus chemo. And I think these trials are needed. There was TheraP. There is this Canadian trial. The PIs are the main Canadian investigators, Kim Chi, Fred Saad, François Bernard. It's funded by Movember. They randomized 200 patients, chemo versus lutetium PSMA in the prechemotherapy setting, so I think this one would be very interesting.

In the hormone-sensitive space, as Mike just presented, there is PSMAddition. The recruitment was completed in 2023. Some early completion of data is expected by February 2026. And then there is P6, which is an interesting trial. French, pretty big, phase 3, randomized 500 patients, randomizing patients—let me see if I have a pointer—randomizing patients that did not respond well initially to ADT. They were started on ADT, they still have a detectable PSA. These would be the patients investigated here.

And then there is the STAMPEDE-2 trial, a massive trial, 8,000 patients total. They will look at oligometastatic patients. They will get oligometastatic-directed therapy. Then the polymetastatic patients, they will get randomized into lutetium PSMA versus standard of care. That includes, as always in that stage, triplet/doublet therapy depending on the local setting. So it can include prostate radiotherapy, docetaxel. And this was presented.

So this is a major trial in the lutetium-PSMA arm group. They expect to have close to 2,000 patients across the world. This is coordinated in England from the STAMPEDE-2 platform, and supported by Novartis. So this will really create a lot of data. Now, in the oligometastatic hormone-sensitive setting just presented by Amar, this is the list of the trials I was able to list. So there is PSMA-DC, another case. I think this one is the main next one, really. I think this may be impactful. There is a little bit of J591. And I think soon, one day, we'll have probably actinium-PSMA trials. So I put the list here. Feel free to use it.

And now let’s move to an even earlier disease stage. I was surprised to see all the trials investigating lutetium PSMA or other PSMA-targeting agents in the neoadjuvant or adjuvant setting. So high-risk, localized prostate cancer scheduled for surgery or for radiation therapy. You can see here many trials now trying to investigate the role of lutetium PSMA or even actinium PSMA, either alone or in combination in a randomized fashion. You can see here a major trial from Novartis again looking at more than 200 patients: actinium PSMA versus lutetium PSMA. So this will be very interesting to see.

The first trial was LuTectomy, with Dr. Hoffman. I saw, for example, an interesting thing now coming from Germany where they do an intra-arterial lutetium PSMA before surgery. So interesting data to read out in the coming years. I think the long-term safety is also of concern. We have a few papers suggesting that maybe cumulative dose—maybe we don’t know everything about the late effect of lutetium PSMA. mCRPC patients, they live two years, three years, four years. We don’t have the data when we can monitor patients for 10 years.

So Novartis is now doing a phase 4 long-term follow-up study. They will monitor patients every six months for 10 years—every patient that has been exposed to lutetium PSMA. They hope to have several hundred patients in total. So for myelodysplasia, kidney toxicity, I think this would be very important. Now, what I find interesting, as a nuclear medicine physician that really believes in individualized-based therapy with imaging, is that you start to have nice phase 2/3 trials looking at dosing modulation.

I listed some of them here. With the red arrow, you see the ones that are relying on imaging to tailor the number of doses or the dosing schedule, either based on SPECT or PET. At UCLA, we have the FLEX-MRT trial. There is this trial conducted at Mayo Clinic where they will see if you need additional late cycles even if you had great response. You have extended use, rechallenge. In Canada, they're doing one where they will base it on the cumulative renal dosimetry. They will calculate the kidney dose at the first cycle. Based on that, they will go to a certain threshold and decide the number of cycles they can administer.

The LPS-Boost is an investigator-initiated trial that I do with my colleague, Dr. Iravani, at Seattle, and Dr. Hope, at UCSF. Here, we will select whole-body SUV mean less than 10, so basically low-expressing PSMA patients, but whole-body tumor segmentation. So these guys that will have not a very good likelihood of response to lutetium PSMA therapy, we will double the dose. They will get two doses upfront, one week apart, six weeks. Then again, two doses upfront, one week apart. So it's like a boost for these patients that may need additional dose.

So I think these are really interesting. I really look forward to seeing even more of these trials. This will really help us to improve and refine the use of the six cycles, 7.4 gigabecquerels at six-week time intervals. I think we can do better than that. Now, let’s move to actinium. The alpha is clearly the main next thing. I list here all the new actinium PSMA trials that are ongoing. Some are using 617, PSMA-I&T, R2, and many companies are coming with new compounds. J591, the antibody, also. So many trials are ongoing now. You can see that they have even a 400-patient study coming with a control arm, so that will be interesting.

There are also novel radionuclides that are being tested, so copper-67, another beta-emitting agent, terbium-161, or lead-212. These are the trials that may provide interesting data and good alternatives to lutetium and actinium. There are not yet astatine trials, but I think they will come one day. Let’s talk about J591.

We have Scott Tagawa, who will give a presentation dedicated to radioantibody targeting PSMA. But these are all the trials here, initially done at Weill Cornell in New York, now conducted by Telix and Convergent for the actinium part. So that will be interesting as well. We talk about pre-chemo, post-chemo, but now there is a new category: there is post-lutetium PSMA patients. So what can we offer to these patients that are failing?

And you can see now several trials including post-lutetium PSMA patient categories. Many are, in fact, using alpha therapy to try to salvage them. We also have extended use of lutetium PSMA therapy. Interestingly, I listed this trial that is done in Utah. It's not a radiopharmaceutical therapy trial, but the inclusion criteria is post-lutetium PSMA therapy patients, which I find very interesting.

And now the combination. So tomorrow we will have a keynote lecture by Dr. Hoffman on—or maybe it’s today, I don’t remember—but Dr. Hoffman will talk about all the combination therapy trials we can do, trying to leverage the DNA damage induced by PSMA-targeted radioligand therapy and even further enhance the effect. So you have the trial combining with AR-targeted agents listed here. Some were already published, but some are upcoming, some are with alpha. So that will be interesting as well.

Combination with chemotherapy, we talked about upfront. But there is now the DORA trial that’s in the radium space. It’s not in lutetium PSMA, but you have now several trials looking at the combination of both. Combination with immune checkpoint inhibitors—here, I think the difficulty is to find the right schedule, the right time when to inject, but you have different trials looking at that. Now we even start to have trials with a control group, so that will be very interesting to see. One is even in the neoadjuvant setting as well.

Combination with DNA damage repair inhibitors, PARP inhibitors, CDK4/6 and CDK6 inhibitors. We’re waiting for the LuPARP results. I hope this will come soon. Combination of alpha and beta—I was not able to find so many registered trials, alpha and beta trials. These are, let’s say, phase 1-2, small cohorts. I know that in many countries where they are less bound to regulation, they are already doing some cocktail therapy combining lutetium PSMA and actinium, trying to decrease a little bit the side effect and toxicity profile of actinium.

And I think many of the companies that own the two compounds, actinium and lutetium targeted with PSMA, I think they should do cocktail therapy trials now. That would be the next thing to do. And I will end on this one, because I found it interesting. It’s a phase 1 multicenter trial—small one, 36 patients, multicenter though. But again, I like this biomarker imaging approach.

Every patient with a metastatic neuroendocrine prostate cancer with these features here that are, of course, a main limitation for PSMA-targeted approaches, they will get three scans: PSMA-11, DOTATATE, NeoB. And based on blinded reader assessment, they will elect which therapy the patient should receive and can get up to six cycles. So I find that approach interesting, and I think it just shows us that the future is, I would say, bright for all these new approaches. Thank you very much for your attention.