Phillip J Koo: Hello, we're here today at Tulane Cancer Center, less than 24 hours after the FDA approval of Pluvicto, which is the lutetium-177-PSMA-617 therapeutic agent in prostate cancer.

We have none other than Dr. Oliver Sartor to help us really figure out where we go next from here. And I know there are a lot of trials that are currently underway, but wanted to get your thoughts on what will happen next. And then what is further down in the future?

Oliver Sartor: You know, so one of the first things I want to say is that with the current FDA approval, it's going to require that the patient's be metastatic castrate-resistant, PSMA PET-positive. Have had prior treatment with a taxane chemotherapy and a novel hormone, such as abiraterone, enzalutamide, apalutamide.

And as we begin to look at that sort of complexity, I think the next step, and we're already seeing the trials and they are accruing quite well now, in the space of the non- chemotherapy pretreated. So, you really need to have chemotherapy in order to benefit from this agent, I think not, but nevertheless, the way the VISION trial was constructed, that was a prerequisite.

Now you're stripping away the chemotherapy requirement and, but you are retaining the novel hormone requirement. And they're actually three different trials that are looking at this, this one with PSMA-617-lutetium-177-Pluvicto. And that trial's called PSMA-4. And that PSMA-4 trial's from metastatic castrate-resistant without prior taxane, but with a novel hormone, and then you have to have progressive disease and that trial's are going quite well.

Then there perhaps two surprises. And this is something a lot of people may not be aware of. There's a company called POINT Biopharma and another company called [inaudible 00:01:48] that are looking at another compound, not PSMA-617, but PSMA-I&T, which is a separate PSMA binder. And combining that with lutetium-177 and essentially doing trials in the space is very similar to PSMA-4 So, those trials are already moving forward. They're called the SPLASH trial and the ECLIPSE trial. And then if we take for a moment, this whole concept of metastatic castrate-resistant prostate cancer and say, "Well, wait a minute." Why wait until you fail the hormonal therapies? What about if you just use it right up front?

So there's another trial called the PSMAddition also accruing right now. And this is with PSMA-617-lutetium, Pluvicto. And you're taking this combination with novel hormones and ADT plus, or minus the radio isotope and looking at our PFS and of course OS eventually as well.

And I'll say that trial is growing. So you can see, even though we're starting late with the VISION trial, moving it up with the PSMA-4 of the trials, and then even up further into the hormone sensitive space for those on the PSMAddition trial. So that's the sort of current landscape. And then once we get beyond that, there are of course a whole wide variety of novel concepts that are coming forth, but right now that's sort of the landscape.

Phillip J Koo: Great. So we're seeing it move forward. Everything you've mentioned though, this far has been with the beta emitter, lutetium-177, what's happening outside of the beta emitters. That's exciting for you?

Oliver Sartor: Yeah. So, I'm very excited about some of the alpha emitters and their current trials in place now with actinium 225, and actinium 225 is a alpha emitter that actually gives off a whole string of alpha particles. Alpha particles, very different to the beta particles that come from the lutetium.

The beta particle is actually about the... say it's basically an electron and it comes flying out at the speed of light and that's a pretty destructive element, but it typically only causes single strand breaks. The alpha particle is two protons, two neutrons. So it's like a heavy particle and it's over 7,000 times heavier than the electron. It doesn't quite move the speed of light, but it causes a lot more double strand breaks.

So you end up with a lot more cell kill. It's interesting. The, betas like from lutetium are going to be coming out about 0.3 millimeters. The alphas are coming out in microns typically only about 80 microns or so. So a very small area of radiation, but very heavy particle with double strand breaks, highly lethal. And anyway, I'm very interested in the alpha particles, which include actinium. They're also thorium-227 that is being looked at that's also lead-212 that's being looked at. So a whole series of alpha particles are now in development.

Phillip J Koo: Very exciting. Whenever we talk about radiation, I think it's always exciting to think about combination type therapies. Can you talk about some of the combination trials that might impact [inaudible 00:04:55] care?

Oliver Sartor: Yeah. So there are two big concepts as in the lead and then a whole variety of other concepts that are moving behind. First of all, let me say that the hormonal therapies being used in combination with isotopes is what was done in the VISION trial. And there we use standard of care. Many of the patients are being treated in combination with [inaudible 00:05:19].

So, hormonal agents are sort of one thing, but I think there's a lot of excitement about DNA repair inhibitors. And there's a whole series of trials based around DNA repair inhibitors, things like the PARP inhibitors. And if you take an agent that damages the DNA, like lutetium, you got that little beta particle coming out, DNA damage, and then you inhibit the damage with something like a PARP inhibitors.

Well, that makes sense. You can get one plus one on and maybe equal three. Maybe this synergy between the two and then also there's some data that would imply that immunotherapy might be enhanced. And so if you're killing these cells with some radiation, you might be releasing some tumor antigens and be able to enhance the immunogenicity of the tumor. And then using that say in combination with a checkpoint inhibitor, and there are trials that have already been shown at [ESCO 00:06:07] and ESMO that might think that, "Hey, maybe this combination can be exciting. We need more exploration." But I'll simply say that immunotherapy is DNA repair inhibitors and then hormonal therapy is for all things that are being explored right now.

Phillip J Koo: Very exciting time. I think the fun starts now, now that we have that label. So thank you so much.

Oliver Sartor: Absolutely. And the label's really essential for getting it to patients. And of course we have so much more work to do. This is just step one.

Phillip J Koo: Absolutely. Thank you.