Phillip Koo: Pleasure to be here. Thanks Neeraj.
Neeraj Agarwal: So lutetium therapy. It would be a mouthful if I keep repeating lutetium-177 PSMA-617. So I will just say lutetium moving forward. We have seen lutetium therapy being approved in post-chemo CRPC setting, then pre-chemotherapy CRPC setting. And now hopefully we'll have an approval in metastatic hormone-sensitive prostate cancer setting. So whole spectrum of metastatic prostate cancer for the whole spectrum, we have lutetium available or soon to be available.
My question to you, Phil, is regarding the treatment, could you tell us more about how you view lutetium therapy as a agent, mechanistically speaking, for many of our audience who may not be familiar with lutetium, how does it work? What is the mechanism of action and approval status right now before we go into the further different types of radioligand therapy?
Phillip Koo: It's real interesting to think about the story of Pluvicto. It was first approved by the FDA in 2022. And as you had mentioned, it was approved in the CRPC setting after chemotherapy. And to think where we've come over the past few years, and I think in '25 it was approved in the pre-chemo setting. And as you mentioned, hopefully it'll be approved in the hormone-sensitive setting as well. I think it's such an amazing advancement, but to me, it's just the beginning and there's so much work that needs to be done and will be done moving forward.
It's wonderful to think about, you talked about lutetium, it's just easier to call it lutetium-177 and that's just one part of the puzzle. That's the isotope. And then you talk about the chelator and then you also have the targeting agent that targets PSMA.
And what we're learning is it's really a combination of all three of those pieces that creates potentially that secret sauce that leads to efficacy in patients. So even though we talk about lutetium pretty loosely, eventually we might have lutetium with other targeting moieties. We might have PSMA I&T or other targets. And the interplay between all those different factors is really complex and leads to differences in distribution and in the end, how patients react to this. So I think we're learning a lot more. There's a lot more that we will continue to learn.
But in the end, I think we need to mature in our way that we think about radiopharmaceuticals where we no longer just talk about the isotope. We probably just need to talk about maybe actually in some ways more about the targeting moiety or maybe just the whole piece together. It reminds me of all the different ARPIs that are out there and we know they're the same but they're different and the differences are significant and some patients will do better with one versus another. And I think that's part of the maturation process that we will continue to go down as the field evolves.
Neeraj Agarwal: Very important point. So we cannot just say this is the class of the drug because as you said, and only a nuclear medicine physician can say this so nicely, so clearly that it's not only the radiation particle, which is important, it is how it is linked to the carrier and how carrier is targeting, taking it, carrying it to the prostate cancer cells. And all of them are important to make them effective.
Phillip Koo: Absolutely. And you're learning that even though we think the payload, the isotope, we just think beta versus alpha, but the actual types of betas or alphas and the way it actually interacts with the targeting agent, that all is significant too and it's unique. Just because one thing works good with another doesn't mean you could just replace the isotope and it's going to be better or whatnot. It's a lot more complex and we're learning more about that at every meeting.
Neeraj Agarwal: So moving forward, I should be using the word lutetium-177 PSMA-617 because we cannot just say VEGF-TKI in kidney cancer or chemotherapy for any cancer. It has to be the type and what type or mechanism of action because depending upon how it is overall formulated, the mechanism of action can differ.
Phillip Koo: Yeah, absolutely. And that's where I think yes, it is a mouthful and we do have to find better ways and that's why I think a lot of times we just defer to the trade name.
Neeraj Agarwal: Yeah. And lutetium-177 is being combined with antibodies, even other types of therapies. So it's good to know. Now, moving beyond beta particles, what is going on in terms of other particles being used in radioligand therapies? We keep hearing about alpha and then some other particles. So for our audience today, could you elaborate on what other particles we should be looking at in the near future?
Phillip Koo: I will say the biggest excitement is around alpha particles. And I think most of us in the prostate cancer community are familiar with alpha particles because we've had radium-223 that's been used for metastatic prostate cancer. Alpha particles are bigger and heavier. So they deliver a much more powerful punch, a greater degree of energy to the targets. They also travel shorter distances. So that's a good thing and a bad thing. I think if you target it really, really well and you deliver higher energy, you're going to get greater cell damage that leads to death that should lead to a better response.
But there's also potential adverse events that we need to think about. So if it is targeting perhaps healthy cells like salivary glands or other healthy tissues and delivers that high energy, it could lead to higher toxicity as well. So it's really about finding a target that is as specific as possible and then finding a way to deliver as much energy as possible. And that's why there's so much excitement around alpha particles. Whatever it might be out there, lead-212, I think it's really, really exciting to see these different combinations being investigated. I'm hopeful and optimistic that maybe the next one that might see commercial approval will be an actinium-based product with different carriers that leads to perhaps better responses.
And I think that'll be interesting. Maybe it'll be after betas, at some point maybe it'll replace betas, but these are all questions that will be investigated and hopefully answered in the near future.
Neeraj Agarwal: And if they are configured properly, if they're formulated properly in a very targeted fashion, they may complement beta therapy, maybe a combination of beta and alpha for optimizing cell kill while keeping toxicities down. What do you think?
Phillip Koo: You're absolutely right. I think nothing is off the table. The fact that the mechanisms of action are different, the targets could be different. So this idea of combination therapies, I think about one trial using lutetium plus radium, you could look at radiopharmaceutical therapies with ARPIs plus PARP inhibitors. All of these are potentially possible. I think for those people who have great ideas, it's great to see these little IITs out there being investigated. The idea of an alpha and a beta, yeah, why not? So to me, that's why there's so much excitement and hope around this because it's really opened up a whole new avenue of potential possibilities.
Neeraj Agarwal: I think the most important thing beyond what we discussed, beyond hope and optimism is to make sure that everybody knows about these agents because in metastatic castration-resistant prostate cancer where the approvals are already there, we know from the real-world data that most patients don't get these treatments despite overall survival improvement.
Phillip Koo: And that to me is a huge challenge. And I think it's wonderful. We have this amazing research community and this community of physicians who are looking to answer a lot of these questions. And it's so important though that these treatments be available and be given to the right patients. And that leads to a whole other discussion of what can we do to help facilitate the idea or the question or the challenge of access?
Neeraj Agarwal: So Phil, this is great to know that newer types of radioligand therapies are coming up in terms of alpha particle and it's also great to know that ultimately overall formulation, how do you deliver those alpha particles in a targeted fashion is going to be the key. But for now we have this beta particle, PSMA-617, lutetium-177 available in metastatic CRPC setting for both post-chemo and pre-chemotherapy setting and key is to improve the education and awareness of this available drug associated with overall survival benefit and make sure that our patients have the option of availing this treatment.
Phillip Koo: Well said. Thank you very much.