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Zach Klaassen: Hi, my name is Dr. Zach Klaassen, I'm a urologic oncologist at the Georgia Cancer Center, and I'm pleased to be joined for a UroToday discussion with Dr. Miyahira, who is the senior director of global research and scientific communications at the Prostate Cancer Foundations. Welcome and thank you so much for joining us today.

Andrea Miyahira: Thanks so much for having me, Zach. I'm very excited to be here.


Zach Klaassen: So I think what we're going to talk today about today is basically the role of PCF and how it has translated over the years, as we'll see, with regards to PSMA theranostics.

So just from a high level, can you sort of walk us through why and what the philosophy has been for PCF to be so heavily involved with PSMA theranostics?


Andrea Miyahira: Yeah, happy to. So first of all, in 2023, PCF will be celebrating our 30th anniversary. We're very proud of that achievement, and our primary mission is to fund research that will ultimately lead to new treatments that will end death and suffering from prostate cancer. So our focus tends to be on funding the most high-risk, high-reward projects, and we recognized very early on that targeting PSMA was highly promising.

So since our inception, we funded have funded well over $30 million in research for PSMA biology, molecular imaging, and therapy. And last year we put together a paper that went over the history of PSMA theranostics development and the role of PCF, and we found that many advancements on in PSMA biology and clinical applications do have a foundation in PCF funding.


Right now, I just want to say that there are now three PSMA-targeted PET imaging agents that have been FDA approved, as well as the PSMA-targeted radioligand therapy, 177 Lutetium, PSMA 617, which we all call Pluvicto.


So this is a very nice timeline of the major milestones of the development of PSMA theranostics, and we highlighted those that were supported by PCF funding with the blue PCF logo.


So we'll start at the bottom, down at 1987. PSMA was first discovered when Murphy and Horoszewicz's team developed an antibody against prostate cancer by immunizing mice. They pulled up an antibody, went on to show this antibody 7E11-C5 bound to prostate cancer antigen.


And this same antibody was then used by Heston and Fair's group in 1993 to clone the PSMA gene. So PSMA was founded discovered in '93, and we funded our first projects on PSMA in 1994 to William Fair and Neil Bander, and those were for PSMA theranostics applications and to further describe biology, tissue distribution, and the genomic organization of PSMA. And you can see that those publications were published in the 1998 and 1997 timeframe.


So 7E11-C5 was actually developed into the first theranostic agent against PSMA, the imaging agent ProstaScint. I don't know how many people actually remember that. It was FDA approved in 1996. Unfortunately, this antibody binds an intracellular portion of PSMA, so the imaging quality was very poor.


Neil Bander, with his PCF funding, developed the first antibody against an extracellular epitope of PSMA in 1997. This is J591, who we all know about. And this team developed J591 into the first PSMA-targeted radioligand agents. They were tested in trials in, let's see, I think it's 2000 here in the figure. These agents are still being developed today, looking at different radioisotopes.


The first PSMA-targeted small molecule ligand was developed in 2001 by Kozikowski's group. Although this group was actually attempting to target a CNS version of PSMA to develop neuroprotective agents, Marty Pomper recognized that this small molecule could be used for prostate cancer imaging instead and began using it to develop PET imaging agents. He later developed a series of improved agents, many of which were funded by PCF, including DCFBC and ultimately F18 DCFPyL, which was first tested in patients in 2015 in a PCF-funded study.


In parallel, Eder's group in Germany developed PSMA 11 ligand in 2012, and this ligand ultimately became the first FDA-approved PSMA ligand-based PET imaging agent by a PCF-funded team that was led by Johannes Czernin, Thomas Hope, Jeremy Calais, and Wolfgang Fendler in 2020. And happily, kits to produce this agent beyond UCSF and UCLA have since become available, so this is much more widely available now. And F18 DCFPyL PET Imaging was FDA approved in 2021. And I mentioned earlier that now we also have a third agent, 18F-rhPSMA-7.3. So there are three PET imaging agents that have been FDA approved.


And as the PET imaging agents were steadily been being moved through the trials, so were PSMA radioligand therapies. After in 2016, the first patients with Actinium PSMA 617 were published in, I think it was, the Journal of Nuclear Medicine, and that publication was very exciting. It actually prompted PCF to establish two working groups where we brought together world experts in PSMA, theranostics, and we put together two different meeting reports in 2017 and 2019 about how to advance the field for PSMA theranostics.


And so we finally get to see in 2021, we're so happy to see the results from the VISION trial, that they were positive and that we got the FDA approval of Pluvicto in 2022, which is just beyond where the timeline ends.


Zach Klaassen: Well, that was fantastic. It's fascinating, two things kind of pop out as you're going through that. We've known about PSMA for 30 years, which kind of coincides, as you mentioned, with the 30-year anniversary of PCF, too. So that's a great timeline. I think just seeing that laid out and all the advances, the trials, the money that PCF has put into it is fantastic.


So obviously, as you mentioned, the timeline ends at 2021. Fast-forward next to the next two years and maybe over the next years and moving to 2024, what additional projects or roles is PCF looking at with regards to PSMA theranostics that may not have been highlighted based on that timeline?


Andrea Miyahira: Actually, a few years ago we did fund the establishment of the Prostate Theranostics and Imaging Center of Excellence, which is ProsTIC, at the Peter MacCallum Cancer Centre in Australia, led by Michael Hofman. This center of excellence has developed a world-class theranostics infrastructure to advance theranostics applications, but they also have a large educational arm. So they have a series of global webinars. They have annual preceptorships and masterclasses to teach best practices to practitioners around the world. And their next preceptorship is in March 2024. So I did want to mention that we funded $5 million into this center.

In 2022, PCF started to fund these very large team science projects called TACTICAL Awards, and these are multimillion-dollar team science awards to really try to find the next treatment. The goal is to find the next treatment from bench to trials, in three years. Two of these projects were funded for $18 million in total in theranostics. One was at Peter Mac, led by, again, Michael Hofman, and they are exploring new theranostics targets, so PSMA. But also beyond PSMA, they're developing lead-based alpha radionuclides, as well. So we're very excited to see where that is going to go.


And the second project is led by MSKCC, and they're developing theranostics against DLL3 for imaging and treatment of neuroendocrine prostate cancer.


So we are already looking forward beyond PSMA, we're looking toward how we can improve what we know about PSMA so far and basically hoping to develop many new agents against prostate cancer targets that could impact even more patients.


Zach Klaassen: Yeah, that's great, I think. And you mentioned the groups that you're funding and there was a great webinar just a few weeks ago highlighting some of that early research put on by PCF and the group at Peter Mac. So I think, clearly, the timeline continues, so there may need to be an update to the paper in the next little bit with some additional exciting setting findings.

So I think when people ask about where the field is going, particularly in advanced disease, I think, really, in my opinion, that the next five years of RLT and theranostics is going to be extremely exciting and probably very central to the research you guys are sponsoring that we just discussed.

So where do you see PSMA theranostics in radioligand therapy going in the next, say, five years or so?


Andrea Miyahira: Okay. So what we've learned from Pluvicto is that it's not curative, and the main reason it's not curative is because PSMA is heterogeneous and it gets lost with androgen-targeted therapy. And as you get into later and later stages of CRPC, you tend to get more heterogeneous and less expression of PSMA. So the field is moving toward finding ways to either turn PSMA back on. There are many studies looking at how to turn PSMA back on and maybe combine that with Pluvicto, and other ways to continue to improve Pluvicto by combining with other treatments, whether it's immunotherapies, PARP inhibitors. These studies are all ongoing.

But we're also trying to find out if using Pluvicto earlier may be more beneficial. So there are studies now in hormone-sensitive metastatic prostate cancer. The LuTectomy trial is looking very promising using Pluvicto as a neoadjuvant treatment. So we'll start to learn when should we be using Pluvicto, what should we be combining it with.


But beyond PSMA, I think, and beyond beta, next steps will be looking at alpha, looking at things like terbium and Auger electrons, other types of radioisotopes that may have a better kill, better capability. And also, looking at other targets.

So as we know that PSMA is heterogeneous, there are many studies trying to find other targets that you can either combine with Pluvicto or use in other settings, such as DLL3 and NPC, that's just one example. So a lot of these projects are already ongoing.

And of course, PSMA as a target for other types of therapies. So there are trials looking at CAR T cells, bispecific antibodies, ADCs, and other approaches. And so we've learned a lot from our studies in PSMA and what PCF has funded in PSMA, and we're looking at all the different ways to improve this based on what we've learned.

Zach Klaassen: Yeah, that's a great summary. I think if we look at the next five years of ASCO GU, ASCO, and ESMO, there's going to be exciting phase 1, phase 2, and certainly phase 3 data coming, arguably at all of these meetings coming up, so it'll be really fascinating.

Lastly, I think to sort of round it all out and maybe touch on something that you want to touch on that we haven't already or additionally give our listeners a couple of practical clinical take-homes that they can take to the clinic tomorrow would be fantastic.


Andrea Miyahira: Well, I think I'll start off with saying do check out our webinars that we have with the ProsTIC center. They're very informative.

Zach Klaassen: Absolutely.

Andrea Miyahira: They usually touch on many of the most recent advancements and where the field is going, and there's just a lot to be learned from that group.

Other messages I would say, I think just learning, continuing to learn about how PSMA is turned off and how we can turn it back on and what we can combine it with. And yeah, I'm just very excited to see where the field is going. We're very proud of what the field has achieved. We're very proud of PCF's role in it, so we're very excited to look forward.


Zach Klaassen: No, that's great. I think PCF, the figure speaks for itself, but the additional multimillions of dollars that you guys are committing to this field is fantastic, and we'll certainly see that playing out over the next couple of years.


Thank you very much for your time. It was a great chat, and I know our listeners will really enjoy. Thank you so much.


Andrea Miyahira: Thanks so much for having me.