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Rana McKay: Hello, my name is Rana McKay and I'm a genitourinary medical oncologist at the University of California in San Diego. It is my pleasure today to join Dr. Matthew Abramowitz as part of an educational series highlighting the state-of-the-art interdisciplinary management of prostate cancer. Today we're going to be discussing the topic of radioligand therapy, and Dr. Matthew Abramowitz is a radiation oncologist at the University of Miami Sylvester Comprehensive Cancer Center. It's a pleasure to have you here with us today.

Matthew Abramowitz: Rana, thank you so much for having me and including me in your program. I'm looking forward to today's conversation.

Rana McKay: Absolutely. Matthew is going to be talking to us about radioligand treatments, a very hot topic in advanced metastatic castration-resistant prostate cancer. We'll have Matthew go through some updates and information about how the treatment landscape in advanced prostate cancer is changing, and then we'll have a little bit of discussion. So Matthew, take it away.

Matthew Abramowitz: Thank you again for including me in the conversation or presentation. A little summary of what I'd like to go over today is I think a history of where we're at is always helpful in framing future conversations. And I think the radioligand therapy is based on a long history of unsealed sources in the treatment of metastatic prostate cancer, the current options, and then the future directions and challenges that face us when utilizing this type of therapy. So, some of the history of utilizing unsealed sources in treating metastatic prostate cancer dates back decades with the use of strontium, which is one of the first calcimimetics to treat osteoblastic disease in the bones.

Unfortunately, both strontium, which was the original, and Samarium, which came a couple of decades later, while very effective in treating pain, didn't have major effects on outcomes in terms of survival and came with a significant amount of toxicity, strontium in particular, but also Samarium. More recently, the use of Radium-223, which is an alpha-emitting radioisotope, minimized some of the concerns for hematologic toxicity, but perhaps more importantly, was the first of the unsealed sources to have a survival benefit, small but real, in the treatment of bone disease.

And again, it's only approved for patients with bone-only disease. To highlight the data, it improved survival either in patients who have seen or not seen chemotherapy in the form of Docetaxel in the trial that got it FDA approval, but also delayed the development of skeletal events, which was a secondary component of the trial. When you move forward to radioligands or antibodies with radioisotope, a lot of the formative work for the current therapies came from imaging studies.

And actually, people forget the first agent that was approved for imaging utilizing PSMA was capromab, or the brand name ProstaScint, which was a PSMA antibody tagged to indium-111, which was a SPECT scan agent. Unfortunately, this never really moved forward due to some technical issues due to spectral resolution, some of the challenges with SPECT scanning, and then most of us are familiar now with Fluciclovine PET or PSMA PET. The field has largely moved towards PSMA due to some of the limitations of Fluciclovine.

But there is the advantage that it is better in the prostate bed area or around the bladder due to less sensitivity in that area. PSMA PET is, we talk of it as a single agent, but really, it's not. There are multiple different antibodies for PSMA as well as different PET isotopes that can be utilized for imaging. And there are really some differences, although subtle, between the different antibodies as well as the PET agents, and there's not really been a clear winner in that space.

Regarding therapeutic radioligands, there's one that's been approved currently, which we talk about as a PSMA Lutetium, but there are other agents that are out there. This is a PSMA 617 antibody tagged to radioactive Lutetium has a half-life of six and a half days and is a mix of beta and gamma radiation. And what is becoming more evident is that the benefit may be predicted based upon how active or how avid the lesions take up on PSMA PET, how well they may respond to a PSMA-targeted agent. And there are other isotopes also being tested in this space as well as highlighted there.

This is just to review the data that guided approval and to show the degree of clinical benefit. This is the VISION trial, which was a two-to-one randomization of Pluvicto plus best standard of care versus standard of care in a two-to-one ratio. And what was interesting in the standard of care, there was a lot of flexibility and ability to move between treatment agents in the comparison. So it wasn't a randomization to even a fixed drug. There was the ability to move between the two based upon responses. And this also resulted in a four-month improvement in median survival.

But again, any new treatment with radioisotopes with the nature of the particles emitted by Lutetium, there was some toxicity. And if you work with PSMA-targeted agents, you also know, or imaging modalities, you know that the salivary glands also express PSMA. So you did see significant dry mouth was sort of the one and other GI side effects associated with that. Fatigue was more, but most of these stayed at a very low level with very small differences in grade three or four toxicity.

But there was an increase in multiple grade one or two toxicities with the salivary gland dysfunction being significant. And as you would expect with any radioisotope, there were differences in the hematologic toxicity compared to best standard of care also. And some of these did become significant. So this is one of the issues we need to follow and track whenever utilizing these therapies. Looking at where we're going, the VISION trial was for hormone therapy, next-gen agent refractory and chemorefractory disease. A study has currently been completed.

The data has been presented at ESMO, moving this forward, hence the PSMAfore trial to after a next-gen agent but before chemo. It met its primary endpoint, which was recurrence progression-free survival. So we may see some data that allow treatment. And then in the hormone-sensitive space, there's a big international effort that has completed trial accrual, but we're still waiting on any data presentations from that trial. There are other PSMA antibody Lutetium therapies under study. There's also non-PSMA targets that are under investigation.

And just to highlight, there are toxicity concerns that need to be followed when reviewing these. And something that we often don't think about with systemic therapy, but anytime we're using a radioligand or radiotherapy in an unsealed source capacity, is the radiation safety precautions that need to go through with patients. That may be of concern not just to them but to their family members, their grandchildren, or surrounding people, depending on their place of work. And I think one of the biggest questions we face is how to sequence all of these therapies.

We are having a blossoming of the radioligand field, but we also have a rapid development of other next-generation hormonal therapy and targeted agents. And I think that a lot of times, these therapies are coming out at a pace faster than we know how to integrate them all.

Rana McKay: Thank you so much for providing that summary.

Matthew Abramowitz: Thank you.

Rana McKay: It's really been amazing to see radioligands populate the treatment landscape in mCRPC. I think one of the biggest questions is how to sequence, how to integrate. We have the VISION data. We have the TheraP data. We now have PSMAfore data. So I think there are a lot of questions that come up in clinical practice. I think, can I use it before chemo? Do I need to wait until after chemo? Should I use it with a concurrent ARSI? Should I not? I think, how do you approach patient selection for PSMA therapy and integrating it into clinical practice for pearls?

Matthew Abramowitz: So I think that's the sentinel question. And I used the history of the unsealed sources to highlight the Radium-223. One of the things that was neat about the VISION trial is that patients previously treated were allowed. So we have data that using PSMA Lutetium post-Radium-223 is safe. We have that data on toxicity. So a lot of times, if patients are referred with bone-only disease for PSMA, I'll have a conversation about potentially starting with Radium and keeping that in the background in case we end up with visceral disease later, then we would still have that available.

And that also plays into the radiation safety concerns between the two, where the alpha-emitting bone-targeted agent has a little less restrictive radiation safety precautions than the PSMA Lutetium and also has less risk of renal or kidney concerns. So in terms of sequencing, I think that's a key component. The other part that you highlighted is how to integrate it with the next-generation agent. The Radium-223 data with Abiraterone and Prednisone resulted in, if you're familiar with it, was one of those results that you never want to see where the study arm did worse due to increased skeletal events associated with the Prednisone and Abiraterone added to the Radium-223.

That negative outcome wasn't replicated with other next-generation agents. So whether you can use other next-gen agents with it or not, is there a benefit or not, is still a certain unanswered question, but I think there's some wiggle room there to consider it. Whereas with the PSMA Lutetium, that's how it was tested. So we know that if there is a need or concern for systemic disease going through another next-gen agent, that there is safety in combining those two.

Rana McKay: That's awesome. Yeah. I mean, I think that those are the struggles that we have in the clinic. What about speaking to just the PSMA PET scan itself? We've got TheraP where they used FDG PET alone; they kind of compared the uptake within the saliva glands as determining positivity in VISION. Largely, it was basically uptake above what is present in the liver.

Matthew Abramowitz: Well, yeah. So, in VISION, uptake above liver background was defined as positive for VISION. That was the eligibility criteria. There have been some other institutional analyses looking at the response to PSMA based upon the degree of PET activity. And yeah, there appears to be some correlation there. I mean, not prospectively tested, but looking backwards respectively across the group, patients who have more PSMA avid diseases denoted by higher SUV scores appear to respond better, to have more significant responses. So, that's been sort of hypothesis-generating.

Whether that should be used in clinical decision-making is another unanswered question.

Rana McKay: Yeah. No. Absolutely. And I think too, speaking to some radiologists just about the post-imaging spec and how do you monitor people that are getting PSMA-based therapies or radioligand therapies. We're largely doing serial PSA testing. But when do you reimagine? In your clinical practice, do you reimagine these patients midway through and what kind of imaging modality do you use?

Matthew Abramowitz: I think that's a really tough question. And the reason is, I think PSMA PET is not FDG glucose F18 PET. We're not using a metabolite to look at tumor growth rates. We're looking at a cell surface marker. Dead cancer cells, cancers in the process of dying, may still express it. We know in the radiation external beam space in treating prostate cancer definitively that a year, year and a half out, you may still have cancer cells there showing treatment effect, not viable cells due to having been mortally wounded by the radiation, but that they're still there.

So if the cell's there, you may still pick up PSMA on there, on the cell surface, but that doesn't mean that there's viable cancer or active cancer. So what do you do with an undetectable and ultra-sensitive PSA in an area with persistent PSMA uptake on a PET after treatment? I don't entirely know what to make of it. So I think it often creates more questions than it answers in that situation.

Rana McKay: Yeah.

Matthew Abramowitz: The other interesting thing with PSMA expression is it varies over the course of the cancer. It's not a fixed entity. It could be inducible by hormonal therapy. We know that over treatment courses, more aggressive disease, metastatic disease, often expresses it at a higher rate than the upfront diagnosis. So what the level of expression means in general is less clear. But it would make sense that the more highly expressed it is, the more easily or the better a targeted agent against it might work.

Rana McKay: Yeah. I think in my clinical practice, it's hard to follow people with serial PSMA PETs because we don't really know how to interpret increased or decreased avidity, quite honestly. Flare hasn't been defined. I do follow patients because the course of therapy is long. These are six-week cycles. I do follow them with CT and bone scans, and that was what was used in VISION for determining radiographic progression. So, I'll get serial PSAs when they come in for their treatments every six weeks.

And then, after two to three cycles, depending on what's going on with the individual, I may get a mid-treatment scan to make sure things are going well and scan them again when they're done with treatment. And just again, kind of making routine follow-up, I guess, for people with mCRPC.

Matthew Abramowitz: So, I think that's a great point, whereas there are two separate questions that you ask with follow-up imaging. One is response to the known disease, and the other is the development of new disease. I find it less useful in tracking known disease, but the identification of a new area is a useful finding, right?

Rana McKay: Yeah. Yeah. Absolutely. And then, I think in clinical practice, I love that you highlighted the toxicity. Obviously, the dry mouth and cytopenias that can occur, particularly thrombocytopenia, I think is something to be mindful of. So, I think safeguarding around that is important. It's interesting from ENZA-p, from that study, I think they used a more adaptive kind of style of dosing, giving two cycles, and for patients who had a really great response, holding and staggering out the doses.

And that necessarily isn't routine practice here in the US, but I think if you're running into issues with cytopenias, the worst thing you can do is to push through. It's probably better to pause, hold, allow for that marrow recovery before you get into the critical ranges where you're really going to be in a tough spot.

Matthew Abramowitz: I agree completely.

Rana McKay: Yeah.

Matthew Abramowitz: I mean, you talked about the hematologic, but I think the big difference between some of the other isotopes, other therapies, and the PSMA is you also have to watch liver and kidney dysfunction. So, you can see liver failure issues, elevation in transaminases, and you can see decreases in kidney function due to the clearance of the drug. So, it's not just about the counts.

Rana McKay: Yeah. And the kidney thing. I've certainly seen it as a delayed effect after people are off treatment, six to 12 months out, their creatinine is going up and you're like, "Gosh, why is their creatinine going up?" You don't really have a good explanation for it. So, I think watching out for that is-

Matthew Abramowitz: It's a delayed radiation side effect, right? It's similar if we were using external beam, you don't see the kidney function hit while the beam's on. You would see it at a time point later, and that same issue is a concern.

Rana McKay: Yeah. Well, Matthew, it's been really awesome having you join us here today to share your insights and pearls of wisdom about radioligand therapies. It's really exciting to see all the different therapeutics come into the mCRPC landscape. And as you stated, there's a ton of other radioligands that are in development with alpha particles, beta particles, small molecules, monoclonal antibodies, targeting PSMA, targeting all different other kinds of agents, STEAP1, DLL3, others. So, I think seeing how that pans out over the next couple of years is going to be really exciting.

So, thank you so much for joining us.

Matthew Abramowitz: Thank you for having me again, and I couldn't agree more with that summary. It's pretty exciting to be a part of.