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Alicia Morgans: Hi, I'm so pleased to be here with Professor Emmanuel Antonarakis, who's joining me from University of Minnesota, to talk about the ECLIPSE trial. Thank you so much for joining me today, Emmanuel.

Emmanuel Antonarakis: Thanks, Alicia.

Alicia Morgans: Wonderful. So Emmanuel, can you tell me a little bit about the ECLIPSE trial, and about the unique lutetium agent that is targeting PSMA, maybe in a different way than some of our other studies have?

Emmanuel Antonarakis: So, there's been a lot of interest in radioligand therapies, as we know, in prostate cancer, but they're not all the same. The one that has FDA approval is also called
lutetium-PSMA-617. Brand name of Pluvicto. Now, the ECLIPSE trial is using a similar but different chemical structure radioligand, and that one is called lutetium PSMA-I&T. And the I&T stands for image and treat. Because it was designed as a theranostic agent, so the same radioligand can be used as an imaging agent, then also has a therapeutic agent. And by the way, that's also true of lutetium-PSMA-617. That's also a theranostic agent.

What are the similarities and the differences between PSMA-617 versus PSMA-I&T? Well, they both have a urea-based chemical structure, but they have a different structure, and importantly, they have a different chelator. The chelator is basically the ligand, that itself binds to the PSMA receptor, so a different chelator. And the PSMA-I&T has a slightly shorter half life. So they both target PSMA. They both deliver lutetium-177, which is a beta particle. But they have different proprietary and patent issues, because they are different chemical entities.

Now, the ECLIPSE trial is one that I have the pleasure of leading, together with Thomas Hope. And we've added a third member to the steering committee, Dr. Julie Graff. And we are conducting this study in the US, and also in Europe. Lutetium-PSMA-I&T is made by a European company called Curium Pharma, and Curium has their headquarters in Paris and London. And this is a study of about 400 patients, with about 40 sites in the US, and about 15 sites in Europe. And as you mentioned, this is an ongoing study with open enrollment.

ECLIPSE is a Phase III trial, and could potentially lead to FDA approval. Of course, this is a different radioligand, so it's not a label extension. It'll be a brand new label if this was approved. And the patient population is men who find themselves in the castration resistant metastatic setting, who have previously received one and only one novel AR-directed agent, and no taxane chemotherapy. So for example, a patient with metastatic CRPC, who has previously received abiraterone only in the hormone-sensitive or castration-resistant state, or a similar patient who has received enzalutamide only in the castration resistant or sensitive state, and has not received chemotherapy in any state, is eligible.

And then there's a two-to-one randomization favoring the radioligand arm, where patients have twice the odds of receiving lutetium-PSMA-I&T, versus the control arm. And the control arm is the alternative androgen receptor-directed agent, and you have to choose between either abiraterone or enzalutamide. Now the two-to-one odds does work in the patient's favor, because 66% will get the radioligand therapy, 33% will get the control arm, which is the alternative AR therapy. And very importantly, there is a crossover built in on patients who receive the control arm.

The primary endpoint of the trial is radiographic progression-free survival. So patients in the control arm who develop radiographic progression-free survival, and this is confirmed by an independent radiologist, they then have the option of receiving lutetium-PSMA-I&T, as long as they remain eligible, in terms of their hematology and renal parameters.

Alicia Morgans: So important that you do have crossover built into this trial, Emmanuel. And so, your primary endpoint there is going to be progression. And at that time, how is this going to be delivered? Is this going to be something that you'll be able to get relatively quickly for that control arm? Because this is sort of an international problem, that we want to try to get these agents to people as soon as possible, and there can be some delay.

Emmanuel Antonarakis: One of the challenges right now, as we all know, and as our patients face, is the supply chain and delivery problem with lutetium-PSMA-617. This is a different chemical entity, coming from a different manufacturer, from different European sites, and there is no production problem or supply chain problem at this moment. And hopefully, there will not be. So there is no concern, from the patient's perspective, of not being able to get their dose in time, because this is not Pluvicto, PSMA-617.

The issue of crossover, I think, is important to patients, especially when you have a trial in the modern day with a control arm of abiraterone, enzalutamide. And I should say, that the delivery of this product is two weeks or less, and it has been very robust and very predictable.

Now, with radiographic progression-free survival as a primary endpoint, even if you have a crossover which is patient friendly, we do not contaminate the primary endpoint, or decrease the chance of us seeing a difference if a difference exists.

Of course, overall survival, which is a key secondary endpoint of the ECLIPSE study, could potentially be affected. But the regulatory authorities, in both the US and Europe, have hinted at the fact that if the RPFs endpoint is met, and the OS is trending in the same direction, even without statistical significance, this may be enough for regulatory approval. But I'm certainly delighted for my patients that the crossover is built in. And again, as long as their hemoglobin remains above eight, the GFR is above 50, few other hematological parameters, they can get the lutetium-PSMA-I&T progression.

Alicia Morgans: Wonderful. One of the other things that is not necessarily limiting use of lutetium-PSMA-617, but there was definitely a lot of talk about this, and there's still a possibility of insurance rejections because of it. The study, VISION, was done with gallium-PSMA imaging agents. And so, there is just this question, do we have to use a gallium-PSMA imaging agent with our PET scans? In this study, is there a similar restriction for a type of PSMA-PET that must be done? And how do you anticipate that affecting enrollment in this trial? But then also, use of the data if this is an agent that is approved in the future?

Emmanuel Antonarakis: Yeah. I didn't mention that, and thanks for the reminder. This is a PSMA-PET selected population, and about 90% of patients in this disease setting will have a positive PSMA-PET scan. It can either be gallium-68-PSMA or DCFPyL, also called Pylarify. So it's up to each institution or physician which one they get.

And also, the definition for eligibility is different from VISION. It's relatively simple. They need to have one or more metastatic lesions, with an SUV uptake of at least or higher than liver. So with SUV higher than liver, even in a single lesion, there are no exclusions based on concurrent FDG-PETs because FDG-PET is not required. In my institution, we don't typically do that. And so yes, there is a PSMA selection, of course, as you would expect, but it's either gallium-68 or Pylarify, and one or more lesions with SUV above liver is adequate.

One thing that I also did not mention, and I should, the interval of therapy for this agent, PSMA-I&T, is also six weeks. So it's given as a 10-minute intravenous injection once every six weeks. One small difference is, the number of doses is capped at four. So the interventional arm of the ECLIPSE study gets the PSMA-I&T every six weeks for up to four doses, which is a bit different from PSMA-617 in the VISION trial, and I think, even in the PSMAfore trial, where up to six doses, I believe, of that agent were prescribed.

And again, this has to do with the fact that, there have been fewer early stage studies, Phase I, Phase II studies, of this particular compound in prostate cancer patients. So safety is actually a key secondary endpoint. Then, there was potential theoretical concern about, what if six doses was too much?

Alicia Morgans: Great. So final question, just thinking about this population and this trial design. Are you collecting patient reported outcomes? Are you assessing quality of life? This is a big study, it's a registration trial. It's so important to hear what the patients think.

Emmanuel Antonarakis: I thought you might ask me that, Alicia, and we are, but the tools may not meet your expectations. So we are using the FACT-P instrument, we're using the BPI-sf instrument, and the EORTC instrument, and the patients are filling those out. In my institution, they're filling them out on paper. I'm not sure if there's an electronic version of that. So we are, but of course, we could and should do better. And perhaps, I should have spoken to you when designing the study, to embed more relevant patient reported outcomes, perhaps.

Alicia Morgans: That sounds pretty robust to me. And you always do your best, and which is actually usually excellent, Emmanuel. So I think you've done a great job, and I really look forward to seeing that. So if people are interested in sending their patients, if patients are watching this, and they're interested to find a site, are there many in the US? How would they find out where they can potentially go to get this study?

Emmanuel Antonarakis: Yes, we have 41 active sites in the US. By the way, we are about one third of the way enrolled in the 400 patient study. The projected enrollment stop date, or end date, is going to be August or September of this year, 2023. So we are enrolling very quickly, but there still are several months, I would say, of life left in the study. And there are sites on the East coast, in the Midwest, and the West coast. There are also 15 sites in Europe, in Italy, Spain, and France, in case we have some international audience as well.

Alicia Morgans: Wow. This is phenomenal, and really, really quickly enrolling. So congratulations to you and the team. I really do look forward to hearing more about the ECLIPSE trial in the future. Thank you for your time.

Emmanuel Antonarakis: Thanks very much.