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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist in Augusta, Georgia. I'm delighted to be joined today for an ESMO 2024 discussion with Dr. Evan Yu, who is a medical oncologist at the University of Washington. Evan, thanks so much for joining us today.

Evan Yu: Thanks for having me here again, Zach.

Zachary Klaassen: It's great to have you back on. We're going to discuss your presentation at ESMO on the ARROW trial. So why don't you give us a little background on Iodine-131 and run through your slides to tell us about your data.

Evan Yu: Yeah, sure. Let me just tell you a little bit of background about this trial before we get started. I-131, I-LNTH-1095, is basically a PSMA radioligand therapy, so it's different than other known drugs out there like lutetium-177 PSMA or Pluvicto. It binds to a different spot on PSMA, and it's a small molecule similar to that of Pluvicto, but 1095 is the small molecule.

The difference also in the radiopharmaceutical is that it's not lutetium, it's iodine. So iodine has higher energy, it decays from a beta to a gamma and then has a reasonable amount of residual gamma. So it can be a little bit more cumbersome depending upon the institutional policies of management of use of I-131 in their center. So some places don't have any different regulations in use of I-131 over, let's say, lutetium-177. Others do. But I think the key thing for a patient is just the period of time where they kind of have to keep a distance from their loved ones and from other individuals. For lutetium, it's usually around three days, and for I-131, it's like three to five days.

That's a little bit of a background on the agent, but it is higher energy. And this is a patient population with metastatic castration-resistant prostate cancer who previously received abiraterone and progressed, and they were randomized to either the 1095 agent with enzalutamide or enzalutamide. And the thought at the time, and there's still some data that supports it, is that there might be synergism between adding this together with enzalutamide. For instance, enzalutamide has been shown in some studies to transiently upregulate PSMA expression, and so doing this together could potentially offer some synergism or additive properties. So that's why they studied an mCRPC patient population post-abiraterone.

Here are my disclosures and here's the trial schema. So again, there was a 2:1 randomization, two to 1095 plus enzalutamide and one to enzalutamide alone. And so it was intended for 120 patients, 80 for the combination arm, 40 for the monotherapy control arm, and the primary endpoint was PSA decline. So we do report on radiographic progression-free survival, but I will say this is that it was not statistically powered for such. It was intended to be a smaller trial, signal finding, but to have some randomization to get an idea whether there was benefit or not. And that's why PSA decline was chosen as the primary endpoint there. We did do PyL PET imaging for diagnosis upfront, and you had to have PyL positivity on PET scan to be eligible for the trial.

As you can see, the key efficacy endpoint, which was PSA decline, was met. It was primarily statistically significant, with 62.9% achieving a PSA 50% decline versus 31.3%. And that was for monotherapy. So essentially a doubling and statistically significant difference in PSA 50% decline, and you can see the waterfall plots for all the patients there that were treated.

Now, radiologic progression-free survival, as you can see, not statistically significant for I-131 1095 over enzalutamide monotherapy with median rPFS of 14 months versus 11.5 months. But that being said and done, it was not statistically powered to show this. I suspect if you had a larger study, you would've shown a statistically significant rPFS benefit.

In regards to trial safety, it's kind of the same thing you expect with PSMA radioligand therapy. You can see fatigue, you can see subtle GI side effects, a little bit of nausea, decreased appetite, and of course the xerostomia you get because PSMA is expressed on salivary glands, so you can see xerostomia. And of course with any radiopharmaceutical like this, myelosuppression can happen as well. So this was generally all as expected.

In summary, it met its efficacy endpoint, the ARROW trial did, with statistically significant higher PSA 50% decline amongst those that received 1095 plus enzalutamide versus enzalutamide alone. But it wasn't statistically significant for radiographic progression-free survival, but that was not powered to show that. The safety results showed a very manageable safety profile, very consistent with other agents in this class. I think the challenge will be that there's a competitive landscape, other agents with lutetium-177 PSMA out there, with the SPLASH PSMA-I&T radioligand therapy out there. I think the challenge is it's a very, very, I would say, crowded market space, and so I anticipate this is unlikely to move forward in this current state. In this current construct.

But I think the principle that's shown in this study is the fact that 1095 is an effective PSMA-targeting small molecule, and it lends us to think about the future, meaning as we use more and more targeted therapies, for instance, targeted alpha therapies, could we switch out instead of using something like I-131, which might be more cumbersome to give, for an alpha, like let's say actinium or something like that, and use that to switch that out and put that onto this small molecule and use this. So I do think there are still lessons learned from this study. And even if this drug doesn't move forward in further development, there's clearly some efficacy here and I think maybe using a different radiopharmaceutical might be the way to go in the future.

Zachary Klaassen: Evan, thanks so much for that great presentation on ARROW. I think you really set the context for what the disease space is currently. We saw SPLASH data at ESMO. We've seen PSMAfore, we've seen VISION, and I like your honesty on the context of where this may fit in and some of the challenges you led off with about delivery. Would you say that it's a combination of the crowded space? Maybe it's that three to five days the patient has to stay away from their family? What were some of the challenges that maybe logistically and from a patient standpoint for delivery of this agent?

Evan Yu: Yeah, that's a good question. From my perspective and my institution's perspective, we don't have to do too much more with I-131 than we do with lutetium-177.

Zachary Klaassen: Right.

Evan Yu: No shielding required. At higher doses, yes, we would, but not at the doses that were used in this study. So of course it's higher energy and you worry about that. But not every center's the same, and there are some institutions that have much more stringent requirements, the types of things like study staff needing to be administering this at a greater distance, a single bathroom for patients receiving this, and an isolated path to that bathroom.

So what I would say is this, is that I-131 is something that's effective. I-131 is something we've used for years in thyroid cancer, so it's not that dramatically different, but different institutions' radiation safety policy may be different, and it's just generally, because of that, it's viewed as being a little bit more cumbersome. But I will say this from my institution's point of view, it's not something that's dramatically different as far as the setup where our nuclear medicine docs administer this.

Zachary Klaassen: You were a little provocative on your last point too. I liked it about maybe actinium learning from the iodine experience. Maybe expand on that a bit more. Where's the building blocks here for competing with some of these lutetium agents in that second or even third line setting for mCRPC?

Evan Yu: Yeah, it's a really good question. My thoughts are this, is that the market's going to get crowded there. There's more and more agents being studied. We already have a couple randomized phase III studies that are positive in that situation. But there are other agents out there being developed, and you have to ask yourself what might be the benefits of agents.

So targeted alpha therapy is very promising. The problem with targeted alpha therapy is so far it's mostly been studied very late. So post somebody who's already received, let's say, a beta, gamma-targeted therapy, and some of the challenges when you go in that very late stage setting is that you get really bad xerostomia. So one of the key advantages for targeted alpha therapy is that it has a very short travel distance range, and you can get very, very potent cell kill that way. So if you think about something like a beta emitter, you kind of need a larger tumor mass for it to be very, very effective.

Some of my concerns with some of the agents that are out there already is as we go earlier and earlier to patients with lower tumor volumes, how much of this effect are you going to see, antitumor effect, versus are you going to start to get more into toxicity effect?

So that's one advantage for alpha, is that if you're thinking about going really early, let's say someday you want to go to microscopic disease, adjuvant therapy, or something like that, certainly not going to use some of the agents that are being used out there now. You're going to want to go alpha. So I think for development purposes in the future, that would be an opportunity to go earlier in disease states with agents like that if you were to switch out the beta for an alpha emitter.

Zachary Klaassen: Great answer and thoughtful discussion. I think we appreciate you taking time out of your day for ARROW discussion. Maybe a couple of quick take-home messages for our listeners.

Evan Yu: Yeah. I think the key take-home is this, is that when you're designing a drug, whether it's a radioligand therapy, antibody-based, small molecule-based, and of course we have to think about where oncology and where GU cancers are going with, let's say, antibody-drug conjugates, the construct matters.

And so I think as a clinician, we oftentimes are quite simplistic in thinking about, "Okay, what about the target? How well is the target expressed? Is it heterogeneous? Is it homogeneous? Is it constant expression and throughout different disease states? Is it dynamic?" We put a lot of effort into that, but we need to put just as much thought into the construct. What I think this study shows is the principle that the construct, the small molecule, is effective, but given the market space, et cetera, it's an opportunity to maybe think about manipulating that. And I think there are lessons to be learned there, and we need to put just as much thought into the construct as we do into the target and the target expression.

Zachary Klaassen: Excellent. Very well said. Evan, thanks so much again for joining us on UroToday and discussing ARROW.

Evan Yu: All right, have a great day.