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Neeraj Agarwal: Welcome to this episode of UroToday. My name is Dr. Neeraj Agarwal, and I'm very pleased to welcome Dr. Ramy Saleh to this episode. Dr. Saleh is the Medical Director of Oncology Clinical Trials at the Research Institute at McGill University Health Center. Ramy, welcome, and congratulations for presenting the “Trials in Progress” abstract at the ASCO GU on a very important trial. And its name is ACCEL trial, which is “225-Actinium-PSMA-62 Treatment in Patients with Oligometastatic Hormone-Sensitive and Metastatic Castration-Resistant Prostate Cancer.” And you are characterizing the efficacy, safety, tolerability, and dosimetry in these patients.

Ramy Saleh: Hi, Neeraj. Thank you very much for having me today. Yes, so what we presented in ASCO GU of 2025 is the phase I trial of the Actinium-225 PSMA-62 and the two indications that you have mentioned. So thank you, Neeraj. So yes, we presented in ASCO 2025, ACCEL, which is Actinium-225-PSMA-62. It's a phase Ia, 1b, and hopefully accelerated to phase II clinical trial basically focusing on oligometastatic hormone-sensitive and metastatic castrate-resistant prostate cancer.

So, as we all know, Actinium-225 is a prostate-specific membrane antigen radioligand therapy, or RLT, which is an alpha emitter, unlike lutetium, which is a beta emitter, which is important because it’s different side effects and different efficacies on prostate cancer cells. Unfortunately, a while ago, there have been many PSMA-targeted ligand treatments with Actinium, but they did have high rates of xerostomia that led to dose-limiting levels that were much lower than anticipated or to lead to a biological effect, as well as myelosuppression and renal toxicities.

Lately, there have been a next generation of PSMA ligand Actiniums. One of them is the one that I’m presenting, which is the 225-Actinium-PSMA-62 in order to address those limitations. So we hope that the next generation Actiniums carry a better efficacy towards prostate cancer, however, taking into context that it will have a much lesser toxic profile. The PSMA-62 has a novel linker technology that enhances not only the cellular internalization, but it will lead to improved biodistribution, as well as a better tumor delivery of the Actinium, which we hope will translate to better outcomes for our prostate cancer patients.

This is the PSMA-62 biodistribution in an animal model. And as you can see, there is a much improved uptake with the PSMA-62 versus the Lutetium-177-PSMA I&T. You can see that there is a better affinity and better internalization. So we know that this next generation, at least in the animal models, tend to carry a better outcome with a better control, I would say, over the tumor.

The phase Ia, which is where we are right now—we’re still in the phase Ia and the dose escalation level. So we’ve done multiple doses. And basically, what we’re trying to see is in the metastatic castration-resistant prostate cancer patients who failed standard of care, if they’re able to tolerate the treatment—which is given, by the way, every six weeks for up to four cycles max—in order to see what is the MTD in metastatic castration-resistant prostate cancer?

It is different, though, in oligometastatic hormone-sensitive prostate cancer patients, where the regimen is on a Q8-week cycle, and it’s two cycles. The trial is open in Canada in multiple sites, as well as the hopes to expand it into the US, as well as Australia and in Europe. And we’re still increasing the dose, hoping to hit an MTD at some point. But so far, it’s very well tolerated.

The phase 1b is definitely where we want to dose optimize. So once we hit the MTD, there will be a 1-to-1-to-1 distribution in the metastatic castration-resistant prostate cancer, where we’re going to try the MTD on a six-week regimen, the MTD on a Q4-week regimen, as well as the MTD minus 1 on the Q4 weeks, to see what is the recommended phase II dose, and then take it into an expansion.

In the oligometastatic, we’re going to try the MTD on a Q8 week, as well as the MTD minus 1. And the reason for that—we’re trying to really optimize the dose before we go to a phase II trial in order to really ensure that the dose carries the lowest amount of toxicities, but with the best outcome and effect on the tumor.

The objectives are very straightforward. Like any phase I trial, it’s aimed to evaluate the safety and tolerability, in this case, the 225-Actinium-PSMA-62, as well as determine the MTD. What is important for us and what we are collecting as key secondary endpoint is the PSA response rate—is there a decrease in the PSA?—as well as checking the objective response rate. And in the oligometastatic, we’re trying to check the time to ADT initiation.

Of course, in subset analysis, we are doing also Scout imaging post-treatment in order to see what is the SUV max and what is the highest uptake in the tumors, and what is happening to those as we administer the treatment into our patients? So far, as I mentioned, the study is enrolling in Canada, and there’s hopes to expand it into the US, Europe, Asia, and Australia. I can mention that the patients so far that were on the trial tolerated the treatment well.

I think the fear of massive xerostomias, grade 3–grade 4 xerostomias, have not been seen yet at the dose level that we are on. And what is more important, in my opinion, is that the rate of myelosuppression and renal toxicity is almost negligible. So we do feel that the new generation of Actinium agents tend to have a much lower profile. I think the question is, how high can we go before the patients have severe toxicity that will limit them from treatment?

Neeraj Agarwal: Ramy, that was a great presentation. Thank you for taking the time to do that. So I have a few questions for me and for our viewers today. So there are two distinct aspects of this new drug. Number one is, as you said, Actinium-225, which is an alpha particle and has a different toxicity profile compared to a Lutetium-177 beta particle, as you mentioned—myelosuppression or salivary gland toxicity or renal toxicity. So we’ll be talking about the different side effect profile in a moment.

But another aspect which I found quite intriguing was the carrier molecule. It is different from PSMA-617. It is PSMA-62. We have not seen this yet in the clinic. So you are using two novel molecules, combining them. And of course, there are two different settings. So my third question will be, in the oligometastatic setting, hormone-sensitive prostate cancer setting, are you using it with androgen deprivation therapy or without ADT? So we’ll come to that in a moment, and of course, in the metastatic CRPC, what the role of these molecules has clearly established?

So let’s start with the first question. Ramy, how is Actinium-225 different from Lutetium-177, other than the mechanism—so alpha particle versus beta particle—but what can our patients expect differently from the side effect perspective?

Ramy Saleh: I think the mechanism of action is extremely important for the patient, as it will dictate the difference in responses as well as what can they expect from the treatment. The alpha particle emitter is a high-energy particle with a short range. So what we expect from Actinium is that instead of causing some damage to normal cells, given it is short range, the effects and the side effects should be more localized than Lutetium-177.

The other thing that is important is the mode of delivery. Lutetium is given six times in a different type of regimen. Here, we’re seeing only four injections. Given also the different toxicity profiles, it will definitely have—or we hope that it will have—less myelosuppression and less nephrotoxicity, like we see with Lutetium. It’s a huge concern that we have in our clinic when we put patients on Pluvicto or Lutetium, the rate of myelosuppression as well as the rate of kidney failure.

So I think the mechanism of action is already a huge interest, given that we think that this mechanism of action will yield a more strategic, targeted result with less toxicity on the normal cells, which in itself will translate to a better tolerance for the patients with prostate cancer.

Neeraj Agarwal: And how about this PSMA-62 molecule, which is carrying the Actinium alpha particle? How is it different from, say, PSMA-617 or PSMA-I&T, which have been extensively investigated and one of them is already approved in the clinic, and we saw the SPLASH trial and ECLIPSE trial showing positive results and hope to see those molecules in the clinic. So how is this PSMA-62 being used in this trial different from PSMA-I&T or PSMA-617?

Ramy Saleh: So that’s a great question. Actinium was linked before to what we call the first generation ligands, such as PSMA-617 and PSMA-I&T. The challenge we had with the earlier trials with Actinium with those two delivery agents is that the toxicities were sky high. So the reason why this trial, I found it to be very interesting, is not only they’re changing the Actinium, but also they’re changing the novel delivery method.

The whole aim is, can we still have hope for Actinium with a better side effect profile if we’re able to change the delivery mechanism? And I think this is why in this case, when they did the animal models with the PSMA-62, the pairing showed that there is a higher tumor affinity with less distribution. So I think we’re trying to think outside the box, learn from the lessons of the past, not to repeat the same mistakes, and we’re trying to find a different avenue of delivery of Actinium.

Neeraj Agarwal: Thank you for that. And you mentioned that the doses will be different in the mCRPC setting versus mHSPC setting, which is oligometastatic mHSPC. So let me ask you about oligometastatic mHSPC first. Are you using it with androgen deprivation therapy, or without ADT?

Ramy Saleh: No. So in the phase I escalation, we’re trying to see the time to ADT initiation. So they have to be without ADT. It’s a very small cohort. I think it’s a very small niche of patients. We’re just trying to do an explorative, I would say, cohort to see if there is any need in that sphere.

Neeraj Agarwal: This is like we saw the WOLVERINE trial data, where patients with oligometastatic prostate cancer—really large database—and they got radiation therapy. Essentially, you are doing the same thing, except using a new modality of radiation therapy, if you will. And hopefully, if this trial is successful and expanded in a very similar way in a larger trial, it will delay the androgen deprivation therapy or castration therapy for our patients, which is a huge unmet need in the community among our patients.

Ramy Saleh: You’re absolutely right. Remember, this is a phase I trial, so we’re still checking safety and tolerability. This is why it’s not a huge cohort that we’re looking for in the omHSPC. I think it’s just a discovery cohort, trying to see if there is a signal, should we go into that phase of the prostate cancer patient and see if we should divulge more there and see if there’s a room for Actinium in that?

Neeraj Agarwal: I was just talking about the future potential of these kinds of therapies.

Ramy Saleh: So I think in the future—now, we know that conventional imaging in omHSPC is very tricky, and we should rely more on PSMA testing, or gallium testing at least. So probably right now, we’re under diagnosing omHSPC. But definitely, the better our screening methods, probably there’s going to be more patients. More patients might translate to more need for new novel treatments in the future. And this is the route that we’re taking.

Neeraj Agarwal: How about the mCRPC setting? How many doses are you using in those patients?

Ramy Saleh: So in the metastatic castration-resistant prostate cancer, now we’re looking at four cycles on a Q6-week regimen. Right now, it’s patients who failed at least an ADT with an RP, as well as one agent of chemotherapy. So the patients could have taken one or two agents of chemotherapy—Docetaxel, Cabazitaxel. They could have taken PARP or not. But as long as they took one RP and one chemotherapy, those patients are eligible to take on Actinium. The only patients that right now in the phase I—and it’s worth mentioning—that we’re not taking is patients post Lutetium. So this is not something that we’re ready to go into as of yet.

Neeraj Agarwal: That’s a very important point. Any final message for our audience?

Ramy Saleh: I think prostate cancer—there is a ridiculous amount of new discoveries and new ways of treatment. If people thought that Lutetium is the last RLT in the prostate cancer sphere, I think they’re wrong. In ASCO GU 2025, we saw three different Actinium RLT regimens that were presented. So I think the future is going to be bright. More treatments for our patients means better outcomes, so this is what we’re hoping for. And I think the next year to year and a half are going to be very interesting to show us if there is room for Actinium in prostate cancer or not.

Neeraj Agarwal: Fantastic. Well, congratulations again for presenting this new modality to treat prostate cancer, and for sharing your time with us today.

Ramy Saleh: Thank you very much again for having me.