Fractionated 225Ac-J591 for Progressive mCRPC in Patients with Prior Treatment with 177Lu-PSMA - Jones Nauseef

March 22, 2023

Jones Nauseef speaks with Alicia Morgans about a trial in progress dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA. With the approval of Lutetium 177 Jones Nauseef explains that the study team decided to modify the study design to include a post-177-Lu-PSMA cohort because patient tolerance may differ based on prior exposure to Lutetium. They opened a cohort of patients with prior exposure to the drug, not necessarily 617, but all lutetium-based beta-emitting radioligand therapies.


Jones T. Nauseef, MD, PhD, Weill Cornell Medicine, Division of Hematology & Medical Oncology; Sandra and Edward Meyer Cancer Center, New York, NY, USA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to speak with Dr. Jones Nauseef, who's going to share some information about a trials in progress poster that you did at GU ASCO 2023. Really thinking about actinium and how we can use this drug most effectively in prostate cancer. Tell me a little bit about it, please.

Jones Nauseef: Sure, that'd be great. Yeah, so this is a modification of a trial we've already had in progress. And at Cornell, we have been doing a lot of work with PSMA targeted radiotherapies, particularly with a monoclonal antibody called J591. And were particular proponents of using alpha emitters like actinium in these studies.

So since we started the study, we did see that the landscape changed With the approval of Lutetium-177 PSMA-617, we knew that there was going to be a different patient population, a patient population that may have been exposed to radiopharmaceuticals before. As a consequence, looking back at the data we had already from patients treated with Actinium-225, J591, we did see that perhaps efficacy, but more significantly, patient tolerance may be different after exposure to Lutetium-177.

So as a consequence, we took our study, which initially started as either multiple dose or fractionated dosing. So dosing on days one and day 15 of a single cycle, taking advantage of the idea of fractionated dosing from external beam radiation of J591 conjugated to Actinium-225 in patients who were post chemotherapy post ARSI with metastatic castrate-resistant prostate cancer.
Once we saw those data, we decided to change it because we observed, as I mentioned, that the patient tolerance may be different based on prior exposure to Lutetium. So we opened a cohort of patients that all mandated had to have prior Lutetium radioligand therapy, not necessarily 617, but all Lutetium based beta emitting radioligand therapies.

Alicia Morgans: It's so interesting and important. And just to clarify for listeners, your J591 is actually an antibody targeting PMSA. Correct? So similar target to where Lutetium, a beta emitter, is going. And so, talk that through a little bit and share what you think, how the tolerability might be different? And also of course, the target ends up being the same, and so you really do need to be very cautious, I would think, about you're delivering an alpha now instead of beta, but you're still going to the same cells, you're going to the same compartments in many ways, I would think.

Jones Nauseef: Yeah. Terrific point. When we contrast using a small molecule ligand versus a monoclonal antibody, we do think about where the drug is getting. And we know that, of course, tumor is going to be accessible almost wherever it is, but the physiologic expression of PSMA is in organs in the body, such as salivary glands, small bowel, kidneys, and those places are readily accessible by the small ligands. So things like Lutetium-617 readily get into salivary glands resulting in xerostomia, small bowel GI toxicities, whereas the monoclonal antibodies, the antibodies are bigger. So as a consequence, they stay in circulation longer, and that is both good and bad, of course. There are side effects to that, including greater exposure to the bone marrow and consequent myelosuppression. So to your point, we have to think about this. These are patients who have already been exposed to a beta emitter, which does, of course, have some implicit thrombocytopenia in many patients, and then giving them a more potent drug that's going to expose to the bone marrow quite readily.

Alicia Morgans: Wow. So in this study, has it opened? It's in progress at this time. When do you expect to hopefully complete enrollment, and have some data to share with us?

Jones Nauseef: So we anticipate sharing the non-prior Lutetium data at AACR later this year, but for this, we're enrolling in the cohort now, and enrollment is picking up as more and more patients have already been exposed to commercial or standard of care, Lutetium-177.

I would like to also highlight in the study that, we now with the commonplace use of PSMA targeted radiotherapies, we are incorporating a couple novel things. So one of them is looking at a recently developed tool for patient reported outcomes, the FACT-RNT and PSMA targeted radiotherapies, and I think this will be particularly relevant in this heavily pretreated population.

Alicia Morgans: So let's dig into that a little bit. I think that's a really exciting tool. This is a patient reported outcome measure that was designed by, I'm sure your team was involved, and Brian Gonzalez and his team at Moffitt, who were developing this instrument to understand toxicities that are specific to radioligand therapy, to really capture and understand that patient experience. So have you used this at all in other studies? How is it going? Are patients feeling comfortable with this instrument?

Jones Nauseef: Yeah, it's very, very new for us. We're starting to add it to all of our protocols. But the way I've been explaining it to patients and the few opportunities I've had to, is contrasting when we think about toxicity profiles for drugs, that standard chemotherapy, cytotoxic chemotherapies versus immune therapies. Where in the former, very predictable, I can tell a patient what they'll experience, what it'll be like, what recovery will be like. Whereas for immune therapies, different ballgame, right? Less predictable, potentially very toxic, but most patients do very well. So I use that as a comparison for why there's a new tool, and why we need to think very carefully about the toxicity profile of emerging drugs like radioligand therapy.

Alicia Morgans: Wonderful. Well, I'm excited to hear about all of these special add-ons to this trial, and we look forward to hearing the data from a AACR. If you had to sum up this trial and the work that you and your team are really pioneering in this space, what would that be?

Jones Nauseef: To the first point, I would say that, the summary here is that this is an opportunity to see how drugs like monoclonal antibody Actinium-225 conjugated to it, targeting PSMA, will behave, in a patient who's already had exposure to now the most recent FDA approved drug, Lutetium-177.

And then thinking more broadly about our other work with J591, Actinium-225, we have other ongoing studies and I highlight some other work here at GU ASCO by my colleagues Dr. Tagawa and first author Mike Sun, looking at the combination of pembrolizumab with J591. Now I'm making the transition from Phase I to Phase II. And the Phase I also was in combination with ARSI, and so nice PSA responses, and an interesting signal related to toxicity and pembrolizumab, and now moving into the randomized Phase II.

Alicia Morgans: Fantastic. Well, we will continue to look for updates, and look to talk to you again in the future. Thank you so much for your time
and your expertise.

Jones Nauseef: Thank you.