Scott Tagawa: Happy to be here.
Alicia Morgans: Wonderful. So Scott, you were obviously very involved in the trial. Can you tell me a little bit about how you think about potentially integrating something like lutetium-177-PSMA-617 into that early metastatic setting where patients have this hormone-sensitive or APMN or S disease?
Scott Tagawa: So very brief background that we know that this approach targeting PSMA with a beta-emitting piece of radiation or radioactive particle works when we see metastatic disease following resistance to a couple lines of hormonal therapy. Could be dual upfront or sequential lines of hormone therapy with or without prior chemotherapy. So it made sense to move it forward to a setting where there's less likely to be PSMA-low disease, AR/PSMA-low disease after a lot of hormone therapy, and where there's less likely to be radiation resistance.
So we wanted to test this upfront. Kind of a one- or two-sentence approach in terms of the inclusion criteria was metastatic disease on CT or bone scan. Organ function that's good enough to go into a clinical trial as a relevant for lutetium PSMA-617 include blood counts as well as kidney and liver function.
They had PSMA-positive disease on PETs, which we can get back into. And then we're appropriate to, number one, receive the backbone of ADT plus ARPI and not "need chemotherapy," which is a separate question that hopefully we'll be able to answer in the relatively near future. But that's kind of on the high level. And a benefit in terms of the primary endpoint of radiographic progression-free survival.
Alicia Morgans: Okay. So at this point, at least, this is not an approved agent for us to use. This was a positive study. It prolonged radiographic progression-free survival. Seemed to do this across different subgroups of patients, including patients with high-volume disease, low-volume disease, de novo, recurrent. It was quite beneficial, or so it seemed in those analyses.
Should this drug be approved in the setting, which patients in your clinic would get lutetium PSMA-617?
Scott Tagawa: So it is, I think, nice that when we look at the forest plot for the primary endpoint and for some additional endpoints that was presented at ASCO 2026 by Fred Saad, essentially every single subgroup looks to benefit over just the ADT plus ARPI. So I think that's nice. It also leaves the dilemma of who to treat. So one way that I think about this is in the context of all the other therapies, plus actually may probably be most importantly, the patient. That includes comorbidities, performance status, and what they want.
If we think about the other triplet therapies, so we know that the addition of a PARP inhibitor in molecular selected individuals also benefits in terms of rPFS. We know with protein PTEN loss, there's a benefit with AKT inhibition, and those are both now approved therapies, at least one PARP inhibitor and one AKT inhibitor so far. Those patients were likely included in PSMAddition just because it was a broad patient population. But since we know that those work, it would make sense to me, particularly when we're thinking about something like BRCA2 that happens to also be PSMA positive. I'm going to discuss all the therapies, but I'm likely, if I'm thinking about intensifying, going to look at a PARP inhibitor. So that's kind of a backwards way of doing it.
We don't know if chemotherapy is very helpful or not, and we have an ongoing clinical trial. Everyone please enroll in that clinical trial. But when someone might have AR less driven disease, PSMA-low disease, that's what I'm thinking. Okay, maybe that's a patient that's right for chemotherapy, particularly with, let's say, visceral liver metastasis. I don't know that that is better, but anyway, this is kind of backing in.
Is it all the rest for lutetium PSMA-617? Well, not necessarily. I think that there are some patients with comorbidities walking in the door that would make them higher risk for toxicity, such as preexisting renal dysfunction, things like that. So I think that's another thing. And then clearly there's individuality with the patients. There needs to be some at least periods of isolation away from everyone, at least for... I think we're close enough that I could be treated and we can talk like this for a while, but probably not for a long time.
And then infants and pregnant women probably will want to be a little bit safer. Incontinence, we want to deal with. So I think there are other issues that are a little bit unique to this type of therapy that will, in every setting, that warrant additional discussion in this particular setting.
One of the things that we don't know about this drug in really any setting is what's the right regimen? But besides that, how many cycles should we give? I think that is especially important in this particular setting. So, sorry to keep talking, but I think some people are really excited about low-volume disease. And when I'm thinking about low-volume disease, well, can I give double hormone therapy some amount of lutetium PSMA-617 and potentially pause everything?
That's in my mind. We know that A-DREAM was presented by Atish Choudhury and that didn't include this therapy, but maybe we can even have more patients that we can pause therapy that is not proven, but that is something that's in the back of my mind.
And then for high-volume disease, especially how they say high-volume de novo disease where we think that chemotherapy has the best benefit and there's some interesting biomarkers that will come out that are being validated, but not everyone wants chemotherapy or is a good chemotherapy candidate. And this is a way to be able to have an additional agent that we know can work in that subset as well.
So those are kind of the different ends of the spectrum. It's nice to know that all the different age groups look like they benefited. And this is a treatment that, unlike the other ones, was tested with essentially all the ARPIs, five different ARPIs. So this is not tied to one specific ARPI.
Alicia Morgans: Agreed. That's extremely helpful. And as I think about it, and you've nicely laid out which patients maybe yes, which ones no, you mentioned one thing and I'd love to hear if you have more insights on this. PSMA PET uptake. We've heard a lot about SUV mean different settings where this may be something that could be perhaps predictive of benefit. I have not seen that kind of information in this earlier state of metastatic disease. And there was some suggestion, at least in the PLUDO trial, which was not in this particular setting, but it was an assessment versus docetaxel that SUV mean didn't necessarily fall out as predictive in that setting. It was really more prognostic.
Is this something that you imagine either SUV mean or some other PSMA PET characteristic that might ultimately also help us with this decision making? Or is this something that is a bit less reliable?
Scott Tagawa: I don't know, is the quick answer. So I'll tell you what I do know that this trial required a very specific tracer. So the patients had to sign consent first before they got the tracer, even if they had PSMA PET before. And the majority, about four in five, had prior exposure to ADT and ARPI up to 45 days prior to signing consent. That is, I would say, not the typical, at least in most centers in the real-world community, maybe a little bit different, but many of us are identifying metastatic disease on PSMA PET first.
So that's a little bit of different issue where there can be significant response after weeks of AR-targeted therapy. And then we don't really see PSMA there because of the low volume, because the whole tumor has shrank a lot. So anyway, that's something that we don't really know when the analysis comes out for PSMA PET.
The other is that the inclusion criteria for a positive PSMA PET were different than VISION and PSMAfore in virtually every single other trial because it was with combination therapy that we knew worked. So it was a relatively low bar. I am, like you, very interested in seeing the PET analysis despite that. My supposition is that when we're using a single agent, I think particularly when there's other choices, but using a single agent, that's when the PSMA PET is probably the most important. I think it is important in all settings, but maybe a little less important when we're using a combination.
Alicia Morgans: Okay. Well, that is fair. So just final words then, who is the patient? If you could sum it up in 30 seconds or less, who are the patients for PSMAddition strategy?
Scott Tagawa: So someone that is healthy enough that wants to have intensification beyond the standard ADT ARPI doublet, and is right in terms of organ function as well as the social situation and family situation for lutetium PSMA-617. So that's the answer to that. I think in all situations we should be mindful about how much we should give and monitoring in between. I suspect that these are the patients that are most likely to have a complete response much earlier than six cycles.
Alicia Morgans: Well, that's definitely encouraging. And I really do look forward to seeing more data on PSMA PET. I would love to see a strategy that's more adaptive and potentially get more patients onto this intermittent approach should that be an option for us in the future.
But thank you for sharing your thoughts on this today and helping us understand who might be eligible when this approval, should it come through, is available to us. Thank you so much for your time.
Scott Tagawa: Thank you very much.