Fred Saad: Thank you.
Oliver Sartor: Fred, you've got a couple presentations here and now we're going to pivot over to one called PSMAddition. Now, you and I know what that is, but let's talk a little bit about what PSMAddition is and then we'll pivot over to what you're presenting here this time, but a little background on PSMAddition.
Fred Saad: Yeah. So PSMAddition, and you know this very well, you're the leader of this study, it really tried to build on what we think is the best standard of care for most patients with metastatic hormone-sensitive, which is ADT and ARPI. I mean, we were a little bit criticized in ARASENS because the control arm was ADT and docetaxel, which is no longer what we would consider the standard of care. So this is a really high bar. Can we do better than ADT and ARPI in the majority of patients with mHSPC that don't harbor, let's say, a BRCA mutation or something like that?
So what was done here was add lutetium, that we all use now for very advanced mCRPC, at the time of mHSPC. So the patients were randomized one-to-one, to ADT+ARPI, ADT+ARPI plus lutetium to look at ... the primary endpoint was rPFS, and this was already reported a few months ago and is going to come out very soon. That clearly met its endpoint with a 28% reduction in the risk of radiographic progression-free survival.
Overall survival is trending in the right direction, still too early, because these patients are doing extremely well even in the control arm with ADT and ARPI. So you don't expect that much difference in survival at two, three years. We have to wait a little bit longer. So that's basically the design of the study. Met its primary endpoint. Very little difference in terms of health-related quality of life by adding lutetium. So this was really reassuring. So now these are analyses looking at whether volume makes a difference in the benefit of lutetium.
Oliver Sartor: We'll come back with one more clarification. You mentioned the ARPI. So which ARPIs were available in the trial and people want to know ... you know, this is my favorite, that's my favorite. Which ones were used?
Fred Saad: This is, I think, one of the most beautiful parts of the study. It was left up to the investigator to decide which ARPI. So you're not handcuffed to an ARPI because the belief was that any ARPI can be combined with lutetium as opposed to the PARP inhibitors that we would be concerned of just switching ARPIs as a class effect. And so that's the beauty of the study. Patients were allowed to use abiraterone, enzalutamide, apalutamide, or more recently darolutamide in the study. And that really makes it as real-world as possible because in the real world, you can't dictate which ARPI you want to use. It has to depend on patient preference and investigator ease of use.
Oliver Sartor: Okay. So as you mentioned, rPFS been announced positive, presented at ESMO last year, publication coming out very shortly. But your presentation here at ASCO 2026 drilled down into some other elements. Let's go about this new presentation, help people understand exactly what you're presenting here for the first time.
Fred Saad: Right. So obviously one of the questions is do patients with low-volume or high-volume benefit from the addition of lutetium? Do patients that are de novo metastatic or asynchronous or metachronous metastatic benefit from the addition of lutetium?
And what was reassuring in a nutshell is that we saw benefit across the board in terms of rPFS, the primary endpoint, was clearly favoring the addition of lutetium. The hazard ratio of 0.72 in the overall population is almost identical in each of the four subgroups, whether it's high volume, low volume, de novo or metachronous. So that was quite reassuring. Obviously, the event rates in the low volume patients is smaller, but the hazard ratio remains very favorably in favor of adding lutetium.
Then the other endpoints, time to PSA progression, again, very similar to what we see in the overall population. And especially interesting, the patients who had the best time to PSA progression were the low volume patients. This makes some biological sense. These are patients that are probably less likely to have hormone-insensitive clones. And so hitting them hard ... hitting the adrenoceptor as hard as possible. And I think this is probably the best combination of hitting that adrenoceptor with what we have today.
And we saw that in the AUA presentation, that we're seeing almost 90% undetectable PSA rates by adding lutetium over ADT and ARPI. And I think now the story is starting to ... the pieces are coming together very nicely.
Oliver Sartor: With regard, Fred, to the 0.2 rate, which is known to be prognostic, I wonder if you to briefly cover that, which you covered in your AUA presentation.
Fred Saad: Right. So the ADT+ARPI arm did extremely well. We were up to 74% of patients getting to below 0.2 in the control arm, but that went up to 87%. It's unheard of in patients treated for mHSPC. So we're getting awfully close to this almost 90% and hopefully one day, 100% rate of getting to below 0.2, which is really prognostic and almost predictive of what's going to happen later down the road.
Oliver Sartor: I'm very pleased with that data. Now, we're going to pivot a little bit for a second because, in essence, this is still an interim analysis. We have more analyses to come. But when I saw that PSA less than 0.2 rate and knowing that that is going to be prognostic for survival, it kind of gave me a hope that this is really going to be a positive study for survival. Now, we don't have that now, but just to kind of get your take a little bit on where we are in the study and where we're going to end up with this study when we have a little more mature data.
Fred Saad: Right, right. And you and I are really interested in looking at longer follow-up to get more mature survival data, but clearly we're clearly heading in the right direction. And even looking at the 0.2 rate, we're up to 65%. It's unheard of. 65% can get to ... The ultra sensitive PSA that we use for surgery of getting to below 0.2 is 65%.
Now, I'm an optimist, but I'm also worried those 13% that don't get to ... why don't they get to below 0.2? What are their characteristics? Can we predict we might be able to do even better by doing lutetium plus something else? And I think we're going to get slowly to this kind of analysis of figuring out who these patients are that are really destined to die of the disease. I mean, if you don't get to below 0.2, your survival is quite dismal.
Oliver Sartor: Thank you very much, Fred. Another beautiful presentation. And thank you for your contributions to the field, and let's just keep going and make patient care better.
Fred Saad: Absolutely. Thanks.