Fred Saad: Thanks for having me.
Neeraj Agarwal: In this 2026 annual American Urology Association meeting, you're presenting the data from the PSMAddition trial, the phase three trial of Lutetium therapy, Lutetium-177-PSMA-617, a mouthful, we call it Lutetium. Fred, for those who may not be familiar with the trial, could you please tell us more about the design of the trial and the setting first?
Fred Saad: Okay. So very simply, this is an effort to improve on the best standard of care we now have for mHSPC, which is basically ADT plus an ARPI. I think that's well established that that should be the first-line treatment. Now improving on that is taking a lot of effort because that's a really high bar. So what the trial did was take over 1,200 patients randomized to ADT, ARPI plus or minus Lutetium to see if we could improve the outcome. And the primary outcome from the study was rPFS, which was met and this was presented a few months ago at ESMO with a 28% reduction in the risk of radiographic progression in patients who got Lutetium added to ADT and ARPI.
Neeraj Agarwal: To be more specific, there was a significant, statistically significant improvement in radiographic progression-free survival. Trial met the primary endpoint and we are currently awaiting approval of Lutetium for our patients with metastatic hormone-sensitive prostate cancer. With this background in the AUA meeting, please tell us more about the endpoints you're presenting here.
Fred Saad: The rPFS endpoint was met. Overall survival is still maturing because you have to remember these patients were allowed to cross over when they progressed to CRPC post-ARPI. But here what we're looking at is some early signal of whether or not we're able to improve on ADT and ARPI. And the results are really quite interesting. Number one, ADT, ARPI, over 98% of patients get a PSA response, both arms. Now, when we look at 90% reduction, we're starting to see that we're getting more 90% and greater reductions by adding Lutetium over ADT and ARPI. But you and I know that's not enough to say that we're really successful. We're looking now at below 0.2, which we consider a complete response. And here we're seeing that 74% of patients with ADT, ARPI reach that below 0.2 level, but that goes up to 87% by adding Lutetium. That's some of the best data I've seen so far, especially considering almost 70% were high-volume patients.
And then looking at the below 0.02, ADT, ARPI does a really good job with over 45% of patients reaching below 0.02 and that also increases to about 57% with the addition of Lutetium. So really there's a signal that we're actually getting improved cancer control and the time to PSA progression was also improved with a reduction in the risk of progression by 58%. So really signal that we're doing something that really is changing the biology of the disease by adding Lutetium.
Neeraj Agarwal: Absolutely. And just to take a step back from multiple trials, including you have presented from the most recently Darolutamide trials, PSA undetectable rates less than 0.2 after six months to 12 months of studying androgen deprivation therapy plus ARPI is associated with overall survival.
Fred Saad: Absolutely. Absolutely.
Neeraj Agarwal: And all other endpoints pretty much, radiographic progression-free survival, castration-resistant, delaying castration resistance, delaying pretty much all complications of metastatic prostate cancer. And it is so remarkable to see almost 90%. If I heard it was 87%-
Fred Saad: Right. Exactly.
Neeraj Agarwal: If I heard it correctly. So by adding Lutetium therapy to ADT plus ARPI, you are able to achieve that PSA undetectable response in about 87%, roughly 90% of patients.
Fred Saad: Exactly. And this is what we're all aiming for because we know if we don't get to 0.2, when we get to below 0.2, we do really well. But if you don't get, these patients progress to CRPC, progress radiologically and die much earlier. So this is a first step and we have to continue working. Obviously, I mean, you're leading the Talazoparib effort. And for patients that have mutations, that is probably going to be the approach. So we have to start individualizing patients based on their biology. So if PSMA-positive patients, mHSPC, this is, I hope, will become a therapeutic option for patients in the future to try to add to what we're doing.
Neeraj Agarwal: And I see another attractive part of this strategy. If in patients who achieve a PSA level of less than 0.2 nanogram per mil, they can potentially be candidates for intermittent therapy. Thereby allowing them to take breaks from these therapies which have a lot of side effects long term, cardiovascular side effects, bone health gets affected. So potentially achieving a PSA level of less than 0.2 is not only a number for me, is not only a surrogate for overall survival for me, it is a tool for me to allow intermittent therapy for those patients who really need it.
Fred Saad: And I think that's where the field has to go. We have to stop condemning patients to long-term ADT because they were found to be metastatic. That is unacceptable. Many other tumors metastatic, you hit them really hard and then you stop and you give them a break. We've been doing this for years for testes cancer. We need to get that mindset, whether it's double it, triple it, quadruple it, quintuple it, we need to find the right approach for the right patient so that we can take them off therapy because keeping a man castrate for the rest of their life is really not acceptable.
Neeraj Agarwal: And key maybe to hit the prostate cancer hard early on-
Fred Saad: Exactly.
Neeraj Agarwal: To achieve that optimal control and then take a break.
Fred Saad: Yeah. We have to start using that four-letter word that we're scared to use, cure. I think we can start thinking that we can cure some of these patients.
Neeraj Agarwal: Love it. Well, great news for our patients. And Fred, thank you so much for taking the time from your busy schedule to talk about these wonderful data.
Fred Saad: Always a pleasure. Thanks for the opportunity.