Zachary Klaassen: Hello, my name is Zach Klaassen, and thank you for joining us on UroToday. This is a breaking news discussion with Doctor Neal Shore. We are going to talk about the FDA approval of darolutamide plus ADT doublet therapy for metastatic hormone-sensitive prostate cancer. Just came down from the FDA. I'm excited to have Neal join us. Neal, thanks for joining us on short notice. As always, breaking news—we don't plan it. We just react to it.

Neal Shore: Well, great to be with you, Zach. And this is breaking news, so it's fun to talk about it for sure.

Zachary Klaassen: Absolutely. I know you and I have talked about ARANOTE quite a bit on UroToday. I think the goal here is really just to bring to light the results. And we've got some new results that were just presented at ASCO, too. But really, to talk about what this means to our patients for us, and maybe a couple of key patients that we may use this for.

So again, as mentioned, June 3, 2025, FDA approved darolutamide for metastatic castration-resistant prostate cancer. This is a Bayer trial, as you can see there in the bottom right as well. And if we just look at the the ARANOTE Trial Design, this was presented initially by Fred Saad, ESMO 2024.

It's a global randomized, double-blind, XUS, placebo-controlled phase III study. Six hundred sixty-nine patients metastatic hormone-sensitive prostate cancer. You can see the stratifications in the bottom left at 2 to 1 randomization to darolutamide 600 milligrams BID plus ADT versus placebo plus ADT.

The key primary endpoint here was rPFS, and the secondary endpoint was overall survival. And we can see here that we have OS already in ARASENS, so this was designed to accrue quickly with an rPFS benefit. So, Neal, I'd love for you to walk us through some of these key results before our discussion at the end.

Neal Shore: Yeah, very happy to do that. So here's the Kaplan-Meier. And this is from ARANOTE. And as you said, it was XUS for an equipoise purpose. But it enrolled remarkably quickly. Very high percentage of Black patients coming from Brazil, which I think was fantastic. And a lot of Asian patients as well. So a good diverse patient population.

High volume, low volume based on conventional imaging criteria. And here's the rPFS primary endpoint, as you said. A hazard ratio of 0.54. A pretty dramatic curve separating pretty early. It speaks for itself.

And as you mentioned, ARASENS already taught us that triplet ADT daro DOCE bested ADT DOCE inclusive of an rPFS and OS benefit. And the NMCRPC ARAMIS trial also demonstrated rPFS and OS benefit.

And I think this is really important, but yet really well known to our audience. And this is—as one can look down the list here of treatment-emergent adverse events, Zach, it's so much fun to be part of a development of a therapeutic. And I've been involved with this starting back with Karim Fizazi with the early-phase ARADES and ARAFOR studies.

And that led to ARAMIS and then ARASENS and now ARANOTE. Everything begins with an A in all of the consistency. But what really appealed to me back in the early phase was that this was—in preclinical models, this drug did not cross the blood-brain barrier. And that led me to recognize that there really could be a really clean adverse-event safety profile.

And that's been borne out now in literally multiple phase III trials. And you see this here really nicely. And particularly, the minimization of cognitive impairment, as well as many of the other typical things we look at as a class.

And then, additionally, in ARANOTE, we looked at some really important secondary endpoints. Time to pain progression. You see here, hazard ratio of 0.72. So clearly, for patients, where we typically see pain progression in bone metastases, this clearly favored the combination versus the placebo arm.

And then additionally, in our next slide, we also see if we're looking at the validated FACT-P score. And this was recently. Literally 24 hours ago, that last slide and this slide were presented by Alicia Morgans on behalf of us in the ARANOTE group. And this was just presented at ASCO 2025. So the timing for the announcement, the oral podium presentation by Alicia Morgans yesterday at ASCO, I think is really fantastic.

And as you say, now having this available is a really, really nice capstone to many years of development.

Zachary Klaassen: Yeah. No, absolutely. And congratulations to you and the ARANOTE team, to the Bayer folks, all the patients, of course, that enrolled in this trial. When I look at this, I mean, we've used darolutamide in multiple disease spaces. Like you said, the non-metastatic CRPC in combination with docetaxel and ADT in metastatic hormone-sensitive. In your opinion, what's the significance of this FDA approval of the doublet for our patients at this point?

Neal Shore: Well, it's a great question. Look, it adds to this proverbial embarrassment of riches. We had LATITUDE and STAMPEDE demonstrating doublet with abiraterone acetate with prednisone. We had TITAN demonstrating doublet benefit for apalutamide.

ARCHES demonstrating doublet benefit in enzalutamide. And recently also at ASCO, some very nice five-year OS data presented by Andy Armstrong. So this adds to the treatment armamentarium.

And I think buried or subtextually within that, Zach, is the notion that there's a very, very small percentage of patients who should only be getting monotherapy ADT. This is just yet another important, great phase III study saying, look, double doublet and/or triplet is the way to go. But certainly not monotherapy ADT.

Zachary Klaassen: Yeah, absolutely. It's always important to call that out. Because even in the US, where we have this embarrassment of riches, we still have an unfortunate number of people that are still getting ADT monotherapy. So I'll flip it around a little bit. So for you and I and the listeners out there, Neal, what's the significance to us as providers of these patients?

Neal Shore: Well, honestly, I think a lot of folks were already using this combination somewhat off-label, but based upon the ARASENS data, which was a really great trial that was done looking at triplet versus doublet. The doublet being ADT and DOCE. Now ADT and DOCE by NCCN is not at the highest level of recommendation.

But look, we've come a long way from ADT docetaxel from the CHAARTED study. And I think that the significance here is that it really will help not only for folks who are already getting the ADT-daro doublet, but now from a reimbursement standpoint, which—let's face it, I mean, economic inefficiencies or inability to get things approved affects everyone globally.

So I think that the fact that this is now FDA-approved, but also will go in NCCN recommendations—this will allow for economic accessibility. And again, it's an opportunity for our colleagues to say OK, what can I offer you?

The other thing that I'm proud about this, and we wrote a paper on this a few years ago, is the drug-drug interaction. And we're actually going to revise that because the DDI (Drug-Drug Interaction) on darolutamide is really quite impressive.

Zachary Klaassen: Yeah. No, absolutely. I know exactly what paper. That was the one from ARAMIS, I believe. Correct?

Neal Shore: Yes.

Zachary Klaassen: Absolutely.

Neal Shore: We'll upgrade that. So we'll get you to be a co-author.

Zachary Klaassen: It sounds good to me. I think, just to wrap things up, Neal, I've had a couple conversations over at ASCO, and really, not throwing chemotherapy out with the bathwater because there certainly is patients that will benefit from triplet. But in your mind, who's the ideal candidate for darolutamide plus ADT doublet therapy?

Neal Shore: Well, they're everybody, frankly. I mean, low volume, high volume, chemo-eligible or not. The ARASENS and now ARANOTE—that trial and—those two trials plus the STAMPEDE trials and the PEACE-1 for abiraterone, no one else can really cite that.

But that said, I think that there really isn't a patient who has low volume, high volume, low risk, high risk who wouldn't have an appropriate shared decision-making conversation about using darolutamide.

Zachary Klaassen: Yeah, absolutely. And I think one of the trials in progress at ASCO that I was really excited about was the TRIPLESWITCH trial. And this is the trial that's looking at starting patients on doublet ADT and RPI if their PSA doesn't go to less than 0.2 at six months or 12 months—6 to 12 months, and then randomizing people to stay on that doublet versus adding darolutamide.

So depending what that trial shows, we may have some evidence to have doublet as a backbone, and then adding chemo if we need to.

Neal Shore: Yeah, I love that you brought that up, because we looked at that analysis, and I actually presented that at AUA 2025. The ultra-low sensitivity PSAs and just the less than 0.2. And essentially, with the doublet on ARANOTE, it was about 62% to 18% compared to the monotherapy.

And when you looked at the ultra-low, it was even more impressive. So I like that the trials like that. That'll continue to better inform us.

Zachary Klaassen: Absolutely. Neal, thanks again so much for joining us last minute on UroToday. Breaking news, as we call it. And any last-minute thoughts before we wrap up?

Neal Shore: I think that this is a great study, and it's testimony to so many of our wonderful sites all over the world who do these trials. We actually have a 200-patient, open-label, ADT-darolutamide for just US patients that I co-PI with Rana McKay. And it's what's called a match-adjusted independent comparison to the monotherapy ADT arm from CHAARTED.

I know that's a little bit of a mouthful, but we're looking forward to having that data. Look, I think it's great. FDA approved this ADT-daro with no US patients because of the strength of their trial development platform from ARAMIS and ARASENS. But we're looking forward to presenting the ARASEC data. I have lots of patients in that study. I just think it's great for patients. It's great for health providers.

Zachary Klaassen: Yeah. Well said, Neal. And as always, thanks for joining us on UroToday.

Neal Shore: Thank you.