Zachary Klaassen: Hi, my name is Zach Klaassen, Urologic Oncologist at Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Neal Shore, Urologist in Myrtle Beach, South Carolina. Today we're discussing one of Neal's posters at AUA 2025, looking at the ARANOTE study. Specifically, PSA is less than 0.02, and what this response to the doublet of darolutamide plus ADT had on outcomes. So Neal, thank you for joining us and sharing your expertise on UroToday.

Neal Shore: Oh, thanks so much, Zach. My pleasure.

Zachary Klaassen: So just before we get into your post-hoc analysis, Neal, I know there's been a lot of talk about PSAs and really driving that PSA down to less than 0.2. You're looking at less than 0.2 in this study. Just highlight quickly the ITT results that were presented by Dr. Fred Saad at ESMO 2024 for ARANOTE.

Neal Shore: Yeah, thank you. So ARANOTE was basically mHSPC population, low and high volume. The randomization to the well-known prescribed nmCRPC, ARAMIS, and the triplet ARASENS dose for darolutamide, 600 milligrams BID done outside the US, because really for equipoise purposes. The control arm was ADT and a placebo. This was a successful trial. Hazard ratio for RPFS, 0.54. And it was presented in the plenary presentation by Fred Saad at ESMO in Barcelona, and then at JCO publication.

So it gives us this embarrassment of riches now, so we have four doublets in mHSPC, either ABI, or ENZA, or APA, and now DARO. And what we did was we did a look back at the PSA Nadir, which I think people have clearly been able to see in the mHSPC population, really pioneering work back in the day by Maha Hussain that the Nadir really does matter. And so we looked at the percentage of patients that were 0.2 or less, and it was about a little north of 60%, a little less than 20% in the control arm, so a tripling.

And then we went back, and we looked at the ultra-low. And I don't know that all of our colleagues get the ultra-sensitive or the ultra-low PSA. I haven't routinely. I'm going to start to now, and I'll tell you why in a second. And the ultra-low was less than 0.02 as opposed to 0.2. And what we were able to see, and I think you have some of the graphs in our presentation, really nicely show that if you look at the patients who were really in that super ultra-low versus just less than 0.2 or above 0.2, the time to the next neoplastic therapy, the time to PSA progression or PSA-PFS, and the time to castration resistance dramatically favors the really low, less than 0.02.

It favors the 0.2, but even more dramatically the less than 0.02, so the profundity of that Nadir is extremely prognostic, and it's predictive too of the therapeutic response. So I think that I'm going to start getting this early, because I think I want to know if the patient's 0.2 versus 0.02, because then I'll have an ability to say to the patient, because patients always say, "Well, how long am I going to be on this?"

Well, assuming that there's no tolerability challenge, now there's a way to say, "Well, I can pretty much tell you you're doing so well, the data suggests this is a great marker for letting me forecast how long you'll be able to stay on therapy before we'd have to switch to something else."

Zachary Klaassen: Yeah, it's interesting, I think when patients come in with PSAs of 50 or 60, and they think, OK. They can see the PSA. They understand we want this to come down. They see it on their app. You talk to them about it. We used to think, OK, we got to get less than 0.2. We're not just going from 50 to 1 or 0.5. We got to get it less than 0.2, but this data is really compelling. I mean, comparing head to head in this trial, less than 0.02 to 0.2 makes a huge difference. I think you've mentioned it already, but how do you now re-counsel these patients or change your pre-treatment discussion?

Neal Shore: To your point, I mean, sometimes these patients who come in with a real high PSA and you see them nadir to, I don't know, 2.5, maybe they were 150, and they're like "Oh, that's great." And I'm like, "Well, it's really not as good as I would have liked." I would have liked it to be less than 0.2. And ideally, I would have liked it to be less than 0.02. And that helps me think about how often maybe I'll need to follow those patients up, so there's always that sort of art of medicine.

Do you see them back in 8 weeks, 12 weeks, 16 weeks? And so I think this is a really helpful thing. I don't know that I need to get an ultra-low at each time. It's a little bit more expensive in the lab we use. We do PSA in-house. I have to send out the ultra-lows. But I think I'm going to start getting them more frequently to see initial response to therapy, because I can then counsel patients on how long I think they're going to be responding favorably. And look, one of the best parts about it is the delay in the development of resistance.

A big question patients always ask is, "Well, how long am I going to be on this therapy?" And if I could tell them, "Well, I think you have a great chance to be on for, well, north of 12 months, maybe even north of 18 months to two years." I think you can see a smile break out on patients' faces. So I think this data has been looked at with some of the other ARPIs as well, so I think it is very consistent. The Nadir does really matter in these mHSPC patients.

Zachary Klaassen: I'm glad you mentioned the time to CRPC, because the patients from a metric they see PSAs, but they also know time to CRPC means to them time to a new therapy. Nobody wants the new therapy. They like to stay on what they're on. They get used to, they're comfortable with the side effect profile, so to show that this also makes a difference in that important subgroup, I think, is really important as well. Do you use time to CRPC as something in the initial discussion?

Neal Shore: I don't really frame it so much like that, but I do frame it and I say, "Look, unfortunately, you have advanced, technically not curable disease. We're looking to create as deeper remission as possible. At some point, the cell lines will develop resistance, and frankly, resistance is the bane of our world for all solid tumors and even marrow-based tumors." And patients understand resistance that cell lines start to just find other fuel sources. And I'd like to be able to tell them, but this PSA is not a perfect biomarker.

It's a very good biomarker, clearly in metastatic prostate cancer. Sometimes it's not ideal for certain types of therapies, but for many it is, particularly with ARPIs. And I can tell them, "Look, this is really an optimistic finding to know that you're going to have a good durable response. It's not going to be forever, and we have a lot of other things in our toolbox. And I think I try to explain it in such a way that it provides them with optimism and hope that even though technically they have a terminal disease, we want to keep it in quiescence for as long as possible."

Zachary Klaassen: It's well said. Neal, any final remarks? Great data from ARANOTE. Congratulations on this analysis. Any final thoughts?

Neal Shore: No. We're looking forward to getting it into the guidelines and getting it for FDA approval. I think I'd be shocked if it wasn't. I think there's a lot of really interesting data coming forward. We have this great luxury in the US to have all these different ARPIs, and I encourage my colleagues to get comfortable in using all of them. We have a 200-patient open-label trial that will hopefully read out before the end of the year, called the ARICEPT trial, which mirrors the ARANOTE, except in our control arm is the monotherapy ADT arm from CHAARTED, which the FDA allowed us to use as a match-adjusted independent comparator arm, or what some people call M-A-I-C or MAIC.

So I'm really excited for us to be able to present that data, hopefully before the end of the year.

Zachary Klaassen: Outstanding. We'll look forward to it, and I guarantee you we'll have you on to discuss it. Neal, thanks as always for your time.

Neal Shore: All right, man. Thanks.