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Zachary Klaassen: Hi, my name is Zach Klaassen, a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Gordon Brown, who is a urologic oncologist and director of Advanced Therapeutics at New Jersey Urology South, who's going to be discussing a case around the ARANOTE study, which recently had FDA approval, was presented at ESMO 2024 by Dr. Fred Saad.

Gordon, thanks for joining us on UroToday.

Gordon Brown: Zach, it's my pleasure, and thanks so much for having me. So we're just going to kind of jump into the case here and kind of walk through some of the pertinent clinical highlights and data points which are going to be germane to the audience. Okay?

Really exciting data. Nice trial presented by Dr. Saad. Recent FDA approval. So I think really important topical discussions that we'll have here around a patient population that we're really seeing with increasing frequency within our advanced prostate cancer clinics nowadays.

So this gentleman is a 64-year-old, very active, physically fit male. Presents for evaluation to his urologist after referral from his primary care physician for really lower urinary tract symptoms: urge, frequency. And really upon evaluation has a remarkably elevated serum PSA value. By physical history and social history, he is a very active, for the most part, fit man, travels, engaged both athletically as well as an active caregiver for his aging parents. He is an executive, so he works constantly, and is extremely active both in his business as well as in his community. For the most part for a 64-year-old, has comorbid medical conditions which we would expect, some underlying hypertension, well-controlled hyperlipidemia and type 2 diabetes.

So with a PSA of 97, obviously that patient's going to undergo further evaluation for concerns around prostate cancer. He has a strong family history of the disease in both his father and his uncle. Undergoes biopsy of his prostate and unfortunately found to have high risk of prostate cancer with grade group four and five disease at the time of biopsy. Is staged appropriately with PSMA PET, which really I think most of us are going to obviously use first-line here when available, from an insurance perspective.

Traditional scans really certainly in this patient wouldn't have much of a role, I don't think. Nonetheless, unfortunately he's found to have evidence of bony involvement with three bony sites and retroperitoneal adenopathy, which are PSMA PET avid. He's highly performing, functional, ECOG zero and he does have evaluation for germline somatic multi-gene testing, which is all negative. So this really is kind of the classic patient presenting who has been previously undiagnosed with lower tract symptoms, markedly elevated serum PSA, newly diagnosed, de novo synchronous metastatic hormone-sensitive prostate cancer. Unfortunately, like we said, this is a little bit more of a common scenario than we've seen historically and a lot of the confusion around PSA screening still persists despite data for the need for continual screening of this patient population.

So he comes in and this is really that patient that was studied in the ARANOTE trial, right? So the ARANOTE trial itself was a global phase three placebo-controlled trial, really looked at all ex-US patients. 669 patients, all had hormone-sensitive metastatic disease, performance status less than or equal to two. They were stratified two to one to go on to DARA plus ADT versus placebo plus ADT. Primary endpoint of the trial itself was radiographic progression-free survival by blinded internal central review as well as some really important secondary endpoints, including overall survival, the time at initiation of subsequent neoplastic therapies, PSA progression and development of mCRPC, the lethal phenotype of this disease process.

So when we kind of walk through this, I think stepping back and looking at the trial design, ex-US I think is a little bit important to kind of highlight. Nice very diverse patient population, right? We had roughly about 30% of these patients from Latin America, just over 30% of these patients from Asia, a high percentage of Black patients in this trial. So really when we look at these trials, we want to make sure that the patient populations are going to be representative and therefore translatable to some of the patients we're seeing within our clinic. And certainly in the greater Philadelphia area this is a very, I think, translatable trial for us in terms of the patients that are represented in this patient population studied on ARANOTE.

So with that, further digging down into some of the demographics, the serum PSAs were a little bit higher than some of the other trials. 21 at trial entry. Not surprisingly, the vast majority of these patients had high-volume de novo disease at the time of presentation. Okay? And this patient necessarily isn't classic high-volume, but he's somebody that certainly has de novo hormone-sensitive metastatic prostate cancer.

And when we look at some of his initial treatment paradigm, he was started on a GnRH antagonist and then on to Darolutamide, 300 milligrams, pardon me, 600 milligrams twice a day and then continued on ADT therapy and scheduled with a follow-up physical examination, PSA assessment. I usually see these patients usually at one month to assess toxicity, initial PSA response, and then subsequently at three months if they're otherwise stable. And he ends up having a pretty robust PSA response at three months down to 1.1 from 97. And then has a continuous follow-up visit with his PSA less than 0.1.

We will kind of dig down a little bit into this as we go along. But looking at, obviously we know that the PSA responses in this patient population are going to be predictive a little bit of outcome here and we'll talk about that in subsequent slides. But first kind of focusing on the primary outcome of the ARANOTE trial itself, the rPFS responses, those folks who had Darolutamide plus ADT had improvements in rPFS and a reduction in risk of radiographic progression or death by 46% compared to the placebo group. So very robust response, I think very reasonable endpoint. And understand this is the way this trial was designed, right? This trial was designed to assess rPFS as a primary endpoint.

Furthermore, when we look at toxicity and CYP profile, we want to make sure these patients are able to tolerate treatment and stay on therapy. Treatment-emergent adverse events were lower in the Daro arm, leading to discontinuation, when compared to the placebo arm, speaking to tolerability of therapy itself.

So here we have a patient who's had newly diagnosed hormone-sensitive metastatic disease. He's highly functioning, active, working, taking care of his aging parents, has some comorbid medical conditions, but really wants to improve his outcomes from his life-threatening prostate cancer, but also wants to do so while maintaining his quality of life along the way. I think the data we're going to see will support the ARANOTE patient along this treatment paradigm.

So looking further at some of the secondary endpoints, we see strong correlations with delay in times of development of mCRPC, delay to pain progression or development of pain and delay in PSA progression in the active therapy compared to the placebo arms in the ARANOTE trial. All again supporting the use of this therapy upfront in this patient population. And furthermore, when stratified by PSA response, we see a robust improvement in rate of progression-free survival in those patients who get to a PSA less than 0.2 compared to those who do not get to a PSA of 0.2 or less.

This is kind of a corollary. Some of the work by Maha Hussain and others have highlighted this as a surrogate endpoint for outcome, I would say, and almost as a surrogate marker of response in this patient population. And this is consistently demonstrated in the ARANOTE trial.

So Dr. Shore presented some data at the AUA in 2025 assessing ultra-sensitive PSA responses where we get a PSA less than 0.02. He assessed the response based on entry PSA, whether it was less than 4.1, between 4.1 and 21 or above 21 at the time of therapy initiation. And he looked at this at 24, 36, 48 weeks and at any time following initiation of therapy. And what he found was that those patients who received Darolutamide plus ADT were much more likely to have a profound PSA response than those patients who did not. And that PSA response correlated with significant improvements or likelihood of delay of mCRPC PSA progression as well as times of development of pain in this patient population. Again, really kind of highlighting the importance of an ultra-sensitive PSA, maybe adding a little change in the paradigm for this group of folks in terms of how we're managing and following them over time.

And as we alluded to earlier, the health-related quality of life aspect of this patient population is going to be extremely important, especially in those younger, physically fit, active folks who are engaged in their families and their work lives. We really want to make sure that we're able to confidently give them some conversation around the impact of these therapies from a quality of life perspective. Dr. Morgan presented this data at GU ASCO in 2025 and really highlighted the health-related quality of life outcomes associated with the ARANOTE trial.

Obviously these patients are going to be focused on survival, but they're also going to be focused on maintaining their quality of life, looking at their PSA responses and making sure that they're going to maintain their functional independence and delaying onset of pain.

So when we look at the health-related quality of life, specifically the delay in time to pain progression as well as the FACT-P outcomes from ARANOTE, we see that there's a significant delay in the time to development of pain in the patients receiving active therapy compared to placebo, based on Dr. Morgan's presentation. And furthermore, we see that when we look at the time to deterioration of the FACT-P total scores, there's a significant delay in time to deterioration of the FACT-P total score in the active therapy patient compared to the placebo patient population. Again, suggesting we're seeing not only improvements in rPFS, but we're seeing maintenance of health-related quality of life. This is further supported by a fewer number of patients discontinuing therapy based on treatment-emergent adverse events in the active therapy compared to the placebo arm, which is really remarkable if you think about it in this patient population.

Furthermore, I think one of the things that should be highlighted about our presentation was that fatigue, right, now fatigue in this patient population is ubiquitous. Anybody that's treated an advanced prostate cancer patient really understands that. And that tends to be the bane of both the provider's existence as well as the patient's existence getting through treatment. And so with that, when I looked at fatigue independently, fatigue was actually reported to be lower in the combination therapy group compared to the ADT plus placebo group, which I think should really be highlighted. Because again, any of us who have taken care of this, that's a significant quality of life detriment to this group of folks who are going through treatment for their hormone-sensitive metastatic disease.

So really in summary, we presented a patient who has hormone-sensitive synchronous de novo metastatic prostate cancer. He was initiated on Darolutamide plus a GnRH antagonist, continued on to ADT plus Darolutamide, did well, had a robust PSA response, and he's consistent with somebody that we would expect to have improvements in rPFS and some of the key secondary endpoints that we saw in the ARANOTE trial design.

He's a very active, engaged patient, so we want to make sure that our serious adverse event signals and tolerability are there for him. And really that now we can better, I think, counsel him potentially about the impact of his PSA response on his outcomes and potentially have a little bit more robust conversation around that with him in follow-up.

Zachary Klaassen: Gordon, great presentation. So many awesome points to hit on. I think you really laid out nicely this active patient who wants good cancer control but also wants to continue with his travel and his work, and the quality of life data from ARANOTE really plays out with that.

I think the highlights of the PSA response are really important because when we counsel these patients, that becomes part of our discussion. Maybe just lay out for our listeners how you counsel them maybe at the initial visit or more importantly at that one- and three-month visit based on what their PSA is doing.

Gordon Brown: Yeah. I think, Zach, it's really interesting that this is really all based on Dr. Hussain's work, right? That she kind of came through over a decade ago now with this concept of kind of robust PSA responses and tracking outcomes correlated to those PSA responses in this patient population. We've seen this pulled through conceptually in multiple trials, in subset analyses since that time. And the consistency I think helps us have conversations around risk, right? And helps us have conversations around need for subsequent therapy and timing potentially of that and maybe to some degree serve as a marker. Right? We're all looking for a marker of response in this patient population. They're, I think, reasonably anxious about their diagnosis and they want to get some security that, or some sense that they're going to be one potentially of those super responders or those folks that we're going to be less worried about acutely requiring subsequent therapeutic intervention or the need to pivot onto the second line of treatment.

So for me, I present it just like that. I say, look it, we have some really good compelling data in multiple settings, which suggests that those patients who have a robust PSA response will continue to do well for a longer period of time and we may be able to modify your surveillance appropriately. Right? And that has impacts on their non-clinical aspect of their life. Having to have less doctor's visits, having to come back and forth less often in those patients who achieve the PSA thresholds that we desire, I think is a win for our patient population.

So I let them know the data, I let them know that our goal is to get them as low as possible, and I let them know that that may have an impact on our ability to surveil them and their frequency of surveillance long term. I, generally speaking, don't go longer than three months in this patient population just for a check-in. But in the patient who doesn't respond, I certainly would go shorter than three months in some cases.

Zachary Klaassen: When we pivot to what's coming down the road, I think this PSA response is really important and almost to a credit to the Hussain data as well as all these trials. The TRIPLE-SWITCH trial that's ongoing right now is going to be really important because if you don't hit a PSA less than 0.2, then you may be randomized to Darolutamide versus continuation therapy. So I think we're just continuing to evolve with that PSA of less than 0.2 or even less than 0.02 as you mentioned with Dr. Shore.

Gordon Brown: Yeah, so I think a couple things. So the concepts of intensification and de-intensification are ever-present in our minds, right? And we want to try to self-select appropriately those folks, to your point, who are going to further intensify, right, and/or modify therapy. And having a metric that we can use and has been validated in multiple clinical settings, I think is really valuable for us as providers. One.
Two, in looking at Dr. Shore's data, maybe I think it's probably time we start ordering ultra-sensitive PSAs to follow these patients because, to be frank, I haven't been. And I think that that's going to be a little bit of a paradigm shift for me and my clinic following this data is that we should probably routinely look at that, certainly in this patient group to try to identify those robust long-term responders.

Zachary Klaassen: Absolutely. Final question. So as we mentioned at the top FDA approval for the doublet therapy in June 3, 2025. As you've seen in your practice since then, or maybe importantly as we move to the next six to 12 months, how has this shifted? How has this sort of opened the denominator up for having Darolutamide plus ADT as a bit of a backbone for these patients?

Gordon Brown: Yeah, Zach, well, thanks for the question. I think it really just adds to our armamentarium. We've got LATITUDE and STAMPEDE with Abi, right? We have ARCHES and ENZAMET with Enzalutamide, we have TITAN with Apalutamide. Now we have ARANOTE and Daro. And so we have four approved therapies in this patient population. To me, I think some of the quality of life data and the rPFS data are really compelling. And so I think it just adds a richness to the really kind of substantial armamentarium we already have. One.

Two, there are patients who from a quality of life perspective or from a drug-drug interaction perspective, may have had challenges with other therapies and this may open up some new options for that patient population. And I think it also allows us to have conversations around this as a doublet or as a triplet depending on the patient's clinical scenario and our perceived risk for that patient.

If we look at high- versus low-volume disease, that low-volume patient was really a more robust responder or more consistent with what we presented. But in that higher-volume patient, maybe that is better suited to more of an ARASENS type of treatment paradigm where we intensify treatment up front with systemic chemotherapy. So I think that to me, having this there kind of adds to the richness and robustness of our treatment armamentarium and really gives a kind of full complement of therapies that are now available to this patient population.

So really exciting and really robust data and really exciting for our patients to improve their outcomes from this life-threatening disease and delay the onset of really the lethal phenotype, castration-resistant metastatic prostate cancer.

Zachary Klaassen: Yeah, absolutely. I like your point. We're not going to throw the baby out with the bathwater. There are some patients that will still benefit from triplets. So great point.

Gordon Brown: Yeah, absolutely.

Zachary Klaassen: Gordon, thanks very much for joining us on UroToday, taking time out of your very busy schedule to educate our listeners. Thank you.

Gordon Brown: Zach, it's my pleasure. Thanks so much for having me. It was a pleasure being here.