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Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined by Dr. Fred Saad, who's a urologic oncologist at the University of Montreal. Fred, thanks so much for joining UroToday again.

Fred Saad: It's always a pleasure to talk to you, Zach.

Zachary Klaassen: So we are talking about great data from ESMO 2024 and certainly ARANOTE fits into this. So why don't you walk us through the background of ARANOTE and some of the key exciting findings from this study.

Fred Saad: So thanks for the opportunity to discuss Darolutamide and ADT for metastatic hormone-sensitive prostate cancer. These are some of the results from the ARANOTE phase 3 study that I presented at ESMO. So these are my disclosures. I've worked with many companies that deal with prostate cancer, obviously, and a lot of research. So ARANOTE is a global randomized phase 3 study, placebo-controlled, double-blind, that was conducted in 669 patients, all with metastatic hormone-sensitive prostate cancer. We randomized patients two to one between Darolutamide 600 milligrams twice a day versus placebo plus ADT. The primary endpoint was radiographic progression-free survival by central blinded review with multiple secondary endpoints, obviously including overall survival.

Baseline demographics were quite balanced between both groups and the uniqueness of this study is that we have a really diverse racial population. We actually had over 30% Asians and about 10% of patients of Black race, and we had de novo metastatic disease in over 70% of patients and high-volume disease also in over 70% of patients. So really quite representative of what we see in the clinic. The primary endpoint of the ARANOTE study was clearly a reduction in the risk of radiological progression by 46%. So that's a hazard ratio of 0.54 with a P-value of 0.0001. And this is with a follow-up of about two years.

Now, looking at the subgroup analysis, we see that every subgroup was benefiting and I think this is important because we didn't see any trend towards non-benefit from the use of Darolutamide plus ADT. This includes patients with high-volume disease and low-volume disease, and we see that the benefit is even more interesting in the low-volume disease, again confirming that earlier appears to be better. One of the main important points of ARANOTE was to look at the tolerability and the adverse event profile of Darolutamide in combination with ADT. Here we see that there's very little difference between Darolutamide and placebo. To our surprise and reassurance, there was actually more discontinuation due to adverse events in the placebo arm than in the Darolutamide arm.

And looking at adverse events that we know are more often related to ARPIs, again, very similar between Darolutamide and placebo. Reassuringly, one of the most common complaints is fatigue, and here we actually saw less fatigue with Darolutamide than with placebo in this trial. Looking at secondary endpoints, all secondary endpoints showed a benefit with Darolutamide over placebo. Looking at overall survival, the data is still immature. We are only at about two years of follow-up, and the study was powered for RPFS and not powered for overall survival. Now, in terms of patient-related secondary endpoints that are very important, there was a significant improvement in time to metastatic CRPC with a 60% reduction, and time to pain progression, which is clinically relevant, obviously for patients, showed a 28% reduction in the risk of pain progression.

An endpoint that we are seriously looking at in all trials is achieving this holy grail of less than 0.2 nanograms per milliliter, and here we had an over threefold increased likelihood of reaching that threshold of under 0.2 in patients on Darolutamide, with over 60%, and less than 20% achieved it with ADT alone. Time to PSA progression was reduced by 69%, with a hazard ratio of 0.31 and the confidence interval clearly below one in patients getting Darolutamide.

So in conclusion, and I just want it to be brief so we can have some more discussion, Darolutamide and ADT significantly improved RPFS in patients with metastatic hormone-sensitive prostate cancer across the board, showed benefit across all secondary endpoints, and Darolutamide had a favorable safety profile. The rates of adverse events were similar between Darolutamide and placebo, and this is important because it just confirms for the third time that the safety profile is very reassuring. I think clearly I can say that I hope Darolutamide will become a new standard of care for patients with mHSPC without the need of combining it with docetaxel. So thanks.

Zachary Klaassen: So Fred, thanks so much for sharing that data. Very exciting data from ARANOTE, and this is the best part of these discussions as we get to discuss the context. In your opinion, we had phenomenal data from ENZAMET and triplet therapy has been around for a couple of years now. How do we fit in Darolutamide plus ADT? Who should be candidates for the doublet? Who should still be candidates for the triplet therapy?

Fred Saad: Right. So I think this is an ongoing discussion and the question of ADT alone is out the window.

Zachary Klaassen: Yes.

Fred Saad: I don't think we should give any patient ADT alone. We have to justify why we don't do more.

Zachary Klaassen: Right.

Fred Saad: And I think the new ADT is ADT plus an ARPI. So that should be the new foundation. Anybody who needs ADT because they're likely to progress and die needs to have the combination of a doublet hormonally-based therapy.

Zachary Klaassen: Yeah.

Fred Saad: Now the question of when do we add docetaxel is a question that comes up all the time. Clearly, there are some patients that we are really concerned about. One extreme is patients with visceral mets, especially liver mets.

Zachary Klaassen: Right.

Fred Saad: And including widespread disease. Patients with symptomatic disease at presentation, we know that's a bad, bad thing to have.

Zachary Klaassen: Yeah.

Fred Saad: So those patients I think we seriously have to have the discussion. Even though we don't have the ultimate proof that triplet does better than doublet, I think those patients will progress quickly and will need docetaxel later. And we know that docetaxel works less effectively after you've progressed on an ARPI. So I think that discussion needs to be had with patients, and you and I agree that patients have to be central to that discussion. It really needs to be shared. They need the information.

Zachary Klaassen: Absolutely.

Fred Saad: So I would say almost all patients are okay with a doublet approach. Some would probably need a triplet approach. Now, the other extreme is patients with low-volume disease, low-risk disease, not too many metastases, no symptoms, especially metachronous metastatic disease. I think clearly there's consensus that ADT and ARPI alone is clearly adequate. At the APCCC, there was a vote of 98% that you have a doublet form of therapy in the oligometastatic state. Now the gray zone is all in between. So in patients that have not extremely high-volume disease but are very young, we'll have that discussion of triplet versus doublet.

Zachary Klaassen: Excellent. I liked your discussion on time to mCRPC. Time to mCRPC is important for patients, and when we see those curves splitting wide in the ARANOTE trial, this is an important endpoint for patients because it basically means your disease is progressing and this treatment's not working. So maybe you can put into context the importance of that secondary endpoint.

Fred Saad: What kills patients is mCRPC.

Zachary Klaassen: Right.

Fred Saad: As long as we can delay the lethal form of prostate cancer, we're doing what people in HIV research did.

Zachary Klaassen: That's right.

Fred Saad: Take the disease and make it into a chronic disease. My intent is not to cure every patient who comes in. That's unattainable.

Zachary Klaassen: Right.

Fred Saad: But what I want is to keep them in a non-lethal state. As long as they're responding and not mCRPC, I can clearly say, "You're not going to die." So this is why the mCRPC state is extremely important. It's the beginning of the end.

Zachary Klaassen: That's right.

Fred Saad: We have treatments, but we're always talking about weeks or a few months of difference when we start waiting to treat patients in the mCRPC state.

Zachary Klaassen: Yeah. And I think you gave a great presentation about the PSA decline and I know you've done a subgroup analysis of ENZAMET showing the importance of not just a reasonable response—we're trying to drive this down to zero. And we're clearly seeing this in the ARANOTE trial as well. Maybe you can just highlight again for our listeners the importance of going for the home run, getting that PSA to undetectable.

Fred Saad: Yeah. What's reassuring is this is a recurring theme.

Zachary Klaassen: Yeah.

Fred Saad: Patients who get to undetectable PSA, and for the metastatic patients, we're not going for 0.02. We're going for 0.2 because the prostate is often in place and—

Zachary Klaassen: Sure.

Fred Saad: I mean, this discussion is a little bit moot, but getting to that really is prognostic because we know that patients that reach that are going to do much better in terms of delaying mCRPC and actually improving overall survival. The big question is what do we do when they don't reach it?

Zachary Klaassen: Yeah.

Fred Saad: And that's where I think we need to be focusing on the research. So if we're not reaching it by six or nine months, should we be adding something? We need to get to that undetectable to say that we're putting them in a chronic state of the disease. It's been repeated with every trial. So this is not unique. ENZAMET was clearly very informative, but every time we look, it's a very important endpoint, even in the non-metastatic CRPC setting, hormone-sensitive setting. This is a recurring theme, and we saw it even in the recurrence in hormone-sensitive patients. This is a really important point.

Zachary Klaassen: I have one more ARANOTE question and then one more general question. The context of overall survival is important, and I think we're clearly going to have to wait for these events to accrue. When do you anticipate those results being available, and is it important for overall survival in ARANOTE to really take hold of this new doublet combination we just discussed?

Fred Saad: Yeah. So that's a really important question. I mean, what do we make of overall survival? We designed the trial to be an RPFS endpoint. The number of patients in the study is clearly under the number of patients in all the studies that looked at overall survival. The reason we did that is we already had two studies with Darolutamide that showed very significant improvements in overall survival. So did we need to do a larger, longer study? There were a lot of people saying, "It's too bad we can't use Darolutamide without docetaxel because of its safety profile, because of patients that have drug-drug interaction risks, that have other issues."

So we decided to do this study as quickly as possible just to confirm. So this is the third study. We know it's an effective agent. Now, the patients have crossed over to Darolutamide at the time of opening this study. So we're discussing whether we can follow patients long enough to get more mature overall survival, but at this point what's reassuring is that what we're seeing is very similar to what we saw in other studies with a very short follow-up. We haven't even reached the median overall survival in both arms.

Zachary Klaassen: Right. Yeah.

Fred Saad: It's clearly immature.

Zachary Klaassen: Yeah, absolutely. And you mentioned earlier, and a couple of times, that we have three trials now with Darolutamide showing the tolerability. You and I both know, when we see these patients in the clinic, adding extra comorbidity—and most importantly and arguably most importantly, fatigue—we're clearly not seeing that with the ADT plus Darolutamide combination. So maybe speak to again just the tolerability and safety profile that we've seen now in three trials.

Fred Saad: Yeah. So clearly, I mean, what we're seeing repeatedly with Darolutamide is a very good safety profile. Will it never happen? It happens. I've seen patients getting fatigue, but I've seen it less often than in the other options we have. And importantly, the patients are living with this, and the trials have confirmed it. Compared to placebo, very, very similar.

Zachary Klaassen: Yeah.

Fred Saad: And the other big issue is the drug-drug interactions. A lot of our patients are elderly, taking a lot of drugs that give us some headaches in trying to figure out how we give life-prolonging, progression-free-survival-prolonging drugs in combination with what they're taking.

Zachary Klaassen: Yeah.

Fred Saad: And so these are issues that are in the real world, very, very compelling.

Zachary Klaassen: Yeah, absolutely. Fred, you've always been gracious with your time for UroToday. And again, we thank you for this great discussion, for your expertise, and thank you again for sharing your ESMO data about ARANOTE.

Fred Saad: Thanks for the opportunity, Zach.