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Zach 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 two gentlemen intimately familiar with the ARANOTE trial that was recently presented at ESMO, Dr. Fred Saad from the University of Montreal and Dr. Neal Shore from the Carolina Urologic Research Center. Gentlemen, thanks so much for joining us today for this discussion about ARANOTE.

Fred Saad: Thanks for having us.

Neal Shore: Yeah, it's a pleasure.

Zach Klaassen: So Fred, you presented ARANOTE at ESMO and it was excellent data to sort of digest. And really the purpose of this discussion today is to get into some of the nuances. And this kind of discussion is perfectly set up for the UroToday recording. So maybe just from a background standpoint, Neal, can you talk to us about what's the rationale for another doublet therapy trial in metastatic hormone-sensitive prostate cancer?

Neal Shore: Yeah, that's a fair question. Drug development is not for the faint of heart. And it's been a great pleasure to be part of a lot of different drug development things. And Fred and I have worked together on so many different things. Some have been remarkably successful, some not.

So, darolutamide was the third major phase III trial in the nmCRPC space after enzalutamide (PROSPER) and apalutamide (SPARTAN). And it was successful. And it was interesting because there's some molecular differentiations between darolutamide, enzalutamide, and apalutamide. And there's some tolerability issues. And then similarly, we saw approvals of, and ultimately not only an MFS benefit, but also an overall survival benefit. And that was the ARAMIS trial for darolutamide.

And then moving approximately into the castration-sensitive population, like so many of our prostate cancer trial experiences occur. Typically, we treat the most advanced, then we come earlier when we see signals of benefit. mHSPC, we saw benefit with doublets with abi and enza and apa. And we really had the remarkably positive ARASENS trial, but that was a triplet trial. It was Daro with doce.

So I think what was really great here, and it was honored to be part of it with Fred's leadership, was the ARANOTE study. And to give patients another opportunity to see, will there be a role for darolutamide in mHSPC as a doublet as opposed to the triplet, which was ARASENS? And lo and behold, the answer is yes. So, I love the fact that we now always have more options for clinicians and for patients.

Zach Klaassen: That's a great background. And Fred, I want you to—I'm going to pull up the trial design just to sort of kick us off here. If you can walk through the design of the ARANOTE trial and maybe just summarize by way of background some of the key results that you presented at ESMO.

Fred Saad: So basically, ARANOTE has a very similar design to the other trials that Neal just spoke about, whether we look at TITAN with apalutamide, whether we look at ARCHES with enzalutamide, whether we look at abiraterone in LATITUDE. So really, it's taking the backbone of ADT as the standard of care therapy, which is still the reality in many places around the world, including Canada and the U.S., where many patients are still getting ADT and looking at the value of adding darolutamide to ADT.

So, these were patients—all-comer metastatic hormone-sensitive prostate cancer patients. And really there was no selection of whether they're de novo or recurrent, whether they were high-volume or low-volume—it was really an all-comer population. And the primary endpoint—because exactly as Neal mentioned, we already had two studies with darolutamide showing that it's able to prolong overall survival very significantly. And we know that it's a very effective agent as an androgen receptor inhibitor.

So we didn't want to do a trial that would take too long, so we did a two-to-one randomization with only 669 patients. So really, much smaller study with no intent of having overall survival as a primary endpoint. But rPFS—I think everybody is really convinced with multiple other secondary endpoints, including time to mCRPC, which was really the lethal form of prostate cancer, the percent of patients reaching undetectable PSA, and delaying pain progression.

And in a nutshell, the primary endpoint was clearly met. There was a 46% reduction in the risk of radiographic progression-free survival. And importantly, we saw that we significantly delayed the time to mCRPC. We reached undetectable PSA levels in over 60% of patients compared to only 18% of patients that got ADT alone. And we had a significant delay in time to pain progression. So, all important endpoints.

And obviously immature data, small study, but we already saw a 19% reduction in the risk of death with the addition of darolutamide. What's really important is regardless of what they came in with, whether they were high volume, low volume, de novo, recurrent, that advantage of having darolutamide was seen across the board in the trial.

Zach Klaassen: Yeah, it's a great summary, and I want to dig into some of the nuances of the data. I'll start with Neal. This trial really was different in the patients that were recruited. And almost 50% ECOG one to two. We saw incredible diversity that we've never seen in not only prostate cancer trials but other trials in the GU space—30% Asian, 10% Black. In that context, how do we interpret these data, given the diversity and the appropriate diversity that we've seen in ARANOTE?

Neal Shore: Yeah, I'm really proud of the site selection. It was great to be part of the steering committee with Fred and several others. And we always are trying to get that diverse population. And as you point out, almost 50% ECOG one, two, and 30% Asian and 10% Black. And we don't typically see this in many of our large phase III trials. They tend to be more North American, European-centric. Kudos to our colleagues in Brazil—they enrolled a lot of Black patients. Our Asian countries did remarkably well. We didn't have U.S. sites, largely because there were some challenges because of already the approvals that existed in doublet therapy and some concerns regarding equipoise and crossover. And we enrolled this study really quickly and with really high-quality sites.

So to your point—it's a great point, Zach—we were really proud of the fact that the average age, the median age, was 70. It was a little bit older too. And you'll see—and I don't know that we'll have time—but the safety and the tolerability, there was nothing surprising. It was all consistent with what we've seen with darolutamide in ARAMIS and in ARASENS.

Zach Klaassen: Yeah, absolutely. And I think, Fred, if we look at one of the subgroup analyses you presented specifically looking at low-volume disease, which has been difficult to accrue, difficult to show benefit for one agent versus the other. But here in ARANOTE we saw a hazard ratio of 0.3. Obviously, these are not powered to show differences. But maybe just speak to—is this potentially the new go-to for low-volume metastatic hormone-sensitive prostate cancer?

Fred Saad: Yeah. And we're really happy that we were able to recruit patients both high volume and low volume. And that hazard ratio is below a confidence interval of one in both. It was 0.6 for the high volume, which is really impressive because these patients have undifferentiated cancers in some areas, clearly. But really, the low volume really shows and continues to confirm that if you treat with a hormonally based therapy, the earlier you treat, the bigger bang you get for your buck. So, a 70% reduction in risk of radiographic progression is really outstanding.

And coupled to that, and as Neal said, sometimes we worry—is it worth treating a low-volume patient given the added adverse events? But we saw no added adverse events. We actually had fewer patients discontinuing therapy on the treatment arm. And we actually had less fatigue on the darolutamide arm than on the placebo arm. So really, there's no good argument for not treating patients if you're worried about adding adverse events to your ADT that you're giving in these patients that you consider maybe at lower risk. But actually they're the ones that are most likely to benefit.

Zach Klaassen: Yep, absolutely. Neal, Fred mentioned the overall survival benefit of hazard ratio 0.81. It's early, it's few events, but we're certainly seeing a signal there. And as Fred mentioned, this is not powered to show OS benefit, but how do you interpret that? I mean, certainly we saw ARCHES was powered to rPFS. And if we see an OS benefit even as a secondary outcome, how does that go into the interpretation and rolling out of this doublet therapy?

Neal Shore: Well, I think it's important to put into the context that we have OS benefit in ARASENS in the triplet—the triplet of ADT, daro, doce bested ADT-doce. We see the OS benefit in ARAMIS and nmCRPC patient population. I think this is important that this is clearly demonstrating a trend in that direction. We'll follow these patients longer as a key secondary endpoint.

I just wanted to augment on a really important point that Fred was alluding to. And that is, look, ADT monotherapy in mHSPC, whether it's low volume, high volume, ECOG zero, ECOG one, two, regardless of your demographic and your racial background, your region, monotherapy ADT is no longer the standard of care. And we still see in the United States upwards of 50% of patients in 2024 still getting monotherapy ADT. We have to do better. The OS data—we're following these patients. I'm certainly confident that that'll be positive over time. Most of the events were not survival events, but we'll see. I'm optimistic that that will be positive.

Zach Klaassen: And I think you both have alluded to the tolerability. And I want to ask Fred—just dig into it a little bit more. I think to Neal's point, ADT monotherapy should no longer be even considered standard of care. And perhaps because that fatigue was lower in the doublet versus ADT monotherapy, less discontinuation in the doublet versus monotherapy—is this finally the straw that broke the camel's back that says, "Hey, we should now be giving ADT monotherapy"?

Fred Saad: I certainly hope so. And that's why we need to have these recurrent trials. And the importance of yes, having a fourth is okay because it just confirms that this is not... The very first trial with LATITUDE were all high-risk patients. It was a no-brainer that it would be positive. And the question was always, do we really need to intensify in the lower volume, lower risk patients? And that tolerability is important. And the fact that we had 30% Asians where we're seeing oftentimes more adverse events in patients that are Asian race with our AR-targeted therapies, including multiple adverse events that sometimes makes people scared of intensifying with hormonal therapy, I think should dissipate these worries and these fears.

Zach Klaassen: Yeah, absolutely. The whole conversation has been set up for me to ask this question because I'm excited to hear both of your answers to this. I'll start with Neal. We have ARASENS with triple therapy, we have ARANOTE with doublet therapy. In your patient population, Neal, who are you treating with doublet? Who are you treating with triplet at this point in time? Basically plus or minus chemotherapy, because certainly we have good data for both.

Neal Shore: Yeah. Well, I am in the aggressive camp. If I have someone who's fit for chemo, almost regardless of age, but it's usually going to be someone relatively younger. And that tends to be somewhat subjective, but we do have age cut points that we look at. But if I have someone who has got a strong performance status, who's an ECOG zero, who has typically high-volume disease—invariably lots and lots of bone disease, greater than 10 bone lesions, certainly visceral metastasis—and they are not risk-averse. They say to me, "Hey, doctor, give me my best shot." I have always been a proponent of the triplet therapy.

And I explain to them that the six cycles of docetaxel given over a four-month period—and these patients tend to be younger, better performance status. So, I'm aggressive. I like the triplet. And if the patient says no, then okay, that's shared decision making. But I do believe in the triplet based on ARASENS and based on PEACE-1 trial. So I am a proponent of triplet therapy, when it's appropriate.

Zach Klaassen: Excellent. How about you, Fred, in your practice up in Montreal?

Fred Saad: Well, here we're quite aggressive, very much like Neal. And my approach now has been the new standard of care in terms of hormonal therapies—ADT plus an AR-targeted therapy. That for me is the base. And then the question is, who's going to benefit from more intensification with another mechanism of action? And I think of—I look at the patient, I look at the cancer, and I say, "This patient is probably not going to do so well with a doublet hormonal approach." And so I know they're going to need chemo in the relatively near future. And we know it's less effective if we wait for it to introduce it when they've already become resistant to an ARPI. So, let's give it up front.

And exactly as Neal said, that phenotype clearly is a patient with visceral mets, high-volume disease, but even some low-volume patients that are young. And when I talk about young, 40s, 50s, let's not take any chance. Even early 60s, let's not take any chance, even if it's low volume. But we see that really, the hormonal approach is what's most important in all categories of the disease, especially the low volume. And so many of those low-volume, I will leave alone—I will leave out chemo, saying that these patients are likely to respond, like we saw in the trial, for a long time before they start progressing and becoming mCRPC. And then I'll be more comfortable giving them chemo later. But anybody who's full high volume, I would rather give it early rather than wait for them to become resistant to an ARPI.

Zach Klaassen: I think those are both important strong messages because if we look at the treatment patterns in the United States, 20% of patients are treated at academic centers, 80% in the community. And having discussions with community urologists or medical oncologists, that chemotherapy sort of step can be difficult at times. But I think it's an important message for our listeners, that in those appropriate patients, we have wonderful data from ARASENS to suggest that they're going to benefit from the triple therapy. So I appreciate that, those responses.

I want to end off with just an open statement, maybe a couple of take-home messages from each of you to our listeners based on the ARANOTE and wrapping in ARASENS as well. I'll start with you, Neal.

Neal Shore: Well, I think ARANOTE was probably one of the most important presentations that was allowed and came forward and now published in JCO. At ESMO 2024, you can now have mHSPC patients—de novo, recurrent—when there's level one evidence that ADT daro with or without docetaxel will be a standard of care. It's bright and early and new now. I think it'll invariably be put into the guidelines. And so, that's number one point.

And number two is monotherapy. As we said, ADT is rarely the appropriate choice. Patients and physicians now have additional choices of now four ARPIs including darolutamide as a doublet. And of course, we hope that people have that accessibility.

Zach Klaassen: Absolutely. Fred, you have the final word. Take-home messages for our listeners.

Fred Saad: Choice, choice, choice. Now we have options, we can personalize more and more. And I think ARANOTE does a good job in addressing some of the unmet needs. We've had issues with drug interactions, we've had issues with patients that are more fragile and that we're worried about adverse events. So, now there's very little reason for anybody to be considering ADT alone. So I think now that's out, that's finished, but now you have options. And I think patients have to be part of that decision-making, regardless of whether we're going to give an ARPI or an ARPI plus docetaxel—I think that's great. I think prostate cancer is probably where we have the most personalization. And we have to be very proud of what we're able to do.

Zach Klaassen: Thank you.

Fred Saad: Thanks, Zach.

Neal Shore: Thank you.