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Rashid Sayyid: Hello everyone and thank you for joining us today in this UroToday Journal Club recording. I'm Rashid Sayyid, a Robotic Urological Oncology Fellow at the University of Southern California, and I'm joined today by Zach Klaassen, Associate Professor and Program Director at WellStar MCG Health. And today we'll be discussing the very important publication of the phase III ARANOTE trial that looked at the combination of darolutamide with ADT for patients with metastatic hormone-sensitive prostate cancer.

And this study was recently presented at ESMO 2024 and was published in the Journal of Clinical Oncology with Dr. Fred Saad as the lead author. If we look at the current treatment paradigm of patients with metastatic hormone-sensitive prostate cancer, and specifically if we look at the NCCN recommendations, two things stand out. First of all, we see that the recommendations now are stratified based on the timing of disease as well as the volume of disease. But importantly, what we see is we have the triplet combinations of an ADT plus an androgen receptor pathway inhibitor plus docetaxel or a doublet regimen, mainly now ADT plus an androgen receptor pathway inhibitor. And so we see for the doublet therapy, we have many options. If we look at the results of CHAARTED, STAMPEDE, we see that docetaxel plus ADT has long been an option for these patients, although now it's considered a less favorable option to combine ADT with docetaxel upfront given the increased toxicity of docetaxel compared to androgen receptor pathway inhibitors.

And then when we look at the ADT plus androgen receptor pathway inhibitor combinations, we see that Abi plus ADT is an option based on the results of STAMPEDE, RMG, and LATITUDE. And we also have ADT plus enzalutamide based on the results of ENZAMET and ARCHES. And then apalutamide plus ADT is also an option based on the results of TITAN published in 2019. And so the question that comes to mind is why do we need another ADT-doublet combination? Is it worth studying a combination of ADT plus darolutamide given the availability of all these options in practice? The reality is, although we have all these options, the uptake of ADT doublet and triplet regimens has been poor in clinical practice. And this holds true whether we look at the US VA data, we look at US community academic practices, where we see here that if we look on the right side, that the utilization of ADT plus a novel hormonal therapy and ARPI remains really poor with only a quarter of patients receiving that.

And although that's improving, it's clearly still insufficient. And so people have looked at this and asked the question, what are the reasons for this underutilization? There are concerns about drug accessibility, the drug tolerability, the safety, the drug-drug interactions, and then also issues with healthcare provider education. And so is there a way to overcome this? And it's been proposed that darolutamide or NUBEQA in clinical practice—we know it's a structurally distinct and a highly potent androgen receptor pathway inhibitor. And importantly, it has low blood-brain barrier penetration. And so that's important. We consider the risk of seizures, which we've seen prior with enzalutamide. And there's also limited potential for drug-drug interactions, which is important because these patients are often elderly with many different comorbidities of receiving drugs for other indications. So it's a very important consideration for this cohort of patients. And funnily enough, we've looked at darolutamide before in the triplet setting.

So the triplet preceded the doublet in the ARASENS trial, which was published in 2022, and this trial showed that adding darolutamide to the doublet regimen of ADT plus docetaxel improves overall survival in a primarily de novo MHSPC setting. And if we look at the four-year overall survival of the Kaplan-Meier curves here, the overall survival over four years improves by 13% from 50% to 63%. So clearly this drug is efficacious, but more importantly in this setting, we saw in this trial that the incidence of adverse events and treatment discontinuation secondary to these adverse events is similar in both the darolutamide and placebo groups. So clearly the toxicity profile of this drug is acceptable and that patients have tolerated it well. And we also saw that in the ARAMIS trial, darolutamide in the non-metastatic CRPC setting was very well tolerated then. So based on this rationale, the study objective was to evaluate whether the addition of darolutamide to ADT without chemotherapy—as opposed to ARASENS—would improve survival outcomes and importantly increase therapeutic options for MHSPC patients and hopefully improve the uptake of ADT intensification in clinical practice.

At this point, we'll go over the trial design here and we'll see that this was a global randomized placebo-controlled phase three trial that included about 670 patients with MHSPC. And these patients underwent two-to-one randomization to either darolutamide given 600 milligrams twice daily plus ADT versus only placebo plus ADT. And importantly, if patients had regional lymph node metastasis only, then they were not eligible. They had to have either bone or visceral metastasis to be eligible. And if they had received prior ARPI or chemotherapy, they were not eligible for this trial. And if we look at the study endpoints, the primary endpoint was radiographic progression-free survival as assessed by central blinded review. And key secondary endpoints included overall survival, time to the next therapy, time to castration resistance, PSA progression, rates of undetectable PSA, time to pain progression, and then importantly, the safety outcomes. In terms of sample size calculations and some of the statistical methods, briefly we'll go over these.

The required sample size of 665 patients was based on the number of radiographic progression events. And so with 214 events, this would give you a power of 90%, which is higher than what we typically see, with a two-sided alpha type one error or a false positive error rate of 5%. And then they expected the hazard ratio to be about 0.63, so assuming about a 37% improvement in radiographic progression-free survival when adding darolutamide to ADT. And the primary outcome was radiographic progression-free survival, so it's a time-to-event outcome. And so it was assessed using Kaplan-Meier curves as well as Cox regression modeling, adjusting for important factors that were also used to stratify patients during randomization, namely visceral metastasis being present or not, and use of prior local therapy. And what's interesting, and this is pretty standard with a number of these trials, is that the secondary endpoints will be tested for statistical significance only if the primary endpoint met significance, and then it would also be addressed in a specific hierarchical manner.

And so after rPFS was assessed, next they would go to OS, all the way down to time to pain progression. And what's important is the total alpha or the total type one or false positive error could amount to 0.05. And this wasn't just for every outcome, but for the totality of all outcomes. And at this point, I'll turn it over to Zach. We'll go over the results and discussion for this key trial.

Zachary Klaassen: Thanks so much, Rashid, for that great introduction of ARANOTE. So this is the Prisma flow diagram. We can see here that 889 patients were screened. Ultimately, 669 were randomized for this trial. So this included 446 to darolutamide plus ADT and 223 to placebo plus ADT. So as Rashid mentioned, this was a two-to-one randomization. And so in terms of discontinuation, 203 men in the darolutamide plus ADT arm discontinued therapy and 160 discontinued therapy in the placebo plus ADT arm.

This is the patient demographic and clinical characteristics at baseline. And so this is the table one from the trial. There's some important points that we see in ARANOTE that we don't typically see in some of these phase three trials. So first, the median age was slightly older than what we've seen previously, so this was 70 in both of these arms. What's really important is race.

And typically, this is usually an 80 to 85% white population. This was one-third of the patients being Asian, and roughly 10% of patients being Black. So much higher minority enrollment in this trial than we've seen in previous phase three trials in this disease space. The concomitant to that is that we see region is much different than we typically will note in phase three trials. So roughly one-third of patients from Asia, roughly 26 to 30% from Latin America. And so this is much higher randomization across other regions than we're usually seeing in global trials.

What's also important, this is maybe a less healthy population than some clinical trials. Roughly 50% were ECOG status one to two. As usual in metastatic hormone-sensitive prostate cancer space, high-risk patients, 21 median PSA, roughly three-quarters of patients were de novo metastatic disease. We do see roughly about one-third of patients were low volume, and we see roughly 11 to 12% had visceral metastasis at the time of enrollment.

This is the primary endpoint of radiographic progression-free survival, and this was a positive trial. We can see that for darolutamide plus ADT, the median was not reached, compared to placebo plus ADT, the median was 25 months. The two-year rPFS rate was 70.3% for darolutamide plus ADT compared to 52.1% for placebo plus ADT. This hazard ratio was statistically significant 0.54, 95% confidence interval of 0.41 to 0.71. So this led to a 46% reduction in radiographic progression-free events or mortality, favoring the darolutamide plus ADT arm. So again, this was a positive trial.

When we look at rPFS across pre-specified subgroups, we see generally this was a benefit for darolutamide in all of these subgroups versus placebo. And so what's important here, particularly in some of these populations, we see low-volume disease had a significant benefit for rPFS, which has been difficult to see in other trials. And we also see generally across the geographic regions, there was a benefit for rPFS. So when we look at these subgroups, it's important to find that there's no drastic outliers that did not benefit from darolutamide plus ADT.

One of the key secondary endpoints obviously is overall survival. This was the early first analysis, and so this is immature data. As you can see on the right, the median for both darolutamide plus ADT and placebo plus ADT was not reached. But we do see that this is sort of leaning towards benefit for darolutamide plus ADT. Hazard ratio 0.81. The statistical significance has not been reached yet, but at this point a 19% reduction in mortality for darolutamide plus ADT. And certainly we will see additional analyses with additional follow-up and events for the ARANOTE trial.

Other key secondary endpoints were time to metastatic CRPC. And so we see here a wide and early splitting of the Kaplan-Meier curves favoring darolutamide plus ADT, statistically significant hazard ratio 0.40, 95% confidence interval 0.32 to 0.51. And so this is a very relevant endpoint for patients in terms of disease progression to MCRPC—a 60% reduction with darolutamide plus ADT. In terms of time to PSA progression, again, very similar Kaplan-Meier curve to the one we just saw on the previous slide. Favoring darolutamide plus ADT, hazard ratio of 0.31, 95% confidence interval of 0.23 to 0.41.

Again, significance for time to pain progression—another clinically relevant endpoint for patients. For darolutamide, not reached; for the placebo plus ADT arm, median of 29.9 months. Hazard ratio 0.72, 95% confidence interval of 0.54 to 0.96.

An interesting secondary endpoint is achieving a PSA of less than 0.2. So taking these high-risk men and really driving the PSA down at any point during their treatment. Fred Saad previously showed this was important in the ARASENS trial to reach a PSA less than 0.2 within about a year of treatment. And we see a significant difference between the darolutamide plus ADT arm and placebo plus ADT—62.6%. Nearly two-thirds of patients in the darolutamide plus ADT arm had a PSA less than 0.2 at any time during treatment compared to only 18.5% in the placebo plus ADT arm.

This is a nice summary of all of the secondary endpoints. And so we see here, again, noting that it's early for overall survival, but we see a trend perhaps favoring darolutamide. But again, to recap in a tabular form, time to CRPC or metastatic CRPC, time to PSA progression, time to initiation of subsequent systemic therapy for prostate cancer progression—0.4 hazard ratio—and time to pain progression, all significantly favoring. And so I think when we take the totality, not just the rPFS primary endpoint, but all of these endpoints, we see a clear benefit for darolutamide plus ADT.

Let's talk about safety and treatment emergent adverse events. And so when we look at any treatment emergent adverse events, essentially exactly the same, roughly 90% for both arms. No difference in grade three or four or grade five adverse events, almost exactly the same serious treatment emergent adverse events. And what's really interesting is treatment emergent adverse events leading to permanent discontinuation of the study drug—6.1% for darolutamide plus ADT, 9% for placebo plus ADT. So actually less TEAEs leading to discontinuation for the experimental arm compared to the control arm. In terms of events of special interest, there are several. So when we look at fatigue, there was less fatigue at 5.6% for darolutamide plus ADT compared to 8.1% for placebo plus ADT. So again, the experimental arm having less fatigue, which is important for these patients. Compared to placebo plus ADT, we see slightly higher cardiovascular events in the experimental arm—3.6% for coronary artery disorders compared to 1.4%—and slightly higher bone fracture rate at 4% for darolutamide plus ADT compared to 2.3% for placebo plus ADT.

So by way of discussion, both ARANOTE and ARASENS demonstrate efficacy benefits with darolutamide plus ADT with or without docetaxel for patients with metastatic hormone-sensitive prostate cancer. And certainly as clinicians and providers, it will be our job to decide who will benefit from the addition of docetaxel because certainly there are high-risk patients that would benefit from triple therapy. The efficacy of darolutamide in ARANOTE—notably, the overall survival results are consistent with findings from the ARCHES trial of enzalutamide plus ADT in this disease space. ARCHES was the other trial that was powered for rPFS, and so we see very comparable results for efficacy with ARANOTE compared to ARCHES. And finally, ARANOTE is the first study of an ARPI showing a lower rate of fatigue in the darolutamide group at 5.6% compared to placebo at 8.1%, which is a 30% lower incidence of fatigue. As we discussed, the discontinuation rate secondary to AEs was also lower in the darolutamide group at 6.1% compared to placebo at 9.0%.

There are several limitations and strengths for the ARANOTE trial. The first for limitations, there's three that we list. The use of placebo plus ADT as the comparator—in terms of ADT specifically being monotherapy—is no longer considered a standard of care for these patients. But as Rashid mentioned in his introduction, there is evidence of continued ADT monotherapy use, especially globally, where there may be difficulty with access to medicine that indicates that the findings are relevant to these physicians making treatment decisions for MHSPC patients. Secondly, two-to-one randomization resulted in a smaller control group that may limit subgroup analyses. And third, the design of the trial was to show an rPFS benefit and was not powered for an OS benefit as a secondary endpoint.

Several strengths of this trial: this is a highly diverse population. We have not seen diversification in a phase three registration trial like this. As we mentioned, these were more elderly and comorbid patients. There was excellent representation of minorities—Asians at 31%, Black at 10% of the population in the trial—and we really see a range of healthcare settings in this trial, Asia 30% and Latin America at 29%. Secondly, there's a benefit of rPFS in low-volume patients, which to date has been understudied and undertreated, and certainly we see a benefit at least in the subgroup analyses for darolutamide plus ADT in the low-volume de novo patients.

So in terms of take-home messages, the first is that the result of this second pivotal trial of darolutamide in patients with metastatic hormone-sensitive prostate cancer add to the body of evidence that we already saw from ARASENS, providing the option to select treatment in these patients with or without docetaxel to meet each patient's individual needs and preferences.

Secondly, ARANOTE confirms the proven efficacy and the well-established favorable safety profile of darolutamide, including a low discontinuation rate due to adverse events.

Third, darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer clinically significantly delays radiographic progression with minimal treatment burden. And this may further expand therapeutic options for these patients. And it's exciting to note as well that on September 26, 2023, Bayer announced that they'd applied for an FDA-expanded indication for darolutamide. We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the recently published ARANOTE trial in the Journal of Clinical Oncology.