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Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today we're talking about a recent publication entitled, Darolutamide Plus ADT and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. I'm Chris Wallis, an assistant professor in Division of Urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. You can see here the citation for this recent publication by Dr. Hussain and colleagues that was published concurrent with the presentation at the recent ASCO GU meeting.

As many will know, there's been rapid evolution in the in HSPC disease space. Beginning with the CHAARTED and STAMPEDE data back in 2015 and 2016, we've had a proliferation of treatment options. As of August 2022, darolutamide and docetaxel in addition to ADT were approved by the FDA for this patient population. As we know, there's an increasing number of trials that have looked at the triplet combination including both docetaxel chemotherapy and a novel hormonal therapy. This was clearly part of the portion of PEACE-1, although not all patients in this study received docetaxel. Among patients on PEACE-1, there was evidence of improved overall survival among patients getting the triplet combination as opposed to ADT plus docetaxel alone.

In ARASENS, the primary report published last year demonstrated an increased overall survival among patients receiving the triplet. However, in ENZAMET, while this wasn't a randomized comparison, there was evidence that there's an attenuation of the benefit of enzalutamide in patients who were receiving docetaxel. Some of this is postulated to be due to differences in disease distribution between the studies. We know that both the timing of metastasis, whether synchronous or de novo or metachronous, as well as the volume of disease, are an important prognostic factors and may therefore also be predictive of response to therapy.

This is the first report of the ARASENS trial, and as you can see here, at this time of publication, there was a fairly consistent benefit to the addition of darolutamide both in the top in terms of M status, M1a, b, and c, as well as at the bottom here with synchronicity with both de novo and recurrent patients deriving a benefit from triplet intensification. However, we know that there are more nuanced ways to stratify disease, and so that's what this study seeks to do. Just to reiterate, the ARASENS trial is a multi-center, randomized, double-blind, placebo controlled phase III trial across 23 countries, which enrolled adult men with confirmed prostate cancer and evidence of metastatic disease on conventional imaging who are eligible for both ADT and docetaxel. Patients were excluded if they had a regional lymph node involvement as their only extent of metastatic disease had received ADT for more than 12 weeks prior to randomization, had prior exposure to an androgen receptor antagonist or another hormonal therapy, chemotherapy, or any immunotherapy, or had recently received radiotherapy.

All patients received ADT as well as six cycles of docetaxel with prednisone or prednisolone according to the investigator's preference. Dexamethasone was recommended for patient's with docetaxel-related reactions, and a first-generation antiandrogen was recommended for the flare, although was stopped prior to randomization. Now, with this as the backbone, patients were randomized then in a 1:1 fashion to receive either standard dose of darolutamide or placebo. Patient randomization was stratified according to M status as well as the baseline serum alkaline phosphatase level.

The primary study endpoint was overall survival, with the number of important secondary endpoints including time to CRPC, time to pain progression, SSREs, and many others including safety. Patients were assessed every 12 weeks clinically, as well as with imaging at baseline within 30 days of the last docetaxel cycle and then yearly thereafter.

In this post-hoc analysis, patients were stratified by volume and risk subgroups. In keeping with the CHAARTED criteria, high-volume disease was defined as patients with visceral or four or more boney metastases with at least one of the bony mets being outside the vertebral bodies or pelvis. In keeping with the LATITUDE criteria, high-risk disease was defined as two or more of Gleason score 8 or greater, three or more bony metastatic disease sites, or visceral metastases. After stratification, clearly the high and low-volume and high and low-risk groups were defined as four separate analytic cohorts. Within these, the Kaplan-Meier method was used to determine the median time to events and the treatment groups were compared with unstratified Cox proportional-hazards models comparing darolutamide exposed to unexposed patients in each of the volume or risk groups.
I'm now going to hand it over to Zach to walk us through the results of this post-hoc analysis of the ARASENS trial.

Zacharcy Klaassen: Thanks so much, Chris. This is the concert flow diagram for the trial, and this is similar to the initial publication, where 1,306 patients were randomized, including 651 to darolutamide plus docetaxel plus ADT and 655 to the placebo plus docetaxel plus ADT arm. You can see that in the control group, 526 patients discontinued therapy, and in the darolutamide group, 352 patients had discontinued therapy.

This is a busy table one, looking at the baseline characteristics, and this is stratified by high and low volume as well as high and low risk, and so I'll highlight a few summaries here. You can see at the very top that the majority of these patients were categorized as high volume, over 1000, and roughly just over 900 were categorized as high risk. There's very little difference in the median age of these patients. The ECOG status was roughly two-thirds for the majority of these patients. When we move down to de novo metastases, we see that there's slightly more de novo metastases in the high-volume group versus low-volume, as well as slightly higher de novo metastases in the high-risk versus low-risk patients.

When we move down to metastasis staging at screening, by definition, high volume was M1b and M1c, low volume was predominantly M1a and M1b. Again, for the high-risk patients, majority M1b and M1c, and for the low-risk patients M1a and M1b. Finally, looking at the serum PSA level, the median PSA was certainly higher for high-volume patients, roughly high 20s and 30s compared to 11 to 14 in the low volume. Similarly, median PSA for high-risk patients was over 30 compared to 12 to 19 in the low-risk patients.

This is the primary endpoint for this study. This is overall survival by subgroups. We'll work starting in the top left here at high volume, and we can see that for high-volume disease there was a significant benefit for darolutamide versus placebo, with a hazard ratio of 0.69 and a 95% confidence interval of 0.57 to 0.2. Additionally, we see for high-risk patients in the bottom left here, a survival benefit for the triplet therapy, with a hazard ratio of 0.71 and a 95% confidence interval of 0.58 to 0.86. Moving to the right side of the screen, looking at the low-risk patients in the bottom right corner, again, a triplet therapy survival benefit, hazard ratio of 0.62, 95% confidence interval of 0.42 to 0.90. When we get to the top right here, this is the low-volume disease patients, so we see a splitting of the curves favoring darolutamide, with a hazard ratio of 0.68, but the 95% confidence interval does cross 1, so not statistically significant, 0.41 to 1.13.

This table looks at subsequent life-prolonging therapies in these groups, as previously stratified in table one. Looking at the top, patients with subsequent therapy, roughly 60% in the high-volume darolutamide group compared to 76.1% in the placebo group. In the low-volume group, 38.6% for darolutamide versus 73.1 in placebo. Switching to the risk stratification for high-risk darolutamide, 60.4% had subsequent therapy compared to 77.7 in the placebo group. In the low-risk group darolutamide, 45.3% compared to 69.5% in the placebo group. You can see here the options listed for subsequent therapies. Abiraterone was the most common, as we can see highlighted in the blue box, as the next line of therapy, followed by enzalutamide, cabazitaxel, and docetaxel.

The next two slides will look at this pre-specified subgroups. This is by high-volume disease for overall survival. Just generally looking at this forest plot, we can see that the majority of these patients in the subgroups did have survival benefit with darolutamide compared to placebo. I will make note at the bottom here, with regards to metastatic stage initial diagnosis, we did see a benefit for de novo, but we did not see a survival benefit, significant benefit, for recurrent disease, although the sample is quite small in this group. Similar looking figure for the low-volume disease stratification for overall survival, and in this forest plot, generally looking from a high-level view, we do not see a significant benefit for many of these subgroups, majority of them, in fact. We do see a benefit for white race, with a hazard ratio of 0.461, 95% confidence interval 0.32 to 0.916. Again, to take into context here, these are relatively smaller subgroups compared to the high-volume breakdown.

This is an important secondary endpoint. Looking at time to CRPC by subgroup, again, with a similar looking slide to the overall survival. High volume, high risk on the left and low volume, low risk on the right. To summarize, we can see early consistent splitting of the curves favoring darolutamide plus ADT plus docetaxel for all four of these groups. We can see hazard ratios for high-volume disease of 0.41, for high-risk disease, 0.38, for low-risk disease, 0.32, and for low-volume disease, 0.21. And these were all statistically significant.

This table looks at the secondary efficacy endpoints by subgroups. So I've highlighted a few key points in the asterisk here. As we talked about just a minute ago, all of the subgroups had a significant benefit for darolutamide versus placebo for time to CRPC. With regard to time to pain progression, there's a significant benefit for darolutamide in the high-volume group. With regards to SSE-free survival, again, we see all four of these subgroups have a benefit for darolutamide versus placebo. Time to first symptomatic skeletal event was significant for darolutamide with regards to the high-volume and the low-risk groups. Time to subsequent antineoplastic therapy was significant for high-volume disease favoring darolutamide. And finally, at the bottom of the slide, time to opioid use was improved for high-volume and high-risk patients favoring darolutamide versus placebo.

Next couple figures, we'll look at treatment-emergent adverse events. This is the first table. We can see, not surprisingly, any EE. Essentially, all the patients had had an adverse event of some sort. When we look at the overall worst grade from 1 to 5, generally the take home messages that there is very little difference between darolutamide versus placebo for each of these four stratifications. We look at the second table looking at AEs as special interest by subgroup, we see that the most common was fatigue, roughly 30-45% of these patients having fatigue. Vasodilation, flushing, was second most common, rash was third, and diabetes or hyperglycemia was also around 15-20% regardless of risk or treatment. Of note, at the very bottom, very little seizure activity, as would be expected from the darolutamide mechanism.

Several discussion points from this ARASENS subsequent analysis. Two previous studies have investigated the combination of an androgen receptor pathway inhibitor with ADT and docetaxel, with conflicting results in the subgroups by disease volume. For instance, the PEACE-1 trial showed in significant improvement in the high-volume disease but not in low-volume disease, and ENZAMET showed no significant OS improvement in high-volume or low-volume disease.

The results of this post-hoc analysis of ARASENS showed that the darolutamide plus ADT plus docetaxel combination increases overall survival in all disease volume and risk groups. Of note, as we talked about previously, the small sample size in low-volume subgroup, which was 23% of the ARASENS population, may have contributed to the hazard ratio and confidence intervals crossing 1, with a hazard ratio 0.6895% AND confidence interval of 0.41 to 1.13.

In conclusion, in patients with high-volume and high-risk, low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide plus ADT and docetaxel improved overall survival consistent with the primary analysis. Despite the lack of statistical significance, the results in the low-volume subgroups were suggested of a survival benefit. And finally, the favorable safety profile of darolutamide was confirmed in the disease volume and risk subgroups. We thank you very much for your attention and we hope you enjoyed this UroToday Journal Club discussion of the ARASENS post-hoc analysis published in Journal of Clinical Oncology.