Chris Wallis: Hello, and thank you for joining us for this UroToday Journal Club presentation. Today, we're discussing the recent publication of the trial, examining Darolutamide and Survival and Metastatic Hormone-Sensitive Prostate Cancer. I'm Chris Wallace, an assistant professor in the Division of Urology at the University of Toronto. Joining me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia.

Seen here is the citation for this recent publication, which was published in the New England Journal of Medicine, concurrent with the presentation from Dr. Smith at GU ASCO in February, 2022. The disease space of metastatic castration-sensitive prostate cancer has evolved quite rapidly over the past decade. While not a new approval, per se, Docetaxel was first utilized in for this indication beginning in 2015. And since that time we've seen approval of three novel androgen-access targeting agents in February, 2018, September, 2019, and December, 2019 on the basis of the trials that you can see highlighted around the periphery of this slide. Each of these agents has shown benefit in isolation, and this raised the question of whether we can get intensified therapy leading to intensified benefit. And so the first study to assess this was presented by Dr. Fizazi at ASCO 2021, and ASMO 2021, the PEACE-1 trial. This is a two-by-two factorial randomization assessing the addition of Abiraterone or radiotherapy or both to standard of care. And importantly as you'll notice from the changing accrual period from 2013 to 2018, standard of care changed over time to include Docetaxel.

As a result, we can see here rPFS and OS curves among the subset of patients for whom standard of care comprised ADT plus Docetaxel. And so we're testing the addition of Abiraterone as a triplet therapy compared to the standard doublet therapy. And we see improvements in both rPFS and OS in this piece one data which has been presented, but not yet published. We contrast this with the results of the Enzamet study here. And again, to recall this was a trial comparing ADT with standard first-generation non-steroidal antiandrogen to ADT with Enzalutamide and the use of Docetaxel was allowed. And so you can see at the bottom here, a stratified analysis in which among patients who received Docetaxel, the addition of Enzalutamide provided an incremental improvement in clinical progression-free survival, but as of data that has been presented and published to date, no additional benefit in terms of overall survival, thus, the comparison of triplet therapy to doublet therapy has conflicting data so far.

To address this question, the ARASENS trial assesses the role of Darolutamide, which is a structurally distinct engine receptor inhibitor, which was somewhat novel compared to Apalutamide or Enzalutamide in that it has a lower blood-brain barrier penetration and decreased drug-drug interactions.

As you can see in the schema at the top of the screen, this comes from the ARAMIS study, looking at this agent in non-metastatic disease. And we see as highlighted in the curves below in the first publication improvements in metastasis-free survival and in the follow-up publication, improvements in overall survival, thus is a clearly an active agent in patient with the advanced prostate cancer.

So ARASENS sought to evaluate the efficacy and safety of adding Darolutamide to a backbone of ADT and docetaxel, going to a CHAARTED style protocol in patients with metastatic hormone-sensitive prostate cancer. The study enrolled adult men, age 18 and older with confirmed prostate cancer who had evidence of metastatic disease based on conventional imaging, ECOG performance zero to one, and those who were eligible for ADT and docetaxel. Patients were excluded if they had regional lymph node involvement, and one disease as the only extent of their metastatic disease. Those who received their ADT beginning more than 12 weeks prior to randomization, which had previously received advanced engine receptor targeting agents, chemotherapeutics, or immunotherapy, and those who had radiation within two weeks of randomization. Patients in the study were all treated with the ADT, whether an LHRH agonist, antagonist, or bilateral orchiectomy. Additionally, all patients received standard chart style, a docetaxel with six cycles administered on day one and 21 of each cycle.

The use of prednisone or prednisolone was at investigator discretion, but steroids were given to all, and dexamethasone was recommended to reduce docetaxel-related reactions. Additionally, given that these patients were starting on ADT, a first generation antiandrogen was recommended for four weeks to reduce the flare phenomena, but was stopped prior to a randomization. Patients were therefore randomized in a 1:1 fashion to receive either Darolutamide 600mg PO twice daily, or placebo with stratification. According to the extent of metastatic disease, M1a vs M1b, bony disease or visceral disease, as well as according to randomization Alk phos level, which was dichotomized around the upper limit of normal. The primary endpoint of the trial was overall survival and the number of secondary endpoints, which included time to CRPC, time to pain progression, symptomatic skeletal free survival, time to first subsequent skeletal event, time to initiating subsequent anti neoplastic therapies, time to worsen or disease related physical symptoms, time to initiation of opiates taken from more than a week, and safety.

This is a trial design. We've highlighted most of the features already, but just to emphasize again, that ADT plus Docetaxel form the backbone that all patients received. And there is 1:1 randomization to receive a Darolutamide or placebo in addition. Patients were evaluated every 12 weeks for evidence of castration resistance, the initiation of subsequent therapies or opioids, skeletal related events, as well as pain progression, disease related symptoms as measured by FACT-P, and adverse events. Imaging was performed at baseline within 30 days of the last cycle of Docetaxel and annually thereafter.

The sample size was calculated such that 1300 patients would be required to demonstrate 509 OS events, which with a 5% drop off rate would provide a 90% power to detect a 25% decrease in the risk of death using an alpha of 0.05. Subsequent secondary endpoints were tested using a hierarchical gate-keeping fashion in sequence with statistical testing of subsequent endpoints only performed when the preceding one was statistically significant. All time to event outcomes were assessed using the Kaplan Meier technique, log-rank tests, and Cox proportional hazards models, and the authors performed a number of pre-specified subgroup analyses. Now, I'm going to hand over to Zach to walk us through the results of the AEN trial.

Zachary Klaassen: Thanks for that great introduction, Chris. This is the CONSORT diagram for the ARASENS trial. And as you can see here, there was 1,686 patients that were screened. Ultimately 1,306 were randomized, including 651 to Darolutamide plus docetaxel plus ADT, and 655 the placebo plus docetaxel plus ADT. Ultimately in the Darolutamide arm, 352 patients discontinued therapy and in the placebo arm, 526 patients discontinued therapy. This is the table of baseline characteristics for this trial. You can see in the second column is the Darolutamide arm and in the third column to the right is the placebo arm. The median age of these patients was 67 years. The most common age demographic at 65 to 74 years included 46% of patients in the Darolutamide arm and 47% of patients in the placebo arm. These patients predominantly had great ECOG performance status with a score of zero in almost three quarters of the patients.

So it was truly a global study. As you can see here, just over half of the patients were white, but over one third of the patients were Asian. And again, you can see the global nature of the study broken down by region, including North America, Asia Pacific, and the rest of the world. The in terms of the Gleason scored initial diagnosis, more than three quarters of the patients were Gleason scored greater than or equal to eight. Predominantly, all of these patients were M1 at diagnosis. Over 85% of both arms and including the metastasis stage at screening was M1b, bone metastasis with or without lymph node metastasis in over three quarters of these patients. As you'd expect in this population, the median serum PSA was 30 in the Darolutamide arm in 24 in the placebo arm.

This is the primary outcome of overall survival comparing Darolutamide and placebo. And you can see here there's an early and consistent splitting of the curves in the survival arm with the median survival not yet reached in Darolutamide in 48.9 months in placebo with a hazard ratio favoring Darolutamide of 0.68 and a 95% confidence interval of 0.57 to 0.80. This is the overall survival in the pre-specified subgroups stratified by extensive disease, ALP stratification age, race, geographical region, PSA baseline ECOG Gleason score, metastatic stage of diagnosis. And as you can see on the right, in this figure with the hazard ratio to the left favoring Darolutamide, that essentially to summarize all of majority of these subgroups did favor the Derolutamide group over the placebo group in a statistically significant fashion.

This is the secondary efficacy end points. And as Chris had highlighted, there was several of them, majority of them favoring Darolutamide versus placebo, and including time to castration-resistant prostate cancer with a hazard ratio of 0.3, time to pain progression with a hazard ratio of 0.79, symptomatic skeletal event, free survival with a hazard ratio of 0.61, time to first symptomatic skeletal event at 0.71, and time to initiation of subsequent systemic antineoplastic therapy with the hazard ratio of 0.39. As you can see towards the bottom of the table, there was no difference between these groups in terms of time to worsening of disease-related physical symptoms. Just to reiterate again, these are the Kaplan Meier curves for the secondary outcome. This is time to castration-resistant prostate cancer, not yet reached in terms of median time for Darolutamide and a median time for placebo of 19.1 months, favoring the Darolutamide arm with a hazard ratio of 0.36 and a 95% confidence intervals of 0.30 to 0.42.

This is the Kaplan Meier curve for time to pain progression also favoring the Darolutamide arm with a median time to pain progression not yet reached in the Darolutamide arm in 27.5 months in the placebo arm with a hazard ratio show of 0.79 and a 95% confidence interval of 0.66 to 0.95. This is the adverse events table. And you can see here in terms of any adverse events, these are heavily treated patients. Pretty much every patient had some adverse event. Most commonly was grade three in the Darolutamide arm as well at 38%, as well as grade three in the placebo arm at 35.7%. In terms of adverse events leading to permanent discontinuation of the trial agent, Darolutamide responsible for 13.5% or placebo, excuse me, Darolutamide or placebo accounting for 13.5% in the Darolutamide arm, and 10.6% in the placebo arm in terms of importance selected grade three or four adverse events, neutropenia was most common, 33.7 in the Darolutamide arm in 34.2% in the placebo arm. Also of note febrile neutropenia, 7.8% in the Darolutamide arm, and 7.4% in the placebo arm.

In terms of ARASENS trial, there's several important points to highlight. This trial showed that overall survival was significantly longer for patients receiving Darolutamide plus ADT plus docetaxel compared to those receiving standard ADT plus docetaxel alone. And importantly, this benefit was observed despite a high percentage of patients receiving subsequent life-prolonging systemic therapy in the placebo group and was consistent across the secondary endpoints. As Chris alluded to in the introduction, these results are in line with a PEACE-1 trial, which was presented recently, but not yet published where 1,173 men with metastatic hormone-sensitive prostate cancer, randomized to abiraterone versus prostate radiotherapy versus abiraterone plus radiotherapy versus neither with all patients receiving ADT plus or minus docetaxel. And in this planned subgroup analysis among 710 men that receive docetaxel, overall survival was longer among men that received abiraterone compared to those that did not receive abiraterone with a statistically significant hazard ratio of 0.75 and 95% confidence interval of 0.59 to 0.96.

So in conclusion, the ARASENS trial supports the use of Darolutamide in combination with ADT and docetaxel in patients with metastatic hormone-sensitive prostate cancer. The addition of Darolutamide to ADT and docetaxel increased overall survival, and these improvements were observed with respect to key secondary endpoints with no increase in adverse event rate. Thank you very much for your attention for this URO Today Journal Club discussing the recently published ARASENS trial in the New England Journal of Medicine.