Christopher Wallis: Hello, and thank you for joining us for our UroToday Journal Club discussion. Today we're talking about a recent publication entitled, The Efficacy and Safety of darolutamide in Patients with nmCRPC Stratified by PSA Doubling Time: A Planned Subgroup Analysis of the Phase 3 ARAMIS Trial. I'm Chris Wallis, Assistant Professor in the 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, which has currently in press at the European Urology and led by the team with senior author Dr. Karim Fizazi.

nmCRPC is an interesting disease space. It is defined by a rising PSA in the face of castration with ADT without evidence of metastasis on conventional imaging. These patients are at high risk of disease progression, although at this time of being in nmCRPC most patients are asymptomatic from their disease apart from the effects of prior local therapy and androgen deprivation.

Prognostically, both PSA levels in an absolute fashion and the rate of PSA change conceptualizes PSA doubling time are important. Close monitoring is needed to avoid missing a window of opportunity for treatment in these patients, as shorter PSA doubling time is associated with a higher risk of progression. While a threshold of six months has been suggested in the past, current treatment intensification is recommended when patients reach a PSA doubling time of 10 or less months. In nmCRPC, our goals are to delay the progression to metastatic disease, to prolong survival, and to minimize treatment-related toxicity while preserving patient quality of life.

Darolutamide is one of three agents that's been assessed in this space, and is a structurally distinct androgen receptor inhibitor with evidence of improved metastasis free survival and overall survival based on the ARAMIS trial in a consistently favorable safety profile. In this analysis, the authors sought to gain granular detail from the ARAMIS cohort. While this study enrolled patients with nmCRPC with PSA doubling times of 10 months or less, this pre-planned subgroup analysis aimed to assess both efficacy and safety outcomes stratified by PSA doubling time with a lower doubling time group defined as those with less than or equal to six months, compared to those with six to 10 months.

To highlight and relying on prior publications, ARAMIS was a global, multi-center, double-blind, randomized phase III trial, which included men age 18 years and older with histologically confirmed prostate cancer who had nmCRPC defined based on conventional imaging and a baseline PSA of at least two nanograms per milliliter, a PSA doubling time of 10 months or less, and an ECOG performance status of 0/1.

Unlike other trials in this disease space, patients with seizures or seizure predisposing conditions were not excluded from ARAMIS. The primary outcomes, metastasis-free survival with a number of key secondary endpoints including overall survival, and time to pain progression, time to first chemotherapy, and time to first skeletal-related event. As exploratory endpoints, the authors further included time to first prostate cancer related procedure, time to next prostate cancer therapy, a patient reported health related quality of life and safety endpoints. In ARAMIS, patients are randomized in a 2:1 fashion to receive either darolutamide 600 milligrams twice daily or placebo. This was performed in a double-blind fashion and all patients continued on androgen deprivation therapy.

Randomization was stratified according to PSA doubling time and the use of osteoclast-targeting therapy at randomization. PSA doubling time for the purpose of the trial was calculated locally for screening, but was recalculated centrally for this analysis. Randomization was notably unblinded at the time of primary analysis with crossover among patients in the control arm who had not yet progressed.

In the schematic you can see, highlighted the flow diagram, giving an overview of the ARAMIS Study protocol. The intention to treat a principal and population which utilize for both efficacy and health related quality of life endpoints. Although health related quality of life analyses excluded those who did not provide these data at baseline. The safety analysis are performed among all patients who received at least one dose of study medication. Time to event endpoints were estimated with the Kaplan-Meier method with the log-rank testing and Cox Proportional-Hazards Model were used to compare darolutamide, versus placebo treated patients within each subgroup of PSA doubling time defined as less than and equal to six months or six to 10 months. In terms of health related quality of life, differences between treatment arms are estimated using the least mean squares difference in the time-adjusted area under the curve using an analysis of covariance.

I'm now going to hand it over to Zach to walk us through the results of the subgroup analysis of the ARAMIS trial.

Zachary Klaassen: Thanks so much, Chris. This is the patient demographics and clinical characteristics at baseline, and this is stratified by PSA doubling time greater than or less than six months. Generally, we see that the median age of these patients was roughly 75 years of age. ECOG performance status was roughly two-thirds, these patients being ECOG zero. More than three quarters or roughly three quarters of patients had a Gleason score at initial diagnosis of greater than or equal to seven.

In terms of the median time from initial diagnosis, we see that in patients with the PSA doubling time greater than six, it was roughly 95 to 97 months. And in those with the PSA doubling time less than six, it was 79 to 82 months. In terms of the serum PSA at the time of enrollment in this trial, we see that it was roughly 8.9 to 10 across the stratification. And PSA doubling time amongst those of the doubling time greater than six months was median of 7.3 to 7.8, and for those with a PSA doubling time less than six months, the median time was 3.5 to 3.6 months.

In terms of prior hormonal therapies, greater than or equal to two prior therapies was quite common in roughly three quarters of these patients. And we see that approximately 20% of the patients had a prior prostatectomy with a PSA doubling time greater than six months, compared to just over 25% amongst those with a PSA doubling time of less than six months.

The next several slides will be Kaplan-Meier curves. Similar to this one, the darolutamide patients are in orange and the placebo patients are in gray. This is metastasis-free survival for PSA doubling time greater than six months, and we see that the median metastasis-free survival was not reached in either group. However, the hazard ratio did favor darolutamide at hazard ratio of 0.38, 95% confidence interval of 0.26 to 0.55.

This is MFS for PSA doubling less than or equal to six months, median for darolutamide was 34.3 months, for placebo was 17.2 months, with the hazard ratio of 0.41 favoring darolutamide, and a 95% confidence interval of 0.33 to 0.52.

This is overall survival for PSA doubling time patients more than six months. Again, median not reached in either darolutamide or placebo, but you can see a splitting of the curves at around 20 months of randomization with a hazard ratio favoring darolutamide of 0.55, and a 95% confidence interval of 0.35 to 0.88.

This is overall survival for PSA doubling time less than or equal to six months. Again, the median overall survival not reached in either group. However, we do see, again, a splitting of the curves around 20 months, with a hazard ratio favoring darolutamide of 0.74, and a 95% confidence interval of 0.55 to 0.99.

This is the metastasis-free survival of subgroup analyses by baseline characteristics. Generally, we see that amongst age, race, and region, the subgroups do favor the darolutamide group. There is some heterogeneity, especially with patients aged 74 to 79, doubling time greater than six months, for those that were 47 to 67 years of age, PSA doubling time greater than six months, for non-white patients PSA doubling time greater than six months, and for those from Asia Pacific with a PSA doubling time greater than six months. However, if you look at the number of patients and the events in these subgroups, these were quite small.

This is time to pain progression. So these slides will have PSA doubling time greater than six months on the left, and PSA doubling time less than six months on the right. We see that for both PSA doubling time greater than or less than six months, these both favored darolutamide with hazard ratio of 0.59, and a 95% confidence interval of 0.42 to 0.85 for PSA doubling time greater than six months. And a hazard ratio of 0.67, 95% confidence interval of 0.53 to 0.84 for patients with PSA doubling time less than or equal to six months.

This is time to initiation of first cytotoxic chemotherapy. Again, both of these favor darolutamide, for those with a PSA doubling time greater than six months, hazard ratio of 0.51, and a 95% confidence interval of 0.26 to 0.99. And for PSA doubling time less than or equal to six months, hazard ratio of 0.59, and a 95% confidence interval of 0.44 to 0.79.

These capital markers look the time to first symptomatic skeletal event. Interestingly, we do not see a benefit of darolutamide for PSA doubling time of greater than six months. Its hazard ratio was 0.36, 95% confidence interval with 0.12 to 1.11. However, we do see a benefit among those with the PSA doubling time of less than or equal to six months with a hazard ratio of 0.53, and a 95% confidence interval of 0.29 to 0.96.

This is the results for progression free survival, darolutamide, a benefit in both of these subgroups with early and wide splitting of the Kaplan-Meier curves. For PSA doubling time of greater than six months the hazard ratio is 0.35, and 95% confidence interval of 0.24 to 0.50. And for PSA doubling time less than or equal to six months the hazard ratio is 0.38, and 95% confidence interval of 0.31 to 0.47.

This is the treatment-emergent adverse events of interest, broken down by PSA doubling time of greater than or less than six months. If we focus on the darolutamide groups, in each of these PSA doubling sub-cohorts, looking at the grade 3/4 adverse events, we see that there is some coronary artery disorders, 2.8% of patients in the PSA doubling time greater than or equal to six months. In the PSA doubling time less than or equal to six months, we see that 4.2% of patients had hypertension, 2.1% of patients had cardiac arrhythmias.

So several important discussion points from this study. In this preplanned subgroup analysis of ARAMIS, there was demonstration that patients with PSA doubling time greater than six months benefited from darolutamide treatment, similar to those with PSA doubling time less than or equal to six months. For both of these there was a significant improvement in metastasis-free survival and overall survival. There was favorable trends in other efficacy endpoints in health related quality of life. And ultimately, darolutamide was well tolerated, and the safety profile was similar across the two PSA doubling time subgroups, which was comparable to the overall population.

As we know, ARAMIS was restricted to patients with PSA doubling time less than or equal to 10 months, and we found that men with a PSA doubling time of less than or equal to six months at the highest risk of non-metastatic CRPC, and thus were expected to, and they do benefit from darolutamide.

Importantly, however, the benefits seen in men with PSA doubling time greater than six months from this analysis is important as these patients benefits were seen without imposing undue toxicity burden or adversely affecting health related quality of life, which is important, especially given a long anticipated duration of treatment for these patients.

In conclusion, in patients with non-metastatic CRPC and a PSA doubling of have greater than six months, darolutamide provided a markedly favorable benefit-to-risk ratio characterized by significant improvement in survival and other clinically relevant endpoints, a maintenance of health related quality life, and demonstrating a favorable tolerability profile. Thus, the early initiation of life prolonging therapy with ARI is warranted in these patients.

Thank you very much for your attention and we hope you enjoyed this UroToday Journal Club discussion.