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SES AUA 2025

SES AUA 2025: Overall Survival with Darolutamide Versus Placebo in Combination with Androgen Deprivation Therapy and Docetaxel Accounting for Subsequent Therapy: A Sensitivity Analysis from ARASENS

(UroToday.com) The American Urologic Association (AUA) Southeastern Section (SES) 89th Annual Meeting, held in Nashville, TN, between March 12th and 15th, 2025, was host to a prostate cancer podium session. Dr. Zachary Klaassen presented a post-hoc sensitivity analysis from the phase III ARASENS trial evaluating the overall survival benefit of darolutamide versus placebo, in combination with androgen deprivation therapy (ADT) plus docetaxel, for patients with metastatic hormone sensitive prostate cancer (mHSPC), after accounting for subsequent therapy received.


ARASENS is an international, double-blind, phase III trial that randomized 1,306 mHSPC patients between November 2016 and June 2018 in a 1:1 fashion to darolutamide 600 mg twice daily or matching placebo in addition to ‘standard of care’ therapy with ADT plus docetaxel. Of note, 85% of patients had de novo metastatic disease.ARASENS is an international, double-blind, phase III trial that randomized 1,306 mHSPC patients between November 2016 and June 2018 in a 1:1 fashion to darolutamide 600 mg twice daily or matching placebo in addition to ‘standard of care’ therapy with ADT plus docetaxel. Of note, 85% of patients had de novo metastatic disease
The primary analysis demonstrated that patients in the triplet darolutamide arm had a 32.5% lower rate of death (HR: 0.68, 95% CI: 0.57–0.80, p<0.001), despite 76% of patients in the placebo arm receiving subsequent life-prolonging therapy.1 The primary analysis demonstrated that patients in the triplet darolutamide arm had a 32.5% lower rate of death (HR: 0.68, 95% CI: 0.57–0.80, p<0.001), despite 76% of patients in the placebo arm receiving subsequent life-prolonging therapy
An updated report published in 2023 demonstrated that darolutamide improved overall survival, compared to placebo, in patients with high-volume (HR: 0.69, 95% CI: 0.57–0.82), high-risk (HR: 0.71, 95% CI: 0.58–0.86), and low-risk disease (HR: 0.62, 95% CI: 0.42–0.90).2 

To address the impact of informative intercurrent events (e.g., use of subsequent therapy) in censored patients, as defined by the European Medicines Agency, Dr. Shore and colleagues performed a post hoc sensitivity analysis of overall survival outcomes.

The primary study endpoint was overall survival. Comparisons were performed using a log-rank test, with hazard ratios and 95% confidence intervals calculated using Cox models, stratified by extent of disease and alkaline phosphatase levels. Patients with no documented death were censored at the last known alive or data cut-off date, whichever occurred earlier. The post hoc sensitivity analysis counted initiation of subsequent systemic antineoplastic therapy as an event in censored patients still alive at the end of follow-up.

In the post hoc sensitivity analysis, 776 patients were counted as having an event, which included initiation of subsequent systemic antineoplastic therapy in censored patients, as well as death. This included 45% of patients in the darolutamide group and 73% in the placebo group. In the sensitivity analysis among patients with a censoring event of subsequent antineoplastic therapy, overall survival was also still significantly improved, with the risk of death reduced by 53% with darolutamide compared to placebo (median: 49 versus 32 months; HR: 0.47, p<0.0001). These findings support the primary ARASENS overall survival analysis results and show that the addition of darolutamide to ADT and docetaxel improved overall survival even when accounting for patients initiating subsequent antineoplastic therapy.

These findings support the primary ARASENS overall survival analysis results and show that the addition of darolutamide to ADT and docetaxel improved overall survival even when accounting for patients initiating subsequent antineoplastic therapy

With regard to subsequent therapy data, a higher proportion of patients in the darolutamide group were receiving ongoing study treatment at data cut-off (46% versus 19%). However, more patients in the placebo group were eligible for and received subsequent systemic antineoplastic therapy (48% versus 76%).With regards to subsequent therapy data, a higher proportion of patients in the darolutamide group were receiving ongoing study treatment at data cut-off (46% versus 19%). However, more patients in the placebo group were eligible for and received subsequent systemic antineoplastic therapy (48% versus 76%)
The most common subsequent therapies received were abiraterone, enzalutamide, and cabazitaxel. These data show that the overall survival benefit of darolutamide versus placebo was achieved despite a higher proportion of patients receiving subsequent life-prolonging therapies in the placebo group versus the darolutamide group.

Additionally, treatment with darolutamide significantly reduced the risk of starting subsequent systemic antineoplastic therapy by 61% versus placebo (HR: 0.39, 95% CI: 0.33–0.46, p<0.001).Additionally, treatment with darolutamide significantly reduced the risk of starting subsequent systemic antineoplastic therapy by 61% versus placebo (HR: 0.39, 95% CI: 0.33–0.46, p<0.001).
Overall, the incidences of treatment-emergent adverse events (TEAEs) were similar between the two groups. TEAEs led to discontinuation of study treatment in 13.5% of patients in the darolutamide group versus 10.6% of patients in the placebo group. The cumulative incidences of most TEAEs commonly associated with androgen receptor inhibitor therapy were generally low and similar between the groups.Overall, the incidences of treatment-emergent adverse events (TEAEs) were similar between the two groups. TEAEs led to discontinuation of study treatment in 13.5% of patients in the darolutamide group versus 10.6% of patients in the placebo group. The cumulative incidences of most TEAEs commonly associated with androgen receptor inhibitor therapy were generally low and similar between the groups
Dr. Klaassen concluded his presentation of the ARASENS trial as follows:

  • The combination of darolutamide plus ADT and docetaxel improves overall survival
    • The results of the post hoc sensitivity analysis were consistent with and supportive of the primary overall survival analysis
    • The overall survival benefit with darolutamide was achieved despite including patients censored from the primary analysis for initiation of subsequent life-prolonging therapy
    • Treatment with darolutamide significantly prolonged time to subsequent systemic antineoplastic therapy compared with placebo
  • These data reinforce the combination of darolutamide with ADT and docetaxel as an effective and well-tolerated standard of care option for early treatment intensification in patients with mHSPC

Presented by: Zachary Klaassen, MD, MSc, Associate Professor, Department of Urology, Wellstar MCG Health, Augusta, GA 

Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the American Urological Association (SESAUA) 2025 Annual Meeting, Nashville, TN, Wed, Mar 12 – Sat, Mar 15, 2025.

References:
  1. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022; 386(12): 1132-42.
  2. Hussain M, Tombal B, Saad F, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol. 2023; 41(20): 3595-607.