Darolutamide Plus ADT Cuts Risk of Death in Half in mHSPC

Adding darolutamide (Nubeqa) to androgen deprivation therapy (ADT) reduced the risk of death by 50% vs ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to results from the phase 2 ARASEC trial (NCT05059236) presented at the 2026 American Urological Association Annual Meeting.¹

The hazard ratio (HR) for overall survival (OS) was 0.50 (95% CI, 0.30-0.82; P =.003) with darolutamide plus ADT vs ADT alone. The combination also led to a 71% reduction in the risk of disease progression or death vs ADT alone. At a median follow-up of 26 months in the darolutamide arm and 28 months in the ADT control arm, the HR for progression-free survival (PFS), the study’s primary end point, was 0.29 (95% CI, 0.20-0.40; P <.001).

"The OS benefit was achieved despite proportionally more patients in the ADT arm (65%) vs the darolutamide arm (26%) receiving subsequent life-prolonging therapy," Rana R. McKay, MD, medical oncologist and professor of Medicine, Urology, and Radiation Medicine and Applied Sciences and principal investigator of the ARASEC trial, stated in a press release.

Time to development of mHSPC cancer was also significantly prolonged with darolutamide plus ADT (HR, 0.26; 95% CI, 0.18-0.38; P <.001), as was radiographic PFS (HR, 0.30; 95% CI, 0.19-0.48; P <.001).

PSA response data further reinforced the depth of disease control achieved with the combination. At 6 months, 59% of patients in the darolutamide arm achieved a PSA level below 0.2 ng/mL compared with 23% in the ADT arm (P <.001). At any time point during follow-up, 68% of darolutamide-treated patients reached that threshold versus 33% of ADT-alone patients (P <.001).

“Results from the phase 2 ARASEC trial provide additional evidence regarding the efficacy and safety of darolutamide plus ADT in patients with mCSPC,” said McKay. “The data further support NUBEQA’s ability to offer physicians and patients with prostate cancer a treatment option that is both effective and generally well tolerated.”

ARASEC: Novel Trial Design

As effective combination regimens become standard of care, enrolling patients into an ADT-alone control arm in a prospective, randomized trial in prostate cancer is no longer ethically appropriate or operationally practical. Accordingly, ARASEC (NCT05059236) employed a pragmatic design that paired a prospectively enrolled US investigational cohort receiving darolutamide 600 mg twice daily plus ADT (n = 223) with an external control arm derived from the ADT-alone patients enrolled in the CHAARTED trial (n = 393).

To ensure comparability between the 2 populations, which were enrolled years apart and in different clinical contexts, propensity score matching was applied based on 6 key baseline prognostic characteristics: age, ECOG performance status, extent of disease, prior local therapy, Gleason score, and PSA level. This matching process identified 160 patients per arm with well-balanced baseline characteristics, forming the population for the primary analysis.

Patient and Disease Characteristics

Following propensity score matching, baseline characteristics were well balanced between the darolutamide plus ADT arm (n = 160) and the ADT alone arm derived from CHAARTED (n = 160). The median age was 71 years (range, 45-91) in the darolutamide plus ADT arm and 69 years (range, 39-90) in the ADT alone arm. Patients aged younger than 68 years comprised 40.0% and 39.4% of the darolutamide and ADT arms, respectively, while those aged 68 years or older represented 60.0% and 60.6% of each arm.

ECOG performance status was similarly distributed across both arms. The majority of patients in each arm had an ECOG performance status of 0 (81.9% vs 80.6%), followed by a status of 1 (15.6% vs 19.4%) and a status of 2 (2.5% vs 0%) in the darolutamide and ADT arms, respectively. With respect to Gleason score at initial diagnosis, fewer than 8 was recorded in 28.1% and 30.6% of patients in the darolutamide and ADT arms, respectively, while a Gleason score of 8 or higher was present in 67.5% and 65.0%, and Gleason score was unknown in 4.4% of patients in each arm.

Median baseline PSA was 6.0 ng/mL (range, 0 to 7978) in the darolutamide plus ADT arm and 9.8 ng/mL (range, 0 to 4071) in the ADT alone arm. When categorized by PSA level, 62.5% of darolutamide-treated patients had a baseline PSA of 10 ng/mL or lower compared with 50.0% of ADT alone patients, while 37.5% and 50.0% of patients in the respective arms had a baseline PSA exceeding 10 ng/mL.

Extent of disease was also comparable between arms. High-volume disease with visceral metastases was present in 23.1% of darolutamide plus ADT patients and 20.6% of ADT alone patients. High-volume disease without visceral metastases was observed in 37.5% and 36.3% of patients in the respective arms, while low-volume disease was present in 39.4% and 43.1%. With respect to prior local therapy, the majority of patients in both arms had de novo mHSPC, with no prior local therapy reported in 73.8% of darolutamide plus ADT patients and 70.0% of ADT alone patients. Recurrent mHSPC, defined by prior local therapy, was present in 26.3% and 30.0% of patients in the respective arms.

Safety of Darolutamide in ARASEC Trial

In the ARASEC match-eligible population of 223 patients receiving darolutamide plus ADT, treatment-emergent adverse events (TEAEs) of any grade were reported in 214 patients (96.0%). Grade 1 TEAEs occurred in 37 patients (16.6%), grade 2 in 92 patients (41.3%), grade 3 in 77 patients (34.5%), grade 4 in 3 patients (1.3%), and grade 5 events occurred in 5 patients (2.2%). Serious TEAEs were reported in 52 patients (23.3%), and TEAEs leading to treatment discontinuation occurred in 18 patients (8.1%). Safety data were not recorded in detail in the CHAARTED ADT arm.

Sensitivity Analyses

McKay reported that 2 sensitivity analyses reinforced the robustness of the primary findings. When the full match-eligible population from both ARASEC and CHAARTED was analyzed using inverse probability of treatment weighting, the PFS hazard ratio was 0.28 (95% CI, 0.23-0.33). A second sensitivity analysis comparing the ARASEC darolutamide arm against the contemporary ADT arm from the ARANOTE trial using propensity score matching yielded a PFS hazard ratio of 0.30 (95% CI, 0.21-0.44). The consistency of results across all three analyses (primary, CHAARTED-matched sensitivity, and ARANOTE-matched sensitivity) strengthens confidence that the observed efficacy benefit reflects a true treatment effect.

Practice Implications

The ARASEC results carry particular relevance for the community oncology and urology setting, where the majority of mHSPC patients in the United States are managed. ARASEC provides US-specific evidence to complement the global ARANOTE trial results, which supported the FDA approval of darolutamide for mHSPC.² Further, the tolerability profile observed supports the practical feasibility of this regimen in a broad patient population that frequently carries significant cardiovascular and metabolic comorbidities.

References

1. McKay RR, Ross AE, Preston MA, et al. Darolutamide plus androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC): ARASEC – US prospective, open-label phase 2 study with an external control arm. J Urol. 2025;213(5 suppl):e1. doi:10.1097/01.JU.0001192572.07890.f8.08

2. U.S. Food and Drug Administration. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. FDA. June 3, 2025. Accessed May 15, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-metastatic-castration-sensitive-prostate-cancer