DAROLUTAMIDE combined with androgen-deprivation therapy significantly delays disease progression in metastatic hormone-sensitive prostate cancer without requiring chemotherapy. Findings from the global, randomized, double-blind Phase III ARANOTE trial demonstrate that this doublet regimen substantially reduces the hazards of clinical deterioration while sparing patients the immediate toxicity of cytotoxic agents.
The primary analysis of the trial evaluated 669 patients assigned to either darolutamide 600 mg twice daily or placebo alongside investigator-selected androgen-deprivation therapy. Patients receiving darolutamide experienced a 46% reduction in the risk of radiological progression or death compared to placebo recipients (hazard ratio, 0.54; 95% confidence interval, 0.41 to 0.71; P < .0001). While median radiological progression-free survival reached 25.0 months in the control group, median survival remained unreached in the active treatment cohort at the primary cutoff. The 24-month progression-free survival rate stood at 70.3% with the study drug versus 52.1% with control therapy. Stratified analyses confirmed consistent therapeutic advantages across prespecified groups, benefiting individuals with high-volume and low-volume metastatic burdens alike.
Secondary endpoints reinforced the systemic potency of darolutamide in metastatic hormone-sensitive prostate cancer. Time to metastatic castration-resistant prostate cancer was markedly prolonged (hazard ratio, 0.40; 95% confidence interval, 0.32 to 0.51), as was time to prostate-specific antigen progression (hazard ratio, 0.31). A confirmed undetectable prostate-specific antigen level below 0.2 ng/mL was achieved by 62.6% of patients on the novel agent compared to 18.5% on standard androgen blockade alone. Furthermore, active intervention delayed time to pain progression (hazard ratio, 0.72) and prolonged the interval before subsequent systemic anticancer treatments were required.
The regimen proved exceptionally well tolerated across a globally diverse population comprising Asian, Black, and White participants. Overall treatment-emergent adverse event rates were equivalent between arms, with grade 3 or 4 events documented in 30.8% of darolutamide recipients and 30.3% of placebo controls. Notably, the incidence of fatigue was lower in the darolutamide group (5.6%) than in the control cohort (8.1%). Adverse events prompting treatment discontinuation were also lower with darolutamide (6.1%) than with placebo (9.0%), highlighting a favorable safety profile that addresses long-standing concerns regarding treatment burden.
Reference
Saad F et al. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol. 2024;42(36):4271-4281.
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