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 Dec 20;42(36):4271-4281. doi: 10.1200/JCO-24-01798. Epub 2024 Sep 16.

Abstract

Purpose: For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life. Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC.

Methods: In this global phase III trial, patients were randomly assigned 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary end point was radiological progression-free survival (rPFS).

Results: From March 2021 to August 2022, 669 patients were randomly assigned (darolutamide n = 446; placebo n = 223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46% versus placebo plus ADT (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.71]; P < .0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR, 0.81 [95% CI, 0.59 to 1.12]), and clinical benefits were seen across all other secondary end points, including delayed time to metastatic castration-resistant prostate cancer (HR, 0.40 [95% CI, 0.32 to 0.51]) and time to pain progression (HR, 0.72 [95% CI, 0.54 to 0.96]). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment because of adverse events.

Conclusion: These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase III darolutamide trials.

Trial registration: ClinicalTrials.gov NCT04736199.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Androgen Antagonists* / administration & dosage
  • Androgen Antagonists* / adverse effects
  • Androgen Antagonists* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Double-Blind Method
  • Humans
  • Male
  • Middle Aged
  • Progression-Free Survival
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Pyrazoles* / administration & dosage
  • Pyrazoles* / adverse effects
  • Pyrazoles* / therapeutic use
  • Sulfonamides / administration & dosage
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use

Substances

  • darolutamide
  • Pyrazoles
  • Androgen Antagonists
  • Sulfonamides

Associated data

  • ClinicalTrials.gov/NCT04736199