Darolutamide Plus ADT Gains EU Approval for mHSPC

The European Commission has approved darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) for the treatment of adults with metastatic hormone-sensitive prostate cancer (mHSPC).¹

This approval follows a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, which endorsed the use of darolutamide in combination with ADT in this setting.

Regulatory approval was based on data from the randomized phase 3 ARANOTE trial (NCT04736199) presented at the 2024 ESMO Congress, which showed that the trial met its primary end point, demonstrating a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS). Darolutamide plus ADT reduced the risk of radiographic progression or death by 46% compared with placebo plus ADT (HR, 0.54; 95% CI, 0.41-0.71; P < .0001). The median rPFS was not reached in the darolutamide group compared with 25.0 months in the placebo group.²

Consistent rPFS benefit was observed in patients with high-volume disease (HR, 0.60; 95% CI, 0.44-0.80) and low-volume disease (HR, 0.30; 95% CI, 0.15-0.60).¹

On June 3, 2025, the FDA approved darolutamide for the treatment of patients with metastatic castration-sensitive prostate cancer, based on data from ARANOTE.³

ARANOTE Trial Overview

ARANOTE was a randomized, double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of darolutamide in combination with ADT in patients with mHSPC.² Patients were required to have an ECOG performance status of 0 to 2; and adequate bone marrow, liver, and renal function. Initiation of ADT was allowed within 12 weeks of random assignment. Investigators excluded patients who had only regional lymph node metastases; had a baseline superscan; or had received prior androgen receptor pathway inhibitors or chemotherapy for prostate cancer.

A total of 669 patients were randomly assigned 2:1 to receive either darolutamide at 600 mg twice daily or a matching placebo, both in combination with ADT.

The primary end point of the trial was rPFS. Secondary end points included overall survival (OS), time to first CRPC event, time to initiation of subsequent systemic anticancer therapy, time to prostate-specific antigen (PSA) progression, rate of undetectable PSA, time to pain progression, and safety.

Additional data showed that the darolutamide regimen was associated with improvements in 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).

Regarding safety, the rate of grade 3/4 adverse effects (AEs) was 30.8% in the darolutamide arm vs 30.3% in the placebo arm. AEs led to death in4.7% and 5.4% of patients, respectively. Serious AEs occurred in 23.6% of patients in the darolutamide group vs 23.5% of patients in the placebo group. AEs led to treatment discontinuation in 6.1% and 9.0% of patients, respectively.

Ongoing studies include the phase 3 ARASTEP trial (NCT05794906), which is assessing the efficacy of darolutamide plus ADT compared with ADT alone in patients with HSPC at high-risk of biochemical recurrence.¹ Eligible patients in this trial have no detectable metastases on conventional imaging but exhibit prostate-specific membrane antigen (PSMA)–positive lesions on PET/CT at baseline.

Additionally, darolutamide is being studied in the phase 3 DASL-HiCaP (ANZUP1801) trial, a collaborative effort led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). This trial is evaluating the addition of darolutamide to radiotherapy in patients with localized high-risk prostate cancer.

References

1. Darolutamide receives EU approval in third indication for patients with advanced prostate cancer. News Release. Orion Pharma. Accessed July 21, 2025. https://www.orionpharma.com/newsroom/all-news/releases/press-releases/2025/darolutamide-receives-eu-approval-in-third-indication-for-patients-with-advanced-prostate-cancer/
2. Saad F, Vjaters E, Shore N, 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. doi:10.1200/JCO-24-01798
3. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. FDA. June 3, 2025. Accessed July 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-metastatic-castration-sensitive-prostate-cancer