The FDA has accepted a supplemental new drug application (sNDA) seeking expanded indication for darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). The sNDA is supported by data from the phase 3 ARANOTE trial (NCT04736199). Darolutamide is currently approved by the FDA for use in combination with docetaxel for the treatment of patients with mHSPC and as a monotherapy for patients with nonmetastatic castration-resistant prostate cancer.
ARANOTE Trial Results
Results from the ARANOTE trial presented at the 2024 ESMO Congress demonstrated a 46% reduced risk of radiographic progression or death with darolutamide/ADT compared with placebo plus ADT (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). This met the primary endpoint of the study. At 24 months, the radiologic progression-free survival (rPFS) rates were 70.3% in the darolutamide arm vs 52.1% in the placebo group. The median rPFS was not reached (NR; 95% CI, NR-NR) vs 25.0 months (95% CI, 19.0-NR), respectively.
The darolutamide plus ADT combination also showed benefit across all secondary endpoints, although overall survival (OS) data were immature at the time of the primary analysis. The safety profile of darolutamide was consistent with previous findings, with no new safety signals identified with darolutamide plus ADT. The incidence of treatment-emergent adverse effects (AEs) was low across both arms, with a similar proportion of grade 3 or higher AEs observed.
About the ARANOTE Trial
The ARANOTE trial is a randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of darolutamide plus ADT vs placebo plus ADT in patients with mHSPC. Patients with histologically or cytologically confirmed prostate adenocarcinoma, metastatic disease, an ECOG performance status of 0 to 2, and adequate bone marrow, liver, and renal functions were eligible for enrollment. Patients must have started ADT with or without first-generation antiandrogen, but not earlier than 12 weeks prior to randomization.
Patients were randomly assigned in a 2:1 ratio to receive either darolutamide at 600 mg twice daily with ADT (n = 446) or placebo in combination with ADT (n = 223). The primary endpoint was rPFS, measured as time from randomization to the date of first documentation of radiological disease progression or death due to any cause. Secondary endpoints included OS, time from randomization to the date of first castration-resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety.
Ongoing Darolutamide Studies
In addition to the ARANOTE trial, darolutamide is being evaluated in the phase 3 ARASTEP trial (NCT05794906) in combination with ADT for high-risk biochemical recurrence HSPC without metastatic disease detected by conventional imaging, and a positive prostate-specific maturation antigen PET/CT scan at baseline. It is also being studied in the phase 3 DASL-HiCaP study (ANZUP1801) of adjuvant darolutamide for localized prostate cancer with a high risk of recurrence.
