Fred Saad, MD, FRCS, reacts to FDA approval of darolutamide in mCSPC

On June 3, 2025, the FDA approved darolutamide (Nubeqa) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC).¹

The approval was supported by data from the phase 3 ARANOTE trial (NCT04736199), which showed that darolutamide plus ADT significantly extended radiographic progression-free survival (rPFS) compared with placebo plus ADT in patients with mCSPC.² At 24 months, the rate of rPFS was 70.3% in the darolutamide arm vs 52.1% in the placebo arm, translating to a 46% reduction in the risk of radiographic progression or death (HR, 0.54; 95% CI, 0.41-0.71; P < .0001).

Darolutamide was previously approved in the US for mCSPC in combination with docetaxel.

In a recent interview with Urology Times®, Fred Saad, MD, FRCS, lead author of the ARANOTE trial, shares his thoughts on the recent approval of darolutamide in mCSPC and walks through key data that supported the agency’s decision. Saad is a professor and chairman of the department of surgery as well as the head of GU oncology at the University of Montreal.

In total, the ARANOTE trial included 669 patients who were randomly assigned 2:1 to receive 600 mg darolutamide twice daily plus ADT (n = 446) or to matching placebo plus ADT (n = 223).

In a final analysis of the data, there was no statistically significant improvement in overall survival (OS) with the addition of darolutamide (HR, 0.78; 95% CI, 0.58 to 1.05). At 24 months, the OS rate was 79.8% in the darolutamide arm and 75.5% in the placebo arm.

Data did show improvements in the trial's key secondary end points with the addition of darolutamide.Specifically, darolutamide was associated with a trend toward clinical benefit in the time to metastatic castration-resistant prostate cancer (HR, 0.40; 95% CI, 0.32 to 0.51) and time to prostate-specific antigen PSA progression (HR, 0.31; 95% CI, 0.23 to 0.41). Time to pain progression (HR, 0.72; 95% CI, 0.54 to 0.96), and time to subsequent systemic anticancer therapy (HR, 0.40; 95% CI, 0.29 to 0.56) were also delayed in the darolutamide arm.

Treatment was well-tolerated across both study arms. The incidence of treatment-emergent adverse events (TEAEs) was similar between the 2 groups, with TEAEs leading to permanent discontinuation of study drug occurring in 6.1% of patients in the darolutamide/ADT arm and 9.0% of patients in the placebo/ADT arm. No new safety signals were reported.

Based on these data, Saad concluded, “[It was] very reassuring that the adverse event profile was basically identical to placebo, including fatigue, which is one of the most common complaints, was not greater than the placebo. If anything [it] looked like slightly less fatigue with darolutamide than with placebo, so very reassuring in terms of efficacy and in terms of tolerability and adverse events.”

REFERENCES

1. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. News release. US Food & Drug Administration. June 3, 2025. Accessed June 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-metastatic-castration-sensitive-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 Sep 16:JCO2401798. doi:10.1200/JCO-24-01798