FDA Approves Darolutamide for Metastatic Castration-Sensitive Prostate Cancer

US FDA

The FDA has approved darolutamide (Nubeqa) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC).¹

This regulatory decision was based on data from the randomized, double-blind, placebo-controlled phase 3 ARANOTE trial (NCT04736199), which evaluated darolutamide vs placebo, with concomitant androgen deprivation therapy (ADT), in 669 patients with mCSPC.

Patients who received darolutamide (n = 446) achieved a statistically significant improvement in radiogrtaphic progression-free survival (rPFS) compared with those who received placebo (n = 223).^1,2 The median rPFS was not reached (NR; 95% CI, NR-NR) in the darolutamide arm vs 25.0 months (95% CI, 19.0-NR) in the placebo arm (HR, 0.54; 95% CI, 0.41-0.71; P < 0.0001). The 24-month rPFS rates were 70.3% with darolutamide vs 52.1% with placebo.² Consistent rPFS benefits were seen with darolutamide across patient subgroups, including in patients with high-volume (HR, 0.60; 95% CI, 0.44-0.80) and low-volume (HR, 0.30; 95% CI, 0.15-0.60) disease.

The final analysis revealed no statistically significant improvement in overall survival (OS) with darolutamide vs placebo (HR 0.78; 95% CI, 0.58-1.05).¹ The 24-month OS rates were 79.8% with darolutamide vs 75.5% with placebo.²

ARANOTE enrolled adult patients at least 18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate and metastatic disease that was centrally confirmed by conventional imaging.² Patients needed to have an ECOG performance status of 0 to 2; as well as adequate liver, bone marrow, and renal function.

All patients began treatment with investigator's choice of ADT within 12 weeks prior to initiating study treatment. Patients were also randomly assigned 2:1 to receive darolutamide at 600 mg twice daily or matched placebo. Patients were stratified by use of prior local therapy and the presence of visceral metastases. All patients received study treatment until unacceptable toxicity, radiological disease progression, initiation of new anticancer therapy, study drug interruption lasting longer than 28 consecutive days, or patient or physician decision.

rPFS served as the trial's primary end point. Secondary end points included OS, time to metastatic castration-resistant prostate cancer (mCRPC), time to initiation of subsequent systemic anticancer therapy for prostate cancer, time to prostate-specific antigen (PSA) progression, rates of PSA levels less than 0.2 ng/mL in patients with baseline PSA levels of at least 0.2 ng/mL, and time to pain progression.

Clear benefits with darolutamide vs placebo were seen across many other secondary end points, including time to mCRPC (HR, 0.40; 95% CI, 0.32-0.51), time to PSA progression (HR, 0.31; 95% CI, 0.23-0.41), time to initiation of subsequent systemic anticancer therapy (HR, 0.40; 95% CI, 0.29-0.56), and time to pain progression (HR, 0.72; 95% CI, 0.54-0.96). Additionally, a higher proportion of patients in the darolutamide arm achieved a PSA level lower than 0.2 ng/mL at any time during the treatment period (62.6%) compared with those in the placebo arm (18.5%).

The safety profile of darolutamide was consistent with previously observed toxicities associated with its use as monotherapy.¹ The most common grade 3/4 adverse effects seen with darolutamide in ARANOTE were hypertension (3.6%); pain in extremity (1.8%); bone pain and increased alkaline phosphatase levels (1.4% each); anemia (3.6%); back pain, headache, and COVID-19 (0.9% each); and increased aspartate aminotransferase levels, increased alanine aminotransferase levels, increased weight, urinary tract infection, and fatigue (0.5% each).² The prescribing information for darolutamide includes precautions and warnings regarding ischemic heart disease, seizure, and embryo-fetal toxicity.¹

The recommended dose of darolutamide is 600 mg, divided into 2 300-mg tablets, taken orally twice a day with food until disease progression or unacceptable toxicity.

References

1. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. FDA. June 3, 2025. Accessed June 3, 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;42(36):4271-4281. doi:10.1200/JCO-24-01798