On August 5, 2022, darolutamide was approved for use in combination with docetaxel for patients with metastatic hormone-sensitive prostate cancer.1
Approval was based on the double-blind ARASENS trial (ClinicalTrials.gov identifier NCT02799602), in which 1,305 patients were randomly assigned to receive oral darolutamide at 600 mg twice daily (n = 651) or placebo (n = 654) combined with docetaxel at 75 mg/m2 every 3 weeks for up to six cycles. All patients concurrently received a gonadotropin-releasing hormone analog or had bilateral orchiectomy.
Median overall survival was not reached (95% confidence interval [CI] = not reached to not reached) in the darolutamide/docetaxel group vs 48.9 months (95% CI = 44.4 months to not reached) in the placebo/docetaxel group (hazard ratio [HR] = 0.68, 95% CI = 0.57–0.80, P < .0001). Darolutamide/docetaxel was associated with a significant delay in the time to pain progression (HR = 0.79, 95% CI = 0.66–0.95, P = .006).
How It Is Used
The recommended dose is 600 mg twice daily until disease progression or unacceptable toxicity. Docetaxel at 75 mg/m2 is administered every 3 weeks for up to six cycles. The first dose of docetaxel should be administered within 6 weeks after the start of darolutamide treatment. Patients should concurrently receive a gonadotropin-releasing hormone analog or have had a bilateral orchiectomy. Recommended doses are 300 mg twice daily for patients with severe renal impairment who are not on dialysis and for those with moderate hepatic impairment.
Among patients in the ARASENS trial, the most common adverse events of any grade in the darolutamide/docetaxel group were constipation (23% vs 20% in the placebo/docetaxel group), decreased appetite (19% vs 13%), rash (19% vs 15%), hemorrhage (18% vs 13%), increased weight (18% vs 16%), and hypertension (14% vs 9%). The most common grade 3 or 4 adverse events included hypertension (7% vs 3.7%) and rash (1.8% vs 0.2%).
The most common laboratory abnormalities of any grade (≥ 30%) in the darolutamide/docetaxel group were anemia (72%), hyperglycemia (57%), decreased lymphocytes (52%), decreased neutrophils (49%), increased aspartate aminotransferase (40%), increased alanine aminotransferase (37%), and hypocalcemia (31%). The most common grade 3 or 4 abnormalities were decreased neutrophils (33%), decreased lymphocytes (12%), and hyperglycemia (7%).
Serious adverse events were reported in 45% of the darolutamide/docetaxel group, most commonly febrile neutropenia (6%), decreased neutrophils (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Adverse events led to discontinuation of darolutamide in 14% of patients, most commonly because of rash (1.1%), musculoskeletal pain (0.9%), and aspartate aminotransferase increase (0.9%). Adverse events led to death in 4% of patients, with causes including COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%).
Darolutamide has warnings/precautions for ischemic heart disease, seizure, and embryofetal toxicity.
1. Nubeqa (darolutamide) tablets prescribing information, Bayer HealthCare Pharmaceuticals Inc, August 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212099s002lbl.pdf. Accessed August 10, 2022.