By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved another androgen receptor inhibitor for nonmetastatic, castration-resistant prostate cancer. Darolutamide is the third to be approved, following apalutamide and enzalutamide, for this indication. Notably, darolutamide is chemically distinct from apalutamide and enzalutamide. The FDA granted fast-track designation and priority review. Darolutamide tablets will be distributed as Nubeqa.


Darolutamide should be prescribed to patients with nonmetastatic, castration-resistant prostate cancer.1


The recommended dose is 600 mg (2 × 300 mg) taken orally twice daily with food.1 Darolutamide is available as 300 mg tablets.


In vitro and mice studies suggest that darolutamide may be effective against enzalutamide-resistant prostate cancer and mutated forms of the androgen receptor.2,4 Darolutamide produces minimal blood-brain barrier penetration and minimal effect on serum testosterone levels.3,4 Also, darolutamide carries lower potential for overall drug-drug interactions involving CYP isoenzymes.1,5,6 It does not carry the same class warning for seizures, falls, and fractures as enzalutamide and apalutamide.


The most frequently reported adverse reactions (vs. placebo) include fatigue (16% vs. 11%), reduced neutrophil counts (20% vs. 9%), elevated AST (23% vs. 14%), and elevated bilirubin levels (16% vs. 7%).1 In darolutamide-treated subjects, dosage interruption occurred in 13%, dosage reduction in 6%, and permanent discontinuation in 9%.1 Darolutamide shares the class warning for embryo-fetal toxicity.1 Men with female partners of reproductive potential should use effective contraception during treatment and for one week after the last dose. Concomitant use of combined P-glycoprotein and strong or moderate CYP3A4 inducers should be avoided.1 Concomitant use with breast cancer-resistant protein substrates (e.g., rosuvastatin) increases their systemic exposure.1


The safety and efficacy of darolutamide was evaluated in a double-blind, placebo-controlled trial that included subjects with nonmetastatic, castration-resistant prostate cancer with prostate-specific antigen doubling time (PSADT) of ≤ 10 months.1,7 Subjects were randomized to darolutamide (600 mg twice daily; n = 955) or placebo (n = 554). The median PSADT was 4.5 months; 73% of subjects received prior antiandrogen treatment (bicalutamide or flutamide), 42% had undergone surgery or radiotherapy to the prostate, and 73% had a Gleason Score of ≥ 7 at diagnosis. The primary efficacy endpoint was metastatic-free survival (MFS; time from randomization to radiographic progression or as the time to death without radiographic progression). Secondary endpoints included overall survival and time to pain progression. Median MFS was 40.4 months for darolutamide subjects and 18.4 months for placebo subjects (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.34-0.50). Benefit was observed regardless of PSADT status (≤ 6 months or > 6 months). The first interim analysis suggested lower risk of death (HR, 0.71; 95% CI, 0.50-0.99). However, median survival has not been reached. Also, there was longer time to pain progression (40.3 months vs. 25.4 months; HR, 0.65; 95% CI, 0.53-0.79).

The primary outcomes (MFS) were similar to those outcomes reported for apalutamide (40.5 months vs. 16.2 months; HR, 0.28; 95% CI, 0.23-0.35) and enzalutamide (36.6 months vs. 14.7 months; HR, 0.29; 95% CI, 0.24-0.35).8,9 Fracture and fall rates were similar to placebo (4.2% vs. 3.6% for fracture; 4.2% vs. 4.7% for falls).7 In contrast, fracture and fall rates were numerically higher than placebo for apalutamide (6.3% vs. 4.6% for fracture; 7.4% vs. 7.0% for falls) and enzalutamide (combined nonpathologic fractures and falls 17% vs. 8%).8,9


Prostate cancer is the most commonly diagnosed solid tumor and is the second leading cause of cancer deaths among U.S. men.10 Generally, androgen deprivation is standard treatment (medical or surgical castration). However, despite castrate levels of testosterone, most cancers eventually become castration-resistant. Nonmetastatic, castration-resistant prostate cancer represents a small portion of advanced prostate cancers.

Darolutamide is the third agent approved for this cancer; all three options are recommended by the National Comprehensive Cancer Network (version 4.2019) for those with PSADT of ≤ 10 months and no or minimal symptoms. Darolutamide may be better tolerated, but its role in enzalutamide- or apalutamide-resistant cancer remains to be confirmed through further clinical trials. Darolutamide costs $11,550 for a 30-day supply, which is similar to enzalutamide ($11,549) and apalutamide ($11,673).


  1. Bayer HealthCare Pharmaceuticals Inc. Nubeqa Prescribing Information, July 2019. Available at: Accessed Sept. 11, 2019.
  2. Borgmann H, Lallous N, Ozistanbullu D, et al. Moving towards precision urologic oncology: Targeting enzalutamide-resistant prostate cancer and mutated forms of the androgen receptor using the novel inhibitor darolutamide (ODM-201). Eur Urol 2018;73:4-8.
  3. Shore ND. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opin Pharmacother 2017;18:945-952.
  4. Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep 2015;5:12007.
  5. Astellas Pharma US Inc. Xtandi Prescribing Information, July 2018. Accessed Sept. 11, 2019.
  6. Janssen Products, LP. Erleada Prescribing Information, February 2018. Available at: Sept. 11, 2019.
  7. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2019;380:1235-1246.
  8. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378:1408-1418.
  9. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378:2465-2474.
  10. American Urological Association. Castration-Resistant Prostate Cancer (2018). Available at: Accessed Sept. 11, 2019.