Oncology Overview: Darolutamide, a New-Generation Oral Androgen Receptor Inhibitor

Darolutamide (Nubeqa; Bayer) is a new-generation oral androgen receptor (AR) inhibitor indicated for patients with non-metastatic castration-resistant prostate cancer.¹

Although androgen deprivation therapy is the mainstay of care for patients with advanced hormone-sensitive prostate cancer, most patients will subsequently develop castration-resistant prostate cancer.² The FDA approved darolutamide in 2019 for these patients. The drug’s novel molecular structure theoretically results in fewer and less severe toxic adverse effects (AEs) than other androgen-receptor inhibitors currently on the market.^1,3

Indications and Dosage

Darolutamide is available as a 300 mg oral tablet. The recommended dose is 600 mg administered twice a day with food.¹

Patients on darolutamide should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy. Patients may continue treatment with darolutamide until disease progression (assessed radiographically) or unacceptable toxicity occurs.¹

If a patient experiences grade 3 toxicity or higher or an intolerable reaction to darolutamide, withhold dosing or reduce the dose to 300 mg twice a day until improvement of symptoms.¹ Patients may then resume the standard regimen of 600 mg twice a day. The manufacturer does not recommend dose reduction below 300 mg twice a day.¹

Mechanism of Action

The primary targets for treatment in prostate cancer are androgens and androgen receptor signaling pathways.² Darolutamide exerts its effects via competitive inhibition of this androgen binding, leading to blockade of both:²

• androgen receptor nuclear translocation
• androgen receptor-mediated transcription

This then decreases signaling from androgen receptors and reduces overall serum androgen levels.

FDA Approval

The FDA approved darolutamide after review of the phase 3 multinational, randomized, double-blind, placebo-controlled Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) trial.³ ARAMIS’s primary endpoint was metastasis-free survival, the standard endpoint in trials involving castration-resistant prostate cancer.³

Median metastasis-free survival was 40.4 months in the darolutamide group, compared to 18.4 months in the placebo group (95% CI, P<0.001).³ Darolutamide reduced the risk of metastasis or death from any cause by 59%, a benefit evident across patient subgroups.³

AEs

Darolutamide’s most common adverse reactions are fatigue, pain in extremities, and rash (see Table 1).¹

Serious AEs occurred in 25% of patients receiving darolutamide and 20% of patients receiving the placebo.¹

In ARAMIS, researchers reported that the incidence of AEs was generally similar in the darolutamide and placebo groups.³ Further, after adjustment for treatment duration or observation period, the differences between treatment and placebo groups in the incidences of relevant AEs either decreased or disappeared.³

About the Author

Lisa E Ruohoniemi, PharmD, is a Clinical Staff Pharmacist at LewisGale Hospital, Montgomery Blacksburg, VA.

References

1. Nubeqa. Prescribing Information. Bayer; 2021. Accessed October 28, 2021. http://labeling.bayerhealthcare.com/html/products/pi/Nubeqa_PI.pdf .
2. Fizazi K, Albiges L, Loriot Y, Massard C. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2015;15(9):1007-1017. doi:10.1586/14737140.2015.1081566. Published September 2015. Accessed October 26, 2021.
3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671. Published February 2019. Accessed October 25, 2021.