On July 30, 2019, darolutamide was approved for the treatment of patients with nonmetastatic castration-resistant prostate cancer.^1,2

Approval was based on findings in the double-blind phase III ARAMIS trial (ClinicalTrials.gov identifier NCT02200614), in which 1,509 patients were randomly assigned 2:1 to receive oral darolutamide at 600 mg twice daily (n = 955) or matching placebo (n = 554).^2,3 All patients concurrently received a gonadotropin-releasing hormone (GnRH) analog or had undergone previous bilateral orchiectomy. Treatment continued until radiographic disease progression as assessed by blinded independent central review, unacceptable toxicity, or withdrawal.

Patients had to have a prostate-specific antigen (PSA) doubling time of ≤ 10 months. Patients with a history of seizure were not excluded; 12 patients with seizure history were treated in the darolutamide group.

Patients had a median age of 74 years (range = 48–95 years); 79% were white, 13% Asian, and 3% black; Gleason score was ≥ 7 in 73% at diagnosis; median PSA doubling time was 4.5 months; 42% of patients in both groups had prior surgery or radiotherapy; 11% had enlarged pelvic lymph nodes < 2 cm at study entry; 73% received prior treatment with an antiandrogen (bicalutamide or flutamide); all patients had Eastern Cooperative Oncology Group performance status of 0 or 1; and 6% were retrospectively identified on blinded independent central review as having metastases at baseline.

The primary endpoint was metastasis-free survival, defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. Median metastasis-free survival was 40.4 months (95% confidence interval [CI] = 34.3 months to not reached) in the darolutamide group vs 18.4 months (95% CI = 15.5–22.3 months) in the placebo group (hazard ratio = 0.41, P < .0001). Results were consistent across patient subgroups for PSA doubling time (≤ 6 months or > 6 months) and prior use of bone-targeting agents. Overall survival data were not mature at the time of analysis.

How It Works

Darolutamide is an androgen receptor (AR) inhibitor. It competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. A major metabolite, keto-darolutamide, has exhibited in vitro activity similar to darolutamide.

Darolutamide has also functioned as a progesterone receptor antagonist in vitro (approximately 1% activity compared to AR). Darolutamide has decreased prostate cancer cell proliferation in vitro and reduced tumor volume in mouse xenograft models of prostate cancer.

How It Is Used

The recommended dosage of darolutamide is 600 mg orally twice daily. Patients should receive a GnRH analog concurrently or should have had a bilateral orchiectomy. The recommended dosage is 300 mg twice daily in patients with severe renal impairment not receiving dialysis and in patients with moderate hepatic impairment.

For patients experiencing toxicity ≥ grade 3 or intolerable adverse reactions, dosing should be withheld or reduced to 300 mg twice daily until symptoms improve. Treatment may then be resumed at a dose of 600 mg twice daily. Dose reduction below 300 mg twice daily is not recommended.

Concomitant use of darolutamide with combined P-glycoprotein and strong or moderate CYP3A inducers (eg, phenytoin, rifampin, carbamazepine, St. John’s wort) should be avoided. If darolutamide is used with combined P-glycoprotein and strong CYP3A inhibitors (eg, ketoconazole, conivaptan, clarithromycin), patients should be monitored more frequently for darolutamide adverse reactions. Concomitant use with drugs that are breast cancer resistance protein substrates should be avoided when possible; if concomitant use occurs, patients should be monitored more frequently for adverse reactions, and dose reduction of the breast cancer resistance protein substrate drug should be considered.

Safety Profile

In the ARAMIS trial, the median duration of exposure to darolutamide was 14.8 months (range = 0–44.3 months). The most common adverse events of any grade with a ≥ 2% higher incidence in the darolutamide group vs placebo group were fatigue (16% vs 11%, grade ≥ 3 in 0.6% vs 1.1%), pain in an extremity (6% vs 3%, grade ≥ 3 in 0% vs 0.2%), and rash (3% vs 1%, grade ≥ 3 in 0.1% vs 0%).

Other clinically significant adverse events occurring in ≥ 2% of patients in the darolutamide group were ischemic heart disease (4.0% vs 3.4%) and heart failure (2.1% vs 0.9%). The incidence of seizure was 0.2% in both groups.

The most common laboratory abnormalities of any grade included increased aspartate transaminase (23% vs 14%, grade 3 or 4 in 0.5% vs 0.2%), decreased neutrophils (20% vs 9%, grade 3 or 4 in 4% vs 0.6%), and decreased bilirubin (16% vs 7%, grade 3 or 4 in 0.1% vs 0%).

Serious adverse events occurred in 25% vs 20% of patients, with those occurring in ≥ 1% of the darolutamide group being urinary retention, pneumonia, and hematuria. In the darolutamide group, adverse events led to dose interruption in 13% of patients (most common = hypertension in 0.6% and diarrhea and pneumonia in 0.5% each), dose reduction in 6% (most common = fatigue in 0.7% and hypertension and nausea in 0.3% each), and discontinuation of treatment in 9% (most common = cardiac failure in 0.4%).

Adverse events led to death in 3.9% of the darolutamide group vs 3.2% of the placebo group. Causes of death in the darolutamide group included cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%).

Darolutamide carries warnings/precautions for embryofetal toxicity. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer. Accessed August 12, 2019.

2. Nubeqa (darolutamide) tablets prescribing information, Bayer HealthCare Pharmaceuticals, July 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf. Accessed August 12, 2019.

3. Fizazi K, Shore N, Tammela TL, et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 380:1235-1246, 2019.