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July 30, 2019, with PAP

On July 30, 2019, the Food and Drug Administration approved darolutamide (NUBEQA, Bayer HealthCare Pharmaceuticals Inc.) for non-metastatic castration-resistant prostate cancer.

Approval was based on ARAMIS (NCT02200614), a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with non-metastatic castration resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

The primary endpoint was metastasis free survival (MFS), 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. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001). OS data were not mature.

The most common adverse reactions (≥2%) in patients who received darolutamide were fatigue, pain in extremity, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm. The seizure incidence was similar on the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300 mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

View full prescribing information for NUBEQA.

FDA granted darolutamide fast track designation. FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Darolutamide for the Treatment of Nonmetastatic Castration-Resistant Prostate Cancer

Author: Jacquelyn Day, PharmD
PGY-1 Pharmacy Resident
Vanderbilt University Medical Center
Nashville, TN

What is the potential role for darolutamide in the treatment of nonmetastatic castration-resistant prostate cancer (M0 CRPC)? 

  • Darolutamide is an androgen receptor inhibitor that competitively inhibits the binding of testosterone to the androgen receptor and subsequent androgen receptor nuclear translocation and transcription, which results in decreased proliferation and apoptosis in tumor cells.1 This blockade results in a cessation or reduction in tumor growth.
  • On the basis of the ARAMIS trial, the U.S. Food and Drug Administration (FDA) approved darolutamide on July 30, 2019, for nonmetastatic castration-resistant prostate cancer. Prior to this approval, two other medications in this same class were approved for M0 CRPC, apalutamide and enzalutamide.2
  • ARAMIS was a randomized double-blind multicenter trial that compared darolutamide 600 mg twice daily (n = 955) versus matched placebo (n = 554) for patients with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time (PSADT) of ≤10 months. All patients enrolled were required to also receive a gonadotropin-releasing hormone agonist or antagonist or have had a bilateral orchiectomy. Treatment was continued until radiographic progression, unacceptable toxicity, or withdrawal. Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 before enrollment, confirmed adenocarcinoma of the prostate, and a baseline PSA of at least 2 ng/mL. Patients with a history of seizures were not excluded (n = 12). However, patients with a history of metastasis were excluded. Additionally, patients with pelvic lymph nodes below the aortic bifurcation that measured less than 2 cm were allowed to enroll.
  • The primary endpoint was metastasis-free survival (MFS) from the time of randomization. Secondary endpoints were overall survival (OS), time to pain progression, time to first skeletal event, and time to first cytotoxic chemotherapy. Exploratory endpoints included progression-free survival (PFS), time to invasive prostate procedure, time to initiation of subsequent antineoplastic agent, change in ECOG score to ≥3, PSA progression and response, and quality of life. The median MFS was 40.4 months versus 18.4 months in the darolutamide and placebo groups, respectively (95% confidence interval [CI] 0.34–0.50; p < .001). Darolutamide also showed a greater benefit in all secondary endpoints including OS (p = .045) and most exploratory endpoints excluding quality of life, which was similar in the two groups. Darolutamide was associated with a lower risk of death (hazard ratio [HR] 0.71, 95% CI 0.50–0.99; two-sided p = .045). The frequency of all-grade seizures was similar in the darolutamide group versus placebo, occurring in 0.2% (n = 2) versus 0.1% (n = 1), respectively, and there were no grade 3 or 4 seizure events in either group. The most frequent adverse reactions that required dose interruption were hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%). The most common reasons for therapy discontinuation were cardiac failure (0.4%) and death (0.4%).
  • The National Comprehensive Cancer Network guideline for the treatment of prostate cancer indicates darolutamide as a category-1 first-line therapy for M0 CRPC in patients with PSADT of ≤10 months. Similarly, apalutamide and enzalutamide are also indicated in this population as a category-1 recommendation. In patients who continue to have an increase in PSA while on therapy without radiographic evidence of metastasis, all agents are feasible second-line options for M0 CRPC, because the guidelines allow the options of continuing current therapy or changing therapy with continued monitoring.3
  • Although darolutamide, apalutamide, and enzalutamide have not been compared in a head-to-head analysis, all three drugs had similar median MFS versus placebo. MFS for darolutamide was 40.4 months versus 18.4 months with placebo. For apalutamide, MFS was 40.5 months versus 16.2 months with placebo, and for enzalutamide it was 36.6 months versus 14.7 months with placebo.2,4,5
  • The most common adverse reactions and warnings:
    • darolutamide: fatigue, pain in extremity, diarrhea, hypertension, and rash. Warning for embryo-fetal toxicity.1
    • apalutamide: fatigue, arthralgia, rash, decreased appetite, hypertension, and diarrhea. Warning for ischemic cardiovascular events, fractures, falls, seizures, and embryo-fetal toxicity.6
    • enzalutamide: fatigue, diarrhea, edema, musculoskeletal pain, headache, and hypertension. Warnings for seizure risk, spinal cord compression, ischemic cardiovascular events, and embryo-fetal toxicity.7

What role can the pharmacist play in the management of patients on darolutamide?

  • Patients should use effective contraception during treatment and for at least 1 week after discontinuation because darolutamide may cause fetal harm.1
  • Liver function, renal function, and complete blood count should be performed prior to initiation of darolutamide and throughout treatment because increases in aspartate aminotransferase/bilirubin and neutropenia were side effects of this medication. Additionally, a baseline PSA and continued monitoring should take place as a surrogate marker for disease progression.1,2
  • The patient’s baseline cardiac function should also be considered because cardiac failure resulted in treatment discontinuation in the ARAMIS trial (0.4%).2
  • Darolutamide is taken as two 300-mg tablets twice daily (1,200-mg total daily dose) with food.
  • In patients who experience grade ≥3 toxicity or an intolerable reaction, doses can be reduced to 300 mg twice daily or withheld until symptoms improve and then restarted at 600 mg twice daily. The minimum recommended dose is 300 mg twice daily.1
  • The most common adverse reactions of grades ≥3 were hypertension (3.1% vs. 2.2% in darolutamide vs. placebo), urinary retention (1.6% vs. 2%), and fatigue (0.4% vs. 0.9%).2
  • Patients with moderate hepatic impairment (Child-Pugh class B) or with severe renal impairment (estimated glomerular filtration rate 15–29 mL/min/1.73 m2) who are not receiving hemodialysis should receive a maximum of 300 mg twice daily.1
  • Concomitant use of darolutamide with both a strong P-glycoprotein inducer and strong or moderate CYP3A4 inducer is not recommended. If the combination cannot be avoided, patients should be monitored closely because this combination can decrease the levels and efficacy of darolutamide. No dose adjustments have been established.1
  • Patients may be eligible for 2 months of free drugs provided by Darolutamide User Drug Experience (DUDE), and commercially insured patients may qualify for a $0 co-pay card. The access service can be reached Monday through Friday, 9 am–7 pm EST, at 1.833.337.DUDE.8

Clinical Pearls

  • Darolutamide is supplied as 300-mg tablets. The bioavailability is increased 2- to 2.5-fold when the drug is administered with food.1
  • Unlike its predecessors apalutamide and enzalutamide, darolutamide does not cross the blood-brain barrier and has a lower affinity for gamma-aminobutyric acid receptors and a higher affinity for the androgen receptor, which reduces its central nervous system side effects, including seizures, falls, and cognitive impairment.2
  • Patients on darolutamide should also be concurrently receiving a gonadotropin-releasing hormone analog or have previously received a bilateral orchiectomy.1
  • Darolutamide should be stored at room temperature in the original bottle with the cap tightly sealed.1 
  • Drug interactions differ significantly between darolutamide, apalutamide, and enzalutamide. Darolutamide has the fewest clinically relevant drug interactions.1 Darolutamide is a weak CYP3A4 inducer, whereas apalutamide and enzalutamide are strong CYP3A4 inducers.1,6,7 Enzalutamide is a major CYP2C8 and CYP3A4 substrate, as well as a moderate CYP2C19 and CYP2C9 inducer.6 Apalutamide is also a strong CYP2C19 inducer.7
  • Patients should take a missed dose as soon as they remember but should not take two doses together if one has been missed.1


  1. Nubeqa (darolutamide) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc., 2019.
  2. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 4.2019 (August 19, 2019). Available at Accessed September 8, 2019.
  4. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.
  5. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474.
  6. Erleada (apalutamide) [package insert]. Horsham, PA: Janssen Pharmaceuticals, 2019.
  7. Xtandi (enzalutamide) [package insert]. Northbrook, IL: Astellas Pharma Inc., 2012.
  8. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals, Inc., 2019. Accessed at