PRECLINICAL STUDIES

ARI=androgen receptor inhibitor.

AR=androgen receptor.
Two studies demonstrated low blood-brain barrier penetration with NUBEQA5,6
In a preclinical mouse model
NUBEQA DEMONSTRATED MINIMAL PENETRATION ACROSS THE BLOOD-BRAIN BARRIER
3%
BRAIN-TO-PLASMA RATIO
In a preclinical rat model
NUBEQA DEMONSTRATED LOW BLOOD-BRAIN BARRIER PENETRATION
8%
BLOOD-BRAIN BARRIER PENETRATION
The penetration of NUBEQA across the human blood-brain barrier has not been studied; therefore, no such assumptions can be made
HIGHEST-LEVEL RECOMMENDATIONS IN AUA AND EAU GUIDELINES
Recommended for men with nmCRPC by:
AMERICAN UROLOGICAL
ASSOCIATION
(AUA/ASTRO/SUO Guideline)
Strong recommendation; Evidence Level Grade A
with continued ADT for men with nmCRPC at high risk
for developing metastatic disease (PSADT ≤10 months)7
EUROPEAN ASSOCIATION
OF UROLOGY
(EAU/EANM/ESTRO/ESUR/ISUP/SIOG Guidelines)
Strong recommendation for men with M0 CRPC at
high risk of developing metastasis (PSADT <10 months)
to prolong time to metastases and overall survival8
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Category 1 Preferred Treatment Option
NCCN GUIDELINES®
Category 1 Preferred Treatment Option with ADT for men with nmCRPC with a PSADT ≤10 months9
nmCRPC=non-metastatic castration-resistant prostate cancer; ASTRO=American Society for Radiation Oncology; SUO=Society of Urologic Oncology; ADT=androgen deprivation therapy; PSADT=prostate-specific antigen doubling time; EANM=European Association of Nuclear Medicine; ESTRO=European Society for Radiotherapy and Oncology; ESUR=European Society of Urogenital Radiology; ISUP=International Society of Urological Pathology; SIOG=International Society of Geriatric Oncology; CRPC=castration-resistant prostate cancer; NCCN=National Comprehensive Cancer Network ® (NCCN ®).
Indications
NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:
- Non-metastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel
Important Safety Information
Warnings & Precautions
Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 2.9% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease.
Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment.
Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.
Adverse Reactions
In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure.
In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury.
Drug Interactions
Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.
Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.
Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.
NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.
Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.
Please see the full Prescribing Information.
You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
References:
1. Data on file. Bayer HealthCare Pharmaceuticals, Inc.; Whippany, NJ. 2. NUBEQA (darolutamide) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; August 2022. 3. Fizazi K, Smith MR, Tombal B. Clinical development of darolutamide: a novel androgen receptor antagonist for the treatment of prostate cancer. Clin Genitourin Cancer. 2018;16(5):332-340. 4. Moilanen A-M, 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. Moilanen A, Riikonen R, Oksala R, et al. ODM-201—new generation antiandrogen with excellent antiandrogenic and antitumor activity in nonclinical models of CRPC. Abstract presented at: The European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. 6. Sandmann S, Trummel D, Seidel D, et al. Higher blood-brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography. Poster presented at American Society of Clinical Oncology Genitourinary Cancers Symposium, February 14-16, 2019; San Francisco, CA. 7. Lowrance W, Breau R, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline 2020. American Urological Association; 2020. 8. Mottet N, Cornford P, van den Bergh RCN, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer. European Association of Urology; 2022. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2023. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed September 20, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.