IMPORTANT SAFETY INFORMATION

Embryo-Fetal Toxicity: Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Continue reading »

NUBEQA (darolutamide) 300 mg tablets logo

IMPORTANT SAFETY INFORMATION

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. Continue reading »

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STUDY DESIGN

 

ARAMIS IS THE LARGEST PHASE III
STUDY IN nmCRPC TO DATE1-3

Double-blind, placebo-controlled, international, multicenter study1,4

Study design: double-blind, placebo-controlled, international, multicenter study, non-metastatic CRPC (N=1509)
  • Men with prior seizure or conditions predisposing to seizure were allowed in the study
  • Treatment continued until radiographic disease progression as assessed by conventional imaging (CT, MRI, 99mTc bone scan) by blinded independent central review, discontinuation due to adverse reactions, or withdrawal of consent

PRIMARY ENDPOINT

  • Metastasis-free survival (MFS)

SECONDARY ENDPOINTS

  • Overall survival (OS)
  • Time to pain progression
  • Time to first cytotoxic chemotherapy
  • Time to first symptomatic skeletal event

EXPLORATORY ENDPOINTS

  • Progression-free survival
  • Time to first prostate cancer–related procedure
  • Time to initiation of subsequent chemotherapy
  • PSA progression and response
  • Deterioration in ECOG PS
  • Quality of life§

*All patients received concurrent ADT (treatment with GnRH analog or previous bilateral orchiectomy).

Lymph nodes located below the aortic bifurcation as measured by the short axis.

Time to pain progression was defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory–Short Form or initiation of opioids, in patients treated with NUBEQA as compared to placebo. Pain progression was reported in 28% of patients on study.

§Tools used to prespecify quality of life exploratory endpoints are the EQ-5D-3L, a preference-based instrument, and the FACT-P, BPI-SF, and EORTC-QLQ-PR25 prostate-specific questionnaires.

CRPC=castration-resistant prostate cancer; PSADT=PSA doubling time; PSA=prostate-specific antigen; ECOG PS=Eastern Cooperative Oncology Group performance status; CT=computed tomography; GnRH=gonadotropin-releasing hormone.

Well-balanced study arms in ARAMIS4

Study arms in ARAMIS study: Baseline characteristics, NUBEQA (darolutamide) + ADT (n=955), ADT Alone (n=554)
  • ECOG performance status is graded according to the following criteria: 0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work, office work5
  • Bone-sparing agents included bisphosphonates, denosumab, vitamin D and analogs, calcium and calcium combinations, fluorides, and calcitonins6
  • Common previous hormonal therapies for prostate cancer (received by ≥10% of all patients) included leuprolide (52%), goserelin (32%), triptorelin (29%), bicalutamide (66%), flutamide (13%), and cyproterone (11%)4

IMPORTANT SAFETY INFORMATION (cont’d)

Adverse Reactions
Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥ 1 % of patients who received NUBEQA were urinary retention, pneumonia, and hematuria. Overall, 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for NUBEQA.

Please see additional Important Safety Information below.

EFFICACY

 

40 MONTHS MFS ACHIEVED with
NUBEQA + ADT1,4

Significant increase in median MFS vs ADT alone

  • MFS results were consistent across patient subgroups for1:
    • PSA doubling time (≤6 months or >6 months)
    • Prior use of bone-targeting agents (yes or no)

*95% CI: 34.3-NR.

95% CI: 15.5-22.3.

MFS=metastasis-free survival; ADT=androgen-deprivation therapy; PSA=prostate-specific antigen; HR=hazard ratio; CI=confidence interval; NR=not reached.

PSA response

• NUBEQA exposure at 600 mg twice daily results in PSA mean reduction of more than 90% from baseline1

Prespecified secondary endpoints1,4

Prespecified secondary endpoints: Median Duration (mo), NUBEQA (darolutamide) + ADT (955), ADT alone (554), HR (95% CI)
  • The MFS result was supported by a delay in time to pain progression, defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in men treated with NUBEQA + ADT as compared to ADT alone. Pain progression was reported in 28% of all men on study
  • OS data were not mature at the time of MFS analysis (57% of the required number of events). Secondary endpoints were evaluated in a hierarchical order, with a significance level of 0.05 split between the primary analysis and the final analysis (planned to occur after 240 deaths from any cause) of secondary endpoints. The endpoint OS was used to determine the alpha spend and significance threshold for each of the secondary endpoints. This prevented the significance criteria from being met in all secondary endpoints at the interim analysis
  • The planned final analysis has been conducted and mature data on OS and other secondary endpoints will be presented at an upcoming scientific meeting

IMPORTANT SAFETY INFORMATION (cont’d)

Adverse Reactions (cont'd)
Adverse reactions occurring more frequently in the NUBEQA arm (≥ 2% over placebo) were fatigue (16% vs. 11%), pain in extremity (6% vs. 3%) and rash (3% vs. 1%). Clinically significant adverse reactions occurring in ≥ 2% of patients treated with NUBEQA included ischemic heart disease (4.0% vs. 3.4% on placebo) and heart failure (2.1% vs. 0.9% on placebo).

Please see additional Important Safety Information below.

SAFETY

 

PROVEN TOLERABILITY IN MEN WITH nmCRPC

Three adverse reactions occurred more frequently with NUBEQA + ADT (≥2% over ADT alone)1,4

  • Overall, serious adverse reactions occurred in 25% of men receiving NUBEQA + ADT and in 20% of men receiving ADT alone1
    • Serious adverse reactions in ≥1% of men who received NUBEQA + ADT included urinary retention, pneumonia, and hematuria
  • Additionally, clinically significant adverse reactions occurring in ≥2% of men treated with NUBEQA + ADT vs ADT alone included ischemic heart disease (4.0% vs 3.4%) and heart failure (2.1% vs 0.9%)1
The only observed adverse reaction in ≥10% of patients receiving NUBEQA was fatigue1

Other adverse events (AEs) examined in ARAMIS4


Click each category below to expand.

% ALL GRADES

  • NUBEQA + ADT (n=954)
  • ADT Alone (n=554)

% GRADES 3/4

  • NUBEQA + ADT (n=954)
  • ADT Alone (n=554)

% ALL GRADES

  • NUBEQA + ADT (n=954)
  • ADT Alone (n=554)

% GRADES 3/4

  • NUBEQA + ADT (n=954)
  • ADT Alone (n=554)

*This Medical Dictionary for Regulatory Activities, version 20.0 (MedDRA) High Level Group Term includes coronary-artery disorders not elsewhere classified, coronary-artery arteriosclerosis, coronary artery disease, coronary-artery occlusion, and coronary-artery stenosis. Grade 5 events occurred in three patients receiving darolutamide and one patient receiving placebo.

This MedDRA High Level Group Term includes heart failure not elsewhere classified, cardiac failure, acute cardiac failure, chronic cardiac failure, congestive cardiac failure, and cardiogenic shock. Grade 5 events occurred in four patients receiving darolutamide and three patients receiving placebo.

This category combines the following MedDRA terms: any fractures and dislocations, limb fractures and dislocations, skull fractures, facial bone fractures and dislocations, spinal fractures and dislocations, and thoracic cage fractures and dislocations.

§All events that had been recorded under the MedDRA term “accident” were determined to have been accidental falls and are included in this category.

||This category combines the following MedDRA terms: cerebral infarction, cerebral ischemia, cerebrovascular accident, ischemic stroke, and transient ischemic attack. Grade 5 events occurred in one patient receiving NUBEQA and three patients receiving ADT alone.

ADT=androgen deprivation therapy.

NUBEQA did not cause more men to permanently discontinue due to adverse reactions1

The most frequent reasons in patients treated with NUBEQA included cardiac failure (0.4%) and death (0.4%)

Low rates of dose reductions and interruptions due to adverse reactions1

ADMINISTRATION

 

DOSING WITH NUBEQA

Recommended dosage1

  • Two 300 mg tablets administered twice daily with food for a total daily dose of 1200 mg

    • Swallow tablets whole with food
    • Patients should also receive a GnRH analog concurrently or have had a bilateral orchiectomy
  • Advise patients to take a missed dose when they remember prior to the next scheduled dose, and not to take two doses together to make up for a missed dose
Dosing and administration

NUBEQA pill size is
smaller than a dime

NUBEQA (darolutamide) pill size is smaller than a dime

For illustrative purposes only

For illustrative purposes only

Modify dose to 300 mg twice daily in patients with1:

  • Severe renal impairment (eGFR 15-29 mL/min/1.73 m2) not receiving hemodialysis
  • Moderate hepatic impairment (Child-Pugh Class B)
  • Grade ≥3 toxicity or an intolerable adverse reaction
    • Withhold dose or reduce to 300 mg twice daily until symptoms improve. Then increase to 600 mg twice daily
    • Dosage below 300 mg twice daily is not recommended

Limited drug-drug interactions (DDIs) and no contraindications1,7

DDIs with concomitant use of NUBEQA1,7,8

DDIs with concomitant use of NUBEQA (darolutamide): drug to drug interactions

*Decreases darolutamide exposure, which may decrease NUBEQA activity.

Increases darolutamide exposure, which may increase the risk of NUBEQA adverse reactions.

Increases BCRP substrate exposure, which may increase the risk of related toxicities. Consult the approved product labeling of the BCRP substrate when used concomitantly with NUBEQA.

GnRH=gonadotropin-releasing hormone; eGFR=estimated glomerular filtration rate; BCRP=breast cancer resistance protein.

PRECLINICAL

 

PRECLINICAL STUDIES OF MOA AND
BLOOD-BRAIN PENETRATION

NUBEQA inhibits androgen receptor (AR) function1

Mechanism of action (androgen, cell membrane, DNA): inhibits androgen receptor (AR) function

• NUBEQA inhibited transcriptional activity in vitro (IC50 65nM)10

Preclinical analysis of blood-brain penetration with NUBEQA4,11,12

  • The brain-to-plasma ratio of NUBEQA in mice was low at 3%
    • Based on these data, men with a history of seizure were allowed in ARAMIS
    • However, the penetration of NUBEQA across the human blood-brain barrier has not been studied

Low blood-brain penetration in preclinical studies11,12

MOA=mechanism of action.

INDICATION

NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.

IMPORTANT SAFETY INFORMATION

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
Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥ 1 % of patients who received NUBEQA were urinary retention, pneumonia, and hematuria. Overall, 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for NUBEQA.

Adverse reactions occurring more frequently in the NUBEQA arm (≥2% over placebo) were fatigue (16% vs. 11%), pain in extremity (6% vs. 3%) and rash (3% vs. 1%).

Clinically significant adverse reactions occurring in ≥ 2% of patients treated with NUBEQA included ischemic heart disease (4.0% vs. 3.4% on placebo) and heart failure (2.1% vs. 0.9% on placebo).

Drug Interactions
Effect of Other Drugs on NUBEQA – Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide exposure, which may decrease NUBEQA activity. Avoid concomitant use of NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers.

Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure, which may increase the risk of NUBEQA adverse reactions. Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed.

Effects of NUBEQA on Other Drugs – NUBEQA is an inhibitor of breast cancer resistance protein (BCRP) transporter. Concomitant use of NUBEQA increases the exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug. Consult the approved product labeling of the BCRP substrate when used concomitantly with NUBEQA.

For important risk and use information about 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:

  • NUBEQA (darolutamide) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; August 2019. Return to content
  • Erleada (apalutamide) [prescribing information]. Horsham, PA: Janssen Products, LP; February 2018. Return to content
  • Xtandi (enzalutamide) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc.; July 2018. Return to content
  • Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. Return to content
  • Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. Return to content
  • Data on file. Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ. Return to content
  • University of Washington Pharmacy Services. Rivaroxaban Drug Interaction Potential I Anticoagulation Services. https://depts.washington.edu/anticoag/home/content/rivaroxaban-drug-interactionpotential. Accessed August 15, 2019. Return to content
  • Center for Drug Evaluation and Research. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-lnhibitors-and-inducers#table5-1. Accessed August 15, 2019. Return to content
  • 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. Return to content
  • 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. doi:10.1038/srep12007. Return to content
  • 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 27-0ctober 1, 2013; Amsterdam, The Netherlands. Return to content
  • Sandmann S, Trummel D, Seidel D, Nubbemeyer R, Gieschen H, Zurth C. Higher blood-brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rate using whole-body autoradiography. Abstract presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Return to content

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Date of last update: 20/04/2020