PRECLINICAL STUDIES
ARI=androgen receptor inhibitor.
Two studies demonstrate 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
ARAMIS IS THE LARGEST PHASE III STUDY IN nmCRPC TO DATE2,7,8
- 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
*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.
CRPC=castration-resistant prostate cancer; PSADT=prostate-specific antigen doubling time; PSA=prostate-specific antigen; ECOG PS=Eastern Cooperative Oncology Group performance status;
ADT=androgen deprivation therapy; CT=computed tomography; MRI=magnetic resonance imaging; GnRH=gonadotropin-releasing hormone.
PRIMARY ENDPOINT2
- Metastasis-free survival (MFS)
SECONDARY ENDPOINTS2,9
- Overall survival (OS)
- Time to pain progression‡
- Time to first cytotoxic chemotherapy
- Time to first symptomatic skeletal event
EXPLORATORY ENDPOINTS9
- 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§
ECOG PS=Eastern Cooperative Oncology Group performance status.
The majority of patients (68%) had an ECOG PS of 0 at baseline, defined as fully active and able to carry on all pre-disease performance without restriction9,10
- 43% of patients were on an antithrombotic, such as apixaban, clopidogrel, rivaroxaban, or warfarin1
- More than a third of patients were on a statin (34.5%), such as atorvastatin, pravastatin, or rosuvastatin1
Bone-sparing agents included bisphosphonates, denosumab, vitamin D and analogs, calcium and calcium combinations, fluorides, and calcitonins.1
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 housework, office work.10
MORE THAN 1 IN 6 PATIENTS HAD LOCAL OR REGIONAL
LYMPH NODE METASTASES AT BASELINE9
nmCRPC=non-metastatic castration-resistant prostate cancer.
DELAY METASTASIS, HELP PATIENTS LIVE LONGER WITHOUT PROGRESSION2,9
Men lived 2X longer without cancer spreading2,9
Significant increase in MFS vs ADT alone
HR: 0.41; 95% CI: 0.34-0.50; P<0.0001 (intent-to-treat)
- Consistent results for MFS across patient subgroups2:
- PSADT (≤6 months or >6 months)
- Prior use of bone-targeting agents (yes or no)
* 95% CI: 34.3-NE. †95% CI: 15.5-22.3.
Reduced risk of death by nearly a third2,11
Statistically significant overall survival (OS)
SECONDARY ENDPOINT: HR: 0.69; 95% CI: 0.53-0.88; P=0.003 (intent-to-treat)
- Survival going strong: median OS not reached, with more than half of patients still alive at the final analysis11
- At 3 years, 83% of patients treated with NUBEQA + ADT were alive vs 77% treated with ADT alone (HR: 0.69; 95% CI: 0.53-0.88; P=0.003)
- OS was statistically significant despite11:
- 55% (n=307) of patients in the ADT arm who crossed over to NUBEQA or received another life-prolonging therapy prior to this analysis
Delayed time to pain progression2,11
NUBEQA + ADT provided the relief of an extra 15 months without pain progression
SECONDARY ENDPOINT: HR: 0.65; 95% CI: 0.53-0.79; P<0.0001 (intent-to-treat)
35% RISK REDUCTION in time to pain progression with NUBEQA + ADT vs ADT alone
DELAYED TIME TO PAIN PROGRESSION
by 14.9 months over ADT alone
- Time to pain progression was defined as at least a 2-point worsening from baseline of pain score on Brief Pain Inventory Short Form (a validated health-related quality-of-life instrument) or initiation of opioids and reported in 28% of all patients on study2,11
Postponed cytotoxic chemotherapy for more time without chemo2,11
Significantly delayed time to chemotherapy
SECONDARY ENDPOINT: HR: 0.58; 95% CI: 0.44-0.76; P<0.0001 (intent-to-treat)
42% RISK REDUCTION in time to initiation of cytotoxic chemotherapy with NUBEQA + ADT vs ADT alone at the final analysis
Median: NE for both NUBEQA + ADT (n=955) and ADT alone (n=554).
Select exploratory endpoint: time to PSA progression9
EXPLORATORY ENDPOINT: HR: 0.13; 95% CI: 0.11-0.16
These exploratory data are descriptive in nature—the study was not powered to determine statistical significance.
- PSA dropped by an average of >90% from baseline on NUBEQA2
PSA is not a reliable surrogate for overall survival. PSA evaluation should be viewed in the context of patient management and the overall physical condition and clinical course of the patient.
Exploratory endpoint results9,11
||Median: 36.8 mo, NUBEQA + ADT; 14.8 mo, ADT alone.
§Median: 40.3 mo, NUBEQA + ADT: 7.3 mo, ADT alone.
#Median: NE for both NUBEQA + ADT and ADT alone.
CONSIDER NUBEQA AS A 1ST OPTION
FOR YOUR nmCRPC PATIENTS ON ADT
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.
PROVEN TOLERABILITY IN MEN WITH nmCRPC
PRESCRIBE NUBEQA with confidence
6% of men treated with NUBEQA required dose reductions due to adverse reactions1
The most frequent reasons for dose reductions included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%)1
13% of men treated with NUBEQA required dose interruptions due to adverse reactions1
The most frequent reasons for dose interruptions included hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%)1
NO INCREASE IN PERMANENT DISCONTINUATION DUE TO ADVERSE REACTIONS WHEN NUBEQA WAS ADDED TO ADT2
The most frequent reasons in patients treated with NUBEQA included cardiac failure (0.4%) and death (0.4%)2
Three adverse reactions occurred more frequently with NUBEQA + ADT (≥2% over ADT alone)1
- Overall, serious adverse reactions occurred in 25% of men receiving NUBEQA + ADT and in 20% of men receiving ADT alone2
– 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 included ischemic heart disease (4.0% vs 3.4% on placebo) and heart failure (2.1% vs 0.9% on ADT alone)2
- NUBEQA + ADT (n=954)
- ADT Alone (n=554)
MOST PATIENTS DID
NOT REPORT ANY
FATIGUE (84%), AND
99.4% HAD NO SEVERE
(GRADE 3-4) FATIGUE2
- NUBEQA + ADT (n=954)
- ADT Alone (n=554)
NO INCREMENTAL
SEVERE FATIGUE
vs ADT ALONE
(0.6% vs 1.1%)2
*Includes asthenia.
All Grades
MOST PATIENTS DID NOT REPORT
ANY FATIGUE (84%), AND 99.4% HAD
NO SEVERE (GRADE 3-4) FATIGUE2
Proven tolerability in men with nmCRPC
Grades 3-4
NO INCREMENTAL SEVERE FATIGUE
vs ADT ALONE (0.6% vs 1.1%)2
*Includes asthenia.
NO INCREMENTAL SEVERE FATIGUE vs
ADT ALONE (0.6% vs 1.1%)2
Other AEs examined in the first and final analyses of ARAMIS1, 2, 9, 11
Consistent safety profile from first to final analysis. No AE in either arm increased by >2% (14-month follow-up).
Click each category below to view the first analysis AEs compared with the final analysis AEs.
ADT=androgen deprivation therapy; AE=adverse event.
Most patients did not report any fatigue (84%),
and 99.4% had no severe (grade 3-4) fatigue1
DDIs AND DOSING
Limited DDIs with NUBEQA2,12
Drug interactions with concomitant use of NUBEQA2,12-14
Review the prescribing information of the BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly.
- In ARAMIS, patients taking NUBEQA had at least 1 comorbidity (98.4%) and used at least 1 comedication (98.7%)1
*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.
§Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates.
NEARLY ALL PATIENTS WITH nmCRPC ARE ON CONCOMITANT MEDICATIONS,
SO CHOOSE AN ARI WITH LIMITED DRUG-DRUG INTERACTIONS1
NUBEQA pill size is
smaller than a dime
- 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 2 doses together to make up for a missed dose
Modify dose to 300 mg twice daily in patients with2:
- 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
DDIs=drug-drug interactions; BCRP=breast cancer resistance protein; OATP1B1=organic anion transporter polypeptide 1B1; OATP1B3=organic anion transporter polypeptide 1B3; eGFR=estimated glomerular filtration rate.
DDIs=drug-drug interactions; BCRP=breast cancer resistance protein;
OATP1B1=organic anion transporter polypeptide 1B1; OATP1B3=organic anion
transporter polypeptide 1B3; eGFR=estimated glomerular filtration rate.
HIGHEST-LEVEL RECOMMENDATIONS IN AUA AND EAU GUIDELINES
AMERICAN UROLOGICAL
ASSOCIATION
(AUA/ASTRO/SUO Guidelines)15
Strong recommendation; Evidence Level Grade A
with continued ADT for men with nmCRPC at high risk
for developing metastatic disease (PSADT ≤10 months)
EUROPEAN ASSOCIATION
OF UROLOGY
(EAU/EANM/ESTRO/ESUR/
SIOG Guidelines)16
Strong recommendation for men with M0 CRPC at
high risk of developing metastasis (PSADT <10 months)
to prolong time to metastases
NCCN Guidelines® recommend darolutamide (NUBEQA) as a Category 1 Preferred Option
NCCN
PRACTICE GUIDELINES
IN ONCOLOGY
(NCCN Guidelines)17
Category 1 Preferred Option with ADT for men with
nmCRPC with a PSADT ≤10 months
ASTRO=American Society for Radiation Oncology; SUO=Society of Urologic Oncology; EANM=European Association of Nuclear Medicine; ESTRO=European Society for Radiotherapy and Oncology; ESUR=European Society of Urogenital Radiology; SIOG=International Society of Geriatric Oncology; M0=no metastases.
ISI - Important Safety Information
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 – 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.
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:
1. Data on file. Bayer HealthCare Pharmaceuticals, Inc.; Whippany, NJ. 2. NUBEQA (darolutamide) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; January 2021. 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. Erleada (apalutamide) [prescribing information]. Horsham, PA: Janssen Products, LP; September 2021. 8. Xtandi (enzalutamide) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc.; July 2021. 9. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. 10. 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. 11. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. 12. University of Washington Pharmacy Services. Anticoagulation Services. Rivaroxaban Drug Interaction Potential. https://depts.washington.edu/anticoag/home/content/rivaroxaban-drug-interaction-potential. Accessed September 23, 2021. 13. FDA.gov. 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-inhibitors-and-inducers. Accessed September 23, 2021. 14. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693-705. 15. Lowrance W, Breau R, Chou R, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline 2020. American Urological Association; 2020. 16. Mottet N, Cornford P, van den Bergh RCN, et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer. European Association of Urology; 2020. 17. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer NCCN V.2.2022, published 11/30/21. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed December 14, 2021. 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.
