ARAMIS IS THE LARGEST PHASE III STUDY IN nmCRPC TO DATE1-3nmCRPC
- 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 ENDPOINT1
- Metastasis-free survival
SECONDARY ENDPOINTS1,4
- Overall survival
- Time to pain progression*
- Time to first cytotoxic chemotherapy
- Time to first symptomatic skeletal event
EXPLORATORY ENDPOINTS4
- 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†
*Time to pain progression was defined as at least a 2-point worsening from baseline of pain score on BPI-SF (a validated health-related quality-of-life instrument) or initiation of opioids
and reported in 28% of all 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.
PSA=prostate-specific antigen; ECOG PS=Eastern Cooperative Oncology Group performance status; EQ-5D-3L=EuroQol Group 5-dimension 3-level; FACT-P=Functional Assessment of Cancer
Therapy–Prostate; BPI-SF=Brief Pain Inventory Short Form; EORTC-QLQ-PR25=European Organization for Research and Treatment of Cancer quality of life questionnaire, a 25-item questionnaire.
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 restriction4,6
- 43% of patients were on an antithrombotic, such as apixaban, clopidogrel, rivaroxaban, or warfarin5
- More than a third of patients were on a statin (34.5%), such as atorvastatin, pravastatin, or rosuvastatin5
Bone-sparing agents included bisphosphonates, denosumab, vitamin D and analogs, calcium and calcium combinations, fluorides, and calcitonins.5
ECOG PS 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.6
MORE THAN 1 IN 6 PATIENTS HAD LOCAL OR REGIONAL
LYMPH NODE METASTASES AT BASELINE4
ECOG PS=Eastern Cooperative Oncology Group performance status; ADT=androgen deprivation therapy; PSA=prostate-specific antigen; DDIs=drug-drug interactions.
DELAY METASTASIS, HELP PATIENTS LIVE LONGER WITHOUT PROGRESSION1,4nmCRPC
Men lived 2X longer without cancer spreading1,4
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 subgroups4:
- 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 third1,7
Statistically significant overall survival
- Survival going strong: median OS not reached, with more than half of patients still alive at the final analysis7
- 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 despite7:
- 31% (n=170) of patients in the ADT arm who crossed over to NUBEQA
- 55% (n=307) of patients in the ADT arm who crossed over to NUBEQA or received another life-prolonging therapy prior to this analysis
NUBEQA + ADT provided the relief of an extra 15 months
without pain progression1,7
Statistically significant delay in time to 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
- 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 study1,7
Postpone cytotoxic chemotherapy
for more time without chemo1,7
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 progression4
These exploratory data are descriptive in nature—the study was not powered to determine statistical significance.
- Twice-daily dosing of NUBEQA 600 mg in patients with nmCRPC resulted in undetectable PSA levels in 24.2% of patients at 12 months vs 0.4% of patients in the placebo arm1
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.
nmCRPC=non-metastatic castration-resistant prostate cancer; MFS=metastasis-free survival; ADT=androgen deprivation therapy; HR=hazard ratio; CI=confidence interval; PSADT=prostate-specific antigen doubling time; NE=not estimable; OS=overall survival; PSA=prostate-specific antigen.
Exploratory endpoint results4,7
*Median: 36.8 mo, NUBEQA + ADT; 14.8 mo, ADT alone.
†Median: 33.2 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
ADT=androgen deprivation therapy; HR=hazard ratio; CI=confidence interval; PSA=prostate-specific antigen; NE=not estimable; nmCRPC=non-metastatic castration-resistant prostate cancer.
IMPORTANT SAFETY
INFORMATION (cont’d)
Adverse Reactions (cont'd)
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.
Please see additional Important Safety Information below.
DELAY METASTASIS, HELP PATIENTS LIVE LONGER WITHOUT PROGRESSION1,4
Men lived 2X longer without cancer spreading1,4
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 third1,7
Statistically significant overall survival
- Survival going strong: median OS not reached, with more than half of patients still alive at the final analysis7
- 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 despite7:
- 31% (n=170) of patients in the ADT arm who crossed over to NUBEQA
- 55% (n=307) of patients in the ADT arm who crossed over to NUBEQA or received another life-prolonging therapy prior to this analysis
NUBEQA + ADT provided the relief of an extra 15 months without pain progression1,7
Statistically significant delay in time to 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
Postpone cytotoxic chemotherapy for more time without chemo1,7
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 progression4
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 NUBEQA1
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.
MFS=metastasis-free survival; ADT=androgen deprivation therapy; OS=overall survival; HR=hazard ratio; CI=confidence interval; PSADT=prostate-specific antigen doubling time; NE=not estimable; PSA=prostate-specific antigen.
Exploratory endpoint results4,7
*Median: 36.8 mo, NUBEQA + ADT; 14.8 mo, ADT alone.
†Median: 33.2 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 nmCRPCnmCRPC
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 alone1
- Serious adverse reactions in ≥1% of men who received NUBEQA + ADT included urinary retention, pneumonia, and hematuria
- Additionally, clinically relevant 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)1,4,5
MOST PATIENTS DID
NOT REPORT ANY
FATIGUE (84%), AND
99.4% HAD NO SEVERE
(GRADES 3-4) FATIGUE1
NO INCREMENTAL
SEVERE FATIGUE
vs ADT ALONE
(0.6% vs 1.1%)1
MOST PATIENTS DID NOT REPORT
ANY FATIGUE (84%), AND 99.4% HAD
NO SEVERE (GRADE 3-4) FATIGUE1
*Includes asthenia.
†Includes rash, eczema, rash maculo-papular, dermatitis, erythema multiforme, rash macular, rash papular, rash pustular, skin exfoliation.
NO INCREMENTAL SEVERE FATIGUE vs
ADT ALONE (0.6% vs 1.1%)1
Other AEs examined in the first and
final analyses of ARAMIS1,4,5,7
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.
nmCRPC=non-metastatic castration-resistant prostate cancer; ADT=androgen-deprivation therapy; AEs=adverse events.
- No cardiovascular AEs in either arm increased by ≥2% between first and final analyses4,7
- Consistent AEs from first to final analysis: no AE in either arm increased by >2% (14-month follow-up)1,4,7
- Consistent AEs from first to final analysis: no AE in either arm increased by >2% (14-month follow-up)1,4,7
- No GI/GU AEs occurred ≥2% over ADT alone4,5
- Consistent AEs from first to final analysis: no AE in either arm increased by >2% (14-month follow-up)1,4,5
- No metabolic AEs occurred ≥2% over ADT alone4,7
- Consistent AEs from first to final analysis: no AE in either arm increased by >2% (14-month follow-up)1,4,7
- Pain in extremity was the only musculoskeletal AE that occurred ≥2% over ADT alone4
- Consistent AEs from first to final analysis: no AE in either arm increased by >2% (14-month follow-up)1,4,5,7
- The only AE in ≥10% of patients receiving NUBEQA was fatigue1,4
- Consistent AEs from first to final analysis: no AE in either arm increased by >2% (14-month follow-up)1,4,5,7
DDIs AND DOSINGnmCRPC
Limited DDIs with NUBEQA1,8
Drug interactions with concomitant use of NUBEQA1,8-10
Review the prescribing information of the BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.
- In ARAMIS, patients taking NUBEQA had at least 1 comorbidity (98.4%) and used at least 1 concomitant medication (98.7%)5
*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 INTERACTIONS5
DDIs=drug-drug interactions; P-gp=P-glycoprotein; CYP3A4=cytochrome P450 3A4 subtype; BCRP=breast cancer resistance protein; OATP1B1=organic anion transporter polypeptide 1B1; OATP1B3=organic anion transporter polypeptide 1B3; nmCRPC=non-metastatic castration-resistant prostate cancer.
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
NUBEQA pill size is
smaller than a dime
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. NUBEQA may be resumed at a dose of 600 mg twice daily when adverse reaction returns to baseline
- Dosage below 300 mg twice daily is not recommended
GnRH=gonadotropin-releasing hormone; eGFR=estimated glomerular filtration rate.
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. NUBEQA (darolutamide) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; August 2022. 2. Erleada (apalutamide) [prescribing information]. Horsham, PA: Janssen Products, LP; April 2022. 3. Xtandi (enzalutamide) [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc.; January 2022. 4. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. 5. Data on file. Bayer HealthCare Pharmaceuticals, Inc.; Whippany, NJ. 6. ECOG-ACRIN Cancer Research Group. ECOG Performance Status Scale. https://ecog-acrin.org/resources/ecog-performance-status/. Accessed May 5, 2022. 7. 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. 8. University of Washington Pharmacy Services. Anticoagulation Services. Rivaroxaban Drug Interaction Potential. https://depts.washington.edu/anticoag/home/content/rivaroxaban-drug-interaction-potential. Accessed May 5, 2022. 9. 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 May 5, 2022. 10. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693-705.
