ARASENS: DESIGNED TO EVALUATE SUPERIORITY OF THE NUBEQA COMBINATION* VS AN ACTIVE COMPARATOR mHSPC
The only pivotal, prospective, double-blind, multicenter, phase III trial to evaluate the superiority of the NUBEQA combination versus docetaxel + ADT1,2
*NUBEQA combination=NUBEQA + docetaxel and ADT.
†One patient in the placebo arm was excluded from all analyses due to the violation of Good Clinical Practices.
All patients received ADT (an LHRH agonist or an LHRH antagonist) or underwent an orchiectomy within 12 weeks before randomization.2
ADT=androgen deprivation therapy; mHSPC=metastatic hormone-sensitive prostate cancer; ECOG PS=Eastern Cooperative Oncology Group performance status; M1a=nonregional lymph-node metastases only; M1b=bone metastases with or without lymph-node metastases; M1c=visceral metastases with or without lymph-node or bone metastases; ALP=alkaline phosphatase; ULN=upper limit of normal; q3w=every 3 weeks; LHRH=luteinizing hormone–releasing hormone.
SECONDARY ENDPOINTS1,2
- Time to CRPC
- Time to pain progression
- Symptomatic skeletal event–free survival
- Time to first symptomatic skeletal event
- Time to initiation of subsequent antineoplastic therapy
- Time to worsening of disease-related physical symptoms
- Time to initiation of opioid use for ≥7 consecutive days
EXPLORATORY ENDPOINT3
- Time to PSA progression
All patients received ADT (an LHRH agonist or an LHRH antagonist) or underwent an orchiectomy within 12 weeks before randomization.2
CRPC=castration-resistant prostate cancer; PSA=prostate-specific antigen; ADT=androgen deprivation therapy; LHRH=luteinizing hormone–releasing hormone.
ARASENS included a broad range of patient subgroups1,2
Baseline demographics and disease characteristics were balanced between treatment arms
All patients received ADT (an LHRH agonist or an LHRH antagonist) or underwent an orchiectomy within 12 weeks before randomization.2
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.4
mHSPC=metastatic hormone-sensitive prostate cancer; ECOG PS=Eastern Cooperative Oncology Group performance status; M1a=nonregional lymph-node metastases only; M1b=bone metastases with or without lymph-node metastases; M1c=visceral metastases with or without lymph-node or bone metastases; PSA=prostate-specific antigen; ADT=androgen deprivation therapy; LHRH=luteinizing hormone–releasing hormone.
ONLY ARI APPROVED WITH DOCETAXEL THAT EXTENDS SURVIVALmHSPC
The NUBEQA combination significantly reduced the risk of death by nearly a third1,2
- OS was statistically significant despite:
- 76% of patients (374/495) taking placebo + docetaxel having received subsequent life-prolonging systemic antineoplastic therapies2,3*
*At the data cutoff date (October 25, 2021), 45.9% of patients in the darolutamide group and 19.1% of patients in the placebo group were receiving ongoing study treatment. 495 patients entered active or long-term (survival) follow-up, plus 1 patient who did not enter follow-up but received subsequent therapy. Patients could receive more than 1 subsequent life-prolonging systemic therapy.
ARI=androgen receptor inhibitor; ADT=androgen deprivation therapy; HR=hazard ratio; CI=confidence interval; OS=overall survival; NE=not estimable.
Time to disease progression—CRPC
In ARASENS, time to CRPC was a secondary endpoint and assessed by PCWG3 criteria2,3:
- The time from randomization to occurrence of the following events, whichever occurred first: PSA progression with serum testosterone at a castrate level (<0.5 ng/mL) or radiographic progression of soft-tissue, visceral, or bone lesions; radiographic progression by soft-tissue/visceral lesions was determined according to RECIST version 1.1
- PSA was assessed by central review, however radiographic progression was determined by investigator assessment
The NUBEQA combination significantly reduced the risk of progression
vs docetaxel and ADT alone2,3
CRPC=castration-resistant prostate cancer; PCWG3=Prostate Cancer Working Group 3 criteria; PSA=prostate-specific antigen; RECIST=Response Evaluation Criteria In Solid Tumors; ADT=androgen deprivation therapy; HR=hazard ratio; CI=confidence interval; NE=not estimable.
Secondary endpoint results of the ARASENS study1,2
- Secondary endpoints were tested with a hierarchical gatekeeping procedure in the order shown above only if the primary endpoint and each preceding secondary endpoint in the hierarchy were statistically significant2
*Time to pain progression was defined as the time from randomization to the time of pain progression. Pain progression is defined as:
- An increase of 2 or more points in the “worst pain in 24 hours” score (WPS) from nadir observed at 2 consecutive evaluations at least 4 weeks apart, or initiation of short- or long-acting opioid use for pain for at least 7 consecutive days, for asymptomatic patients (WPS=0) at baseline
- An increase of 2 or more points in the “worst pain in 24 hours” score (WPS) from nadir observed at 2 consecutive evaluations at least 4 weeks apart, and a WPS of 4 or greater, or initiation of short- or long-acting opioid use for pain for at least 7 consecutive days, for symptomatic patients (WPS ≥ 1) at baseline
ADT=androgen deprivation therapy; HR=hazard ratio; CI=confidence interval; WPS=worst pain severity.
Patients stayed on NUBEQA for 3+ years after a short course of concurrent docetaxel2
Median treatment duration at time of data cutoff
Within 6 weeks of starting NUBEQA, start docetaxel at 75 mg/m2 once every 3 weeks for 6 cycles.1
ADT=androgen deprivation therapy.
NO SUBSTANTIAL INCREASES IN ADVERSE REACTIONS WITH NUBEQA + DOCETAXEL VS PLACEBO + DOCETAXEL2,3mHSPC
Adverse reactions (≥10% with a ≥2% increase over placebo + docetaxel)1
*Rash includes rash, rash maculo-papular, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis, skin exfoliation, dermatitis acneiform, drug eruption, rash pruritic, rash erythematous, erythema multiforme, rash macular, dermatitis exfoliative generalized, penile rash, dyshidrotic eczema, rash papular, dermatitis bullous, rash follicular, rash pustular, rash vesicular, toxic skin eruption.
†Hemorrhage includes hematuria, epistaxis, anal hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, hemorrhagic stroke, subarachnoid hemorrhage, lower gastrointestinal hemorrhage, cystitis hemorrhagic, gastrointestinal hemorrhage, hemorrhage subcutaneous, intra-abdominal hemorrhage, nail bed bleeding, subdural hemorrhage.
‡Hypertension includes hypertension, blood pressure increased, and hypertensive emergency and hypertensive crisis.
Additional Safety Results1
- 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%), neutrophil count decreased (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%)
- Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures (8%), ischemic heart disease (2.9%), seizures (0.6%), and drug-induced liver injury (0.3%)
- Permanent discontinuation of NUBEQA due to adverse reactions occurred in 14% of patients receiving NUBEQA. Dose interruptions due to adverse reactions occurred in 23% of patients treated with NUBEQA. Dose reductions due to adverse reactions occurred in 9% of patients treated with NUBEQA
DDIs AND DOSING mHSPC
Limited DDIs with NUBEQA1,5
Drug interactions with concomitant use of NUBEQA1,5-7
Review the prescribing information of the BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.
- Administration of NUBEQA in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of docetaxel in patients with mHSPC. There were also no clinically relevant changes in the pharmacokinetics of NUBEQA when used in combination with docetaxel
*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.
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; mHSPC=metastatic hormone-sensitive prostate cancer.
Dosing with docetaxel1,2
*Even if a cycle of docetaxel is delayed, interrupted, or discontinued.
Dosing with NUBEQA1
Recommended dosage
- 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 as soon as they remember prior to the next scheduled dose, and not to take 2 doses together to make up for a missed dose
Dose modifications with NUBEQA1
Modify dose to 300 mg twice daily in patients with:
- 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
ADT=androgen deprivation therapy; q3w=every 3 weeks; 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. Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. 3. Data on file. Bayer HealthCare Pharmaceuticals, Inc.; Whippany, NJ. 4. ECOG-ACRIN Cancer Research Group. ECOG Performance Status Scale. https://ecog-acrin.org/resources/ecog-performance-status/. Accessed May 5, 2022. 5. 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. 6. 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. 7. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693-705.
