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 »

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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)
  • 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 ENDPOINT1

  • Metastasis-free survival (MFS)

SECONDARY ENDPOINTS1,4

  • Overall survival (OS)
  • 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§

*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 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 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.

nmCRPC=nonmetastatic 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; ADT=androgen deprivation therapy; 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 Organisation for Research and Treatment of Cancer quality of life questionnaire, a 25-item questionnaire.

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 housework, 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

ADT=androgen-deprivaton therapy; ECOG PS=Eastern Cooperative Oncology Group performance status; PSADT=prostate-specific antigen doubling time; PSA=prostate-specific antigen.

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

 

DELAY METASTASIS, HELP PATIENTS LIVE LONGER WITHOUT PROGRESSION

Significant increase in MFS vs ADT alone1,4

  • 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-NE.

†95% CI: 15.5-22.3.

ARAMIS First Analysis Publication Callout Button ARAMIS First Analysis Publication Callout Button

Bayer, the manufacturer of darolutamide, is providing you with this article. This peer-reviewed article contains data, conclusions, and recommendations that may not be consistent with the FDA-approved labeling. Darolutamide is only approved for the indication specified in the Prescribing Information. Before prescribing the product, please read the full Prescribing Information.

This study was supported by Bayer HealthCare and Orion Pharma. Authors’ affiliations can be found in the full text of the article. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. There are authors of this journal article who have declared financial interest or reported compensation from Bayer:

Visit openpaymentsdata.cms.gov for specific financial disclosures. Additional significant safety risks not listed in the NEJM Fizazi 2019 reprint are included in the Prescribing Information. For more information, please call 888-84-BAYER (22937) or submit a product information request.

PSA response

  • NUBEQA dosed at 600 mg twice daily results in PSA mean reduction >90% from baseline1

Statistically significant results across all secondary endpoints1,7

Prespecified secondary endpoints in overall survival, time to pain progression, and time to cytotoxic chemotherapy: Median Duration (mo), NUBEQA (darolutamide) + ADT (955), ADT alone (554), HR (95% CI)

‡Median: NE for both arms.
§Median: 40.3 mo, NUBEQA + ADT: 25.4 mo, ADT alone.

  • 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 study1,7
  • Delayed time to first symptomatic skeletal event: 52% risk reduction; HR: 0.48; 95% CI: 0.29-0.82; P=0.005. 3% (n=29) of patients on NUBEQA + ADT vs 5% (n=28) of patients on ADT alone experienced a symptomatic skeletal event. Median not estimable for both arms.7

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

ARAMIS Final Analysis Publication Callout Button ARAMIS Final Analysis Publication Callout Button

Bayer, the manufacturer of darolutamide, is providing you with this article. This peer-reviewed article contains data, conclusions, and recommendations that may not be consistent with the FDA-approved labeling. Darolutamide is only approved for the indication specified in the Prescribing Information. Before prescribing the product, please read the full Prescribing Information.

This study was supported by Bayer HealthCare and Orion Pharma. Authors’ affiliations can be found in the full text of the article. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. There are authors of this journal article who have declared financial interest or reported compensation from Bayer:

Visit openpaymentsdata.cms.gov for specific financial disclosures. Additional significant safety risks not listed in the NEJM Fizazi 2020 reprint are included in the Prescribing Information. For more information, please call 888-84-BAYER (22937) or submit a product information request.

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.

ADVERSE REACTIONS

 

SAME LOW RATE OF PERMANENT DISCONTINUATION

Same low rate of permanent discontinuation due to adverse reactions vs ADT alone1

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

SAFETY

 

PROVEN TOLERABILITY IN MEN WITH nmCRPC

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 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

*Includes asthenia.

Low incidence of grade 3-4 fatigue, pain in extremity, and rash1

ADVERSE EVENTS

 

Other AEs examined in the first and final analyses of ARAMIS4,6,7


Click each category below to view the first analysis AEs compared to the final analysis AEs.

    CARDIOVASCULAR
    Other adverse events examined in ARAMIS study, % all grades, % grades 3/4
     
     
     
     
    • No cardiovascular AEs in either arm increased >2% between first and final analysis
    • AEs were generally consistent from first to final analysis1-3
      • No AE in either arm increased by >2%
      • Final analysis conducted at 14 months after first analysis
    VIEW FOOTNOTES
    CENTRAL NERVOUS SYSTEM
    Central nervous system adverse events examined in ARAMIS study, % all grades, % grades 3-4
     
     
     
     
     
     
     
     
     
     
     
     
    • No CNS AEs occurred ≥2% over ADT alone
    • AEs were generally consistent from first to final analysis
      • No AE in either arm increased by >2%
      • Final analysis conducted at 14 months after first analysis
    VIEW FOOTNOTES
    GASTROINTESTINAL AND GENITOURINARY
    Gastrointestinal and genitourinary adverse events examined in ARAMIS study, % all grades, % grades 3-4
     
     
     
     
    • No GI/GU AEs occurred ≥2% over ADT alone
    • AEs were generally consistent from first to final analysis
      • No AE in either arm increased by >2%
      • Final analysis conducted at 14 months after first analysis
    VIEW FOOTNOTES
    METABOLIC
    Metabolic adverse events examined in ARAMIS study, % all grades, % grades 3-4
     
     
    • No metabolic AEs occurred ≥2% over ADT alone
    • AEs were generally consistent from first to final analysis
      • No AE in either arm increased by >2%
      • Final analysis conducted at 14 months after first analysis
    VIEW FOOTNOTES
    MUSCULOSKELETAL
    Musculoskeletal adverse events examined in ARAMIS study, % all grades, % grades 3-4
    • Pain in extremity was the only musculoskeletal adverse reaction that occurred ≥2 over ADT alone
    • AEs were generally consistent from first to final analysis
      • No AE in either arm increased by >2%
      • Final analysis conducted at 14 months after first analysis
    VIEW FOOTNOTES
    OTHERS
    Other adverse events examined in ARAMIS study, % all grades, % grades 3-4
    • The only adverse reaction in ≥10% of patients receiving NUBEQA was fatigue
    • AEs were generally consistent from first to final analysis
      • No AE in either arm increased by >2%
      • Final analysis conducted at 14 months after first analysis
    VIEW FOOTNOTES
      CARDIOVASCULAR
      Cardiovascular adverse events examined in ARAMIS study, % all grades, % grades 3-4
       
       
       
       
      • No cardiovascular AEs in either arm increased >2% between first and final analysis
      • AEs were generally consistent from first to final analysis1-3
        • No AE in either arm increased by >2%
        • Final analysis conducted at 14 months after first analysis
      VIEW FOOTNOTES
      CENTRAL NERVOUS SYSTEM