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Testing the Addition of Darolutamide to Hormonal Therapy (Androgen Deprivation Therapy [ADT]) After Surgery for Men With High-Risk Prostate Cancer, The ERADICATE Study

NCT04484818

Description:

This phase III trial compares the effect of adding darolutamide to ADT versus ADT alone after surgery for the treatment of high-risk prostate cancer. ADT reduces testosterone levels in the blood. Testosterone is a hormone made mainly in the testes and is needed to develop and maintain male sex characteristics, such as facial hair, deep voice, and muscle growth. It also plays role in prostate cancer development. Darolutamide blocks the actions of the androgens (e.g. testosterone) in the tumor cells and in the body. Giving darolutamide with ADT may work better in eliminating or reducing the size of the cancer and/or prevent it from returning compared to ADT alone in patients with prostate cancer.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Darolutamide to Hormonal Therapy (Androgen Deprivation Therapy [ADT]) After Surgery for Men With High-Risk Prostate Cancer, The ERADICATE Study
  • Official Title: A Phase III Double Blinded Study of Early Intervention After RADICAl ProstaTEctomy With Androgen Deprivation Therapy With or Without Darolutamide vs. Placebo in Men at Highest Risk of Prostate Cancer Metastasis by Genomic Stratification (ERADICATE)

Clinical Trial IDs

  • ORG STUDY ID: EA8183
  • SECONDARY ID: NCI-2020-02383
  • SECONDARY ID: EA8183
  • SECONDARY ID: EA8183
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04484818

Conditions

  • Prostate Carcinoma

Interventions

DrugSynonymsArms
DarolutamideAntiandrogen ODM-201, BAY 1841788, BAY-1841788, BAY1841788, ODM 201, ODM-201Arm B (ADT, darolutamide)
Goserelin AcetateZDX, ZoladexArm A (ADT, placebo)
Leuprolide AcetateA-43818, Abbott 43818, Abbott-43818, Carcinil, Depo-Eligard, Eligard, Enanton, Enantone, Enantone-Gyn, Ginecrin, LEUP, Leuplin, Leuprorelin Acetate, Lucrin, Lucrin Depot, Lupron, Lupron Depot, Lupron Depot-3 Month, Lupron Depot-4 Month, Lupron Depot-Ped, Lutrate, Procren, Procrin, Prostap, TAP-144, Trenantone, Uno-Enantone, ViadurArm A (ADT, placebo)
Placebo AdministrationArm A (ADT, placebo)
Triptorelin6-D-Tryptophan-LH-RH, 6-D-Tryptophanluteinizing Hormone-releasing Factor, AY-25650, CL-118,532, DetryptorelineArm A (ADT, placebo)

Purpose

This phase III trial compares the effect of adding darolutamide to ADT versus ADT alone after surgery for the treatment of high-risk prostate cancer. ADT reduces testosterone levels in the blood. Testosterone is a hormone made mainly in the testes and is needed to develop and maintain male sex characteristics, such as facial hair, deep voice, and muscle growth. It also plays role in prostate cancer development. Darolutamide blocks the actions of the androgens (e.g. testosterone) in the tumor cells and in the body. Giving darolutamide with ADT may work better in eliminating or reducing the size of the cancer and/or prevent it from returning compared to ADT alone in patients with prostate cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine whether 12 months of androgen deprivation therapy (ADT) and darolutamide
      improves metastasis-free survival (MFS) compared to 12 months of ADT plus placebo in men with
      high risk prostate cancer (defined by Cancer of the Prostate Risk Assessment Post-surgical
      [CAPRA-S] score >= 3 and a high Decipher score (>= 0.6) [C3+D+]) who have undergone radical
      prostatectomy.

      SECONDARY OBJECTIVES:

      I. To determine whether 12 months of ADT and darolutamide improves recurrence-free survival
      (RFS) compared to 12 months of ADT plus placebo in men with high-risk prostate cancer that
      have undergone radical prostatectomy.

      II. To determine whether 12 months of ADT and darolutamide improves event-free survival (EFS)
      compared to 12 months of ADT plus placebo in men with high-risk prostate cancer that have
      undergone radical prostatectomy.

      III. To determine whether 12 months of ADT and darolutamide improves overall survival (OS)
      compared to 12 months of ADT plus placebo in men with high-risk prostate cancer that have
      undergone radical prostatectomy.

      IV. To determine the rate of testosterone recovery and time to testosterone recovery in each
      treatment arm.

      V. To evaluate the safety and tolerability of ADT and darolutamide.

      CORRELATIVE OBJECTIVES FOR EXPLORATORY BIOMARKERS:

      I. To discover a novel gene expression signature in the Decipher transcriptome platforms that
      is predictive of clinical outcome, as defined by the primary and secondary objectives of this
      study, in response to ADT by intensification with darolutamide versus ADT alone.

      II. To assess the prevalence of subclasses of established transcriptome expression signatures
      and prospectively validate their predictive value for ADT response, these include: (i)
      androgen (AR) activity (ii) Basal-luminal subtyping based on modified PAM50, and (iii) ADT
      score.

      III. To assess whether the spectrum of high Decipher scores (0.6-1.0), prostate-specific
      antigen (PSA) levels at presentation and post-radical prostatectomy (RP) and final pathology
      variables affect the response and outcome to ADT and darolutamide.

      QUALITY OF LIFE (QOL) OBJECTIVES:

      I. To compare overall quality of life, measured by Functional Assessment of Cancer
      Therapy-Prostate (FACT-P) total score, at 18 months between the two arms. (Primary) II. To
      compare the change in overall quality of life, measured by FACT-P total score, from baseline
      to 18 months between the two arms. (Secondary) III. To compare patient-reported fatigue
      (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scores) at 12 months
      between the two treatment arms. (Secondary) IV. To compare the change in subjective
      patient-reported cognitive function (FACT-Cognitive [Cog]) from baseline to 12 months between
      the treatment arms. (Exploratory) V. To compare subjective patient-reported cognitive
      function (FACT-Cog scores) at 12 months between the two treatment arms. (Exploratory)

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive goserelin acetate, leuprolide acetate, or triptorelin via injection
      every 3 months for 12 months (4 injections), every 4 months for 12 months (3 injections), or
      every month for 12 months (12 injections) in the absence of disease progression or
      unacceptable toxicity. Patients also receive a placebo four times daily (QID) for 52 weeks in
      the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive goserelin acetate, leuprolide acetate, or triptorelin via injection
      every 3 months for 12 months (4 injections), every 4 months for 12 months (3 injections), or
      every month for 12 months (12 injections) in the absence of disease progression or
      unacceptable toxicity. Patients also receive darolutamide QID for 52 weeks in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 36 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (ADT, placebo)Active ComparatorPatients receive goserelin acetate, leuprolide acetate, or triptorelin via injection every 3 months for 12 months (4 injections), every 4 months for 12 months (3 injections), or every month for 12 months (12 injections) in the absence of disease progression or unacceptable toxicity. Patients also receive a placebo four times daily (QID) for 52 weeks in the absence of disease progression or unacceptable toxicity.
  • Goserelin Acetate
  • Leuprolide Acetate
  • Placebo Administration
  • Triptorelin
Arm B (ADT, darolutamide)ExperimentalPatients receive goserelin acetate, leuprolide acetate, or triptorelin via injection every 3 months for 12 months (4 injections), every 4 months for 12 months (3 injections), or every month for 12 months (12 injections) in the absence of disease progression or unacceptable toxicity. Patients also receive darolutamide QID for 52 weeks in the absence of disease progression or unacceptable toxicity.
  • Darolutamide
  • Goserelin Acetate
  • Leuprolide Acetate
  • Triptorelin

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-REGISTRATION INCLUSION (STEP 0)

          -  Patient must have undergone a radical prostatectomy (RP) and must be registered to
             step 0 of this study at least 6 weeks after but not more than 16 weeks after their
             radical prostatectomy

          -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             0- 2

          -  Patient with a prior or concurrent malignancy within 5 years of registration, whose
             natural history or treatment does not have the potential to interfere with the safety
             or efficacy assessment of the investigational regimen are eligible for this trial

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  For patients with no previous Decipher score: Tumor tissue specimen from prostatectomy
             must be available and ready to be shipped

          -  INCLUSION CRITERIA FOR RANDOMIZATION (STEP 1)

          -  For patients who have previously had Decipher score performed by Decipher Biosciences,
             they must have score of >= 0.6

          -  For patients who did not have a Decipher score previously performed by Decipher
             Biosciences, they must have had a Decipher score of >= 0.6 assessed from the
             prostatectomy specimen submitted

          -  For patients who did not have a Decipher score previously performed by Decipher
             Biosciences, patients must also have a CAPRA-S score >= 3. The CAPRA-S score is
             calculated by assigning points for PSA in ng/mL, surgical margin status, seminal
             vesicle invasion, and extra-capsular extension. Lymph node involvement will serve as
             an exclusion criteria and will not count towards CAPRA-S inclusion score. A CAPRA-S
             score is not required for patients who had a Decipher score previously performed by
             Decipher Biosciences

          -  Patient must have an undetectable PSA (< 0.2ng/mL) obtained within 2 weeks prior to
             randomization

          -  Leukocytes >= 3,000/mcL (obtained within 4 weeks prior to registration)

          -  Absolute neutrophil count >= 1,000/mcL (obtained within 4 weeks prior to registration)

          -  Platelets >= 75,000/mcL (obtained within 4 weeks prior to registration)

          -  Total bilirubin =< institutional upper limit of normal (ULN) (obtained within 4 weeks
             prior to registration)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN (obtained within 4 weeks prior to registration)

          -  Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (obtained within 4 weeks prior
             to registration)

        Exclusion Criteria:

          -  PRE-REGISTRATION EXCLUSION (STEP 0)

          -  Patient must not have any previous treatment with androgen deprivation therapy (ADT),
             chemotherapy, or other physician prescribed systemic therapy for treatment of their
             prostate cancer

          -  Patient must not have pathologic evidence of pelvic lymph node involvement

          -  Patient must not have an uncontrolled intercurrent illness including, but not limited
             to, ongoing or active infection, symptomatic congestive heart failure (New York Heart
             Association class III and IV heart failure), unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  EXCLUSION CRITERIA FOR RANDOMIZATION (STEP 1)

          -  Patient must not have pre or post-operative radiographic evidence of cancer recurrence
             or metastasis by abdominal and pelvic imaging (computed tomography [CT]
             abdomen/pelvis, whole body magnetic resonance imaging [MRI], MRI abdomen/pelvis, or
             equivalent, AND bone scan) which must be done before or after prostatectomy prior to
             randomization. If pre-operative risk does not indicate a need for bone scan,
             post-operative Decipher score of >= 0.6 indicates increased risk of metastatic disease
             and may be used to obtain CT abdomen/pelvis and bone scan prior to randomization
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Metastasis-free survival (MFS)
Time Frame:From randomization to development of metastatic disease or death, whichever occurs first, assessed up to 36 months
Safety Issue:
Description:The primary comparison will be an intention-to-treat analysis of all randomized patients. The method of Kaplan and Meier will be used to characterize the time-to-event endpoints, and a logrank test will be used to compare these endpoints across treatments.

Secondary Outcome Measures

Measure:Recurrence-free survival (RFS)
Time Frame:From randomization to any of the MFS events, pelvic lymph node recurrence or detectable prostate-specific antigen (PSA) (PSA >= 0.2 ng/mL, confirmed by a second PSA of the same level or higher), whichever occurs first, assessed up to 36 months
Safety Issue:
Description:The method of Kaplan and Meier will be used to characterize the time-to-event endpoints, and a logrank test will be used to compare these endpoints across treatments.
Measure:Event-free survival
Time Frame:From randomization to any of the RFS events, treatment with salvage radiation therapy with or without systemic therapy, or initiation of systemic therapy for presumed recurrence, whichever occurs first, assessed up to 36 months
Safety Issue:
Description:The method of Kaplan and Meier will be used to characterize the time-to-event endpoints, and a logrank test will be used to compare these endpoints across treatments.
Measure:Overall survival
Time Frame:From randomization to death by any cause or date last known alive, assessed up to 36 months
Safety Issue:
Description:The method of Kaplan and Meier will be used to characterize the time-to-event endpoints, and a logrank test will be used to compare these endpoints across treatments.
Measure:Testosterone recovery rate
Time Frame:At time of disease progression, assessed up to 36 months
Safety Issue:
Description:Exact binomial confidence intervals will be used to describe the proportions of patients with testosterone recovery in each arm.
Measure:Time to testosterone recovery
Time Frame:From randomization to a return of serum testosterone level to greater than or equal to lower limit of normal for the testosterone assay, assessed up to 36 months
Safety Issue:
Description:The method of Kaplan and Meier will be used to characterize the time-to-event endpoints, and a logrank test will be used to compare these endpoints across treatments.
Measure:Incidence of adverse events
Time Frame:Up to 78 weeks
Safety Issue:
Description:Toxicity will be defined using the Common Terminology Criteria for Adverse Events version 5.0.
Measure:Change in quality of life: Functional Assessment of Cancer Therapy (FACT)
Time Frame:Baseline up to 18 months
Safety Issue:
Description:Will be assessed by the Functional Assessment of Cancer Therapy (FACT) - Prostate, FACT - Cognitive, and Functional Assessment of Chronic Illness Therapy - Fatigue. Fatigue instruments at baseline, 6, 12 and 18 months, and descriptive statistics will be used to characterize quality of life over time in each arm. Subgroup analysis will be performed among patients who receive adjuvant radiation therapy and patients who do not receive adjuvant radiation therapy in each arm. Mixed effect models will be constructed as an exploratory analysis to estimate the time profile of quality of life assessments in the two arms and to evaluate treatment-by-time interactions.
Measure:Overall quality of life: Functional Assessment of Cancer Therapy (FACT)
Time Frame:At 18 months
Safety Issue:
Description:Will be assessed by the FACT - Prostate total score. Mixed effect models will be constructed as an exploratory analysis to estimate the time profile of quality of life assessments in the two arms and to evaluate treatment-by-time interactions.
Measure:Change in FACT - Prostate score
Time Frame:Baseline up to 18 months
Safety Issue:
Description:A paired t test will be used to compare FACT - Prostate scores at these two time points in each arm. A two-sample t test will be performed to compare the changes in FACT - Prostate scores from baseline to 18 months between the two arms. Mixed effect models will be constructed as an exploratory analysis to estimate the time profile of quality of life assessments in the two arms and to evaluate treatment-by-time interactions.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:ECOG-ACRIN Cancer Research Group

Last Updated

July 23, 2020