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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Prostate Carcinoma

Intervention / Treatment
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* Drug: Darolutamide
* Drug: Goserelin Acetate
* Drug: Leuprolide Acetate
* Drug: Placebo Administration
* Other: Quality-of-Life Assessment
* Drug: Triptorelin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (ADT, placebo)<br>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. | Drug: Goserelin Acetate<br>* Given via injection<br>* Other names: Zoladex;Drug: Leuprolide Acetate<br>* Given IV<br>* Other names: Viadur;Drug: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Triptorelin<br>* Given via injection<br>* Other names: Detryptoreline;|
| Experimental: Arm B (ADT, darolutamide)<br>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. | Drug: Darolutamide<br>* Given PO<br>* Other names: ODM-201;Drug: Goserelin Acetate<br>* Given via injection<br>* Other names: Zoladex;Drug: Leuprolide Acetate<br>* Given IV<br>* Other names: Viadur;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Triptorelin<br>* Given via injection<br>* Other names: Detryptoreline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-free survival (MFS) | 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. | From randomization to development of metastatic disease or death, whichever occurs first, assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) | 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. | 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 | 
| Event-free survival | 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. | 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 | 
| Overall survival | 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. | From randomization to death by any cause or date last known alive, assessed up to 36 months | 
| Testosterone recovery rate | Exact binomial confidence intervals will be used to describe the proportions of patients with testosterone recovery in each arm. | At time of disease progression, assessed up to 36 months | 
| Time to testosterone recovery | 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. | 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 | 
| Incidence of adverse events | Toxicity will be defined using the Common Terminology Criteria for Adverse Events version 5.0. | Up to 78 weeks | 
| Change in quality of life: Functional Assessment of Cancer Therapy (FACT) | 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. Each item is answered on a 5-point Likert-type scale, where a value of 0 indicates the statement is not applicable, and a value of 5 indicates the statement is applicable to the respondent. 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. | Baseline up to 18 months | 
| Overall quality of life: Functional Assessment of Cancer Therapy (FACT) | Will be assessed by the Functional Assessment of Cancer Therapy (FACT) - Prostate total score. The total score can range from 0 to 156, where a higher value indicates a better quality of life. 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. | At 18 months | 
| Change in Functional Assessment of Cancer Therapy (FACT) - Prostate score | A paired t test will be used to compare Functional Assessment of Cancer Therapy (FACT) - Prostate scores at these two time points in each arm. The total score can range from 0 to 156, where a higher value indicates a better quality of life. 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. | Baseline up to 18 months |