PRE-REGISTRATION INCLUSION (STEP 0)

Patient must be >= 18 years of age

Patient must have undergone a radical prostatectomy (RP) completed at least 2 weeks prior to Step 0 pre-registration. Patient must also meet one of the following criteria:
* For patients with a Decipher score obtained through standard of care testing outside the protocol prior to registration to Step 0:
** The Decipher score must be > 0.6.  
** The patient must be registered to Step 0 no later than 24 weeks (168 days) after surgery. 
** The Decipher Score assay results and report must be available for upload to Medidata Rave prior to proceeding to Step 1 Randomization
* For patients without a previous Decipher score performed through standard of care testing outside the protocol prior to registration to Step 0 
** The patient must be registered to Step 0 no later than 19 weeks (133 days) after surgery to allow time to have tissue submitted and tested before proceeding to Step 1 randomization.  
** The patient must have a Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score >= 3. The CAPRA-S score is calculated by assigning points for PSA in ng/mL, Gleason score, 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.
** Tumor tissue specimen from radical prostatectomy must be available and ready to be shipped within 20 weeks post-surgery.
* NOTE: Every effort should be made to submit adequate tumor tissue specimen to Decipher Biosciences for testing immediately. Decipher Biosciences will notify submitting institution of Decipher score results within 21 days of receipt of adequate tumor tissue specimens. Failure to submit adequate tissue will result in request for additional tissue and delays in testing and reporting

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
* NOTE: Prior treatment with bicalutamide is permitted

Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

INCLUSION CRITERIA FOR RANDOMIZATION (STEP 1)

Patient must be randomized to Step 1 a minimum of 6 weeks and a maximum of 24 weeks (168 days) from radical prostatectomy (RP)

For patients who did not have a Decipher score obtained through standard of care testing outside of the protocol prior to registration to Step 0, the Decipher score is > 0.6 assessed from the prostatectomy specimen submitted

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

Patients with a prior or concurrent malignancy within 5 years of Step 1 randomization, 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

Patient must be able to take oral medications

Patient must have a PSA < 0.2 ng/mL obtained within 2 weeks prior to Step 1 randomization

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) within 24 weeks (168 days) prior to Step 1 randomization. If pre-operative risk does not support a need for CT abdomen/pelvis and/or bone scan imaging, the lack of baseline imaging due to low risk disease should be documented.  
* NOTE: A post-operative Decipher Score of > 0.6 indicates an increased risk of metastatic disease and a bone scan or CT scan is required prior to Step 1 randomization

Due to the potential harm through seminal transfer to an unborn fetus with the treatment regimens being used, sexually active patients must not expect to father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 28 days after the last dose of protocol treatment

Leukocytes >= 3,000/mcL (obtained within 4 weeks prior to Step 1 randomization)

Absolute neutrophil count (ANC) >= 1,000/mcL (obtained within 4 weeks prior to Step 1 randomization)

Platelets >= 75,000/mcL (obtained within 4 weeks prior to Step 1 randomization)

Hemoglobin (Hgb) > 8 g/dL (obtained within 4 weeks prior to Step 1 randomization)

Total bilirubin =< institutional upper limit of normal (ULN) (or =< 3 x ULN for patients with known Gilbert’s disease) (obtained within 4 weeks prior to Step 1 randomization)

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 Step 1 randomization)

Glomerular filtration rate (GFR) > 30 mL/min/1.73 m^2 estimated by Modification of Diet in Renal Disease (MDRD) formula (obtained within 4 weeks prior to Step 1 randomization)

EXCLUSION CRITERIA FOR RANDOMIZATION (STEP 1)

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

PRIMARY OBJECTIVE:
I. To determine whether 12 months (48 weeks) of androgen deprivation therapy (ADT) and darolutamide improves metastasis-free survival (MFS) compared to 12 months (48 weeks) 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+]) that have undergone radical prostatectomy.

SECONDARY OBJECTIVES:
I. To determine whether 12 months (48 weeks) of ADT and darolutamide improves recurrence-free survival (RFS) compared to 12 months (48 weeks) of ADT plus placebo in men with high-risk prostate cancer that have undergone radical prostatectomy.
II. To determine whether 12 months (48 weeks) of ADT and darolutamide improves event-free survival (EFS) compared to 12 months (48 weeks) of ADT plus placebo in men with high-risk prostate cancer that have undergone radical prostatectomy.
III. To determine whether 12 months (48 weeks) of ADT and darolutamide improves overall survival (OS) compared to 12 months (48 weeks) 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 receptor (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 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 12 months (48 weeks) between the two arms. (Primary)
II. To compare the change in overall quality of life, measured by FACT-P total score, from baseline to 12 months (48 weeks) between the two arms. (Secondary)
III. To compare patient-reported fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scores) at 12 months (48 weeks) 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 (48 weeks) between the treatment arms. (Exploratory)
V. To compare subjective patient-reported cognitive function (FACT-Cog scores) at 12 months (48 weeks) between the two treatment arms. (Exploratory)

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive goserelin acetate, leuprolide acetate, triptorelin, or degarelix 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, triptorelin, or degarelix 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.