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.

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.

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