Inclusion Criteria:
* Histologically confirmed prostate adenocarcinoma by biopsy within 1 year (365 days) from registration. The most recent biopsy will determine eligibility
* National Cancer Center Network (NCCN) intermediate risk prostate cancer, defined as clinical T2b-T2c, Gleason 7, or PSA 10-20 ng/mL. Patients who only have radiographic evidence of T3 disease (i.e. extracapsular extension, or seminal vesical invasion radiographically) will not be excluded.
* Able to characterize the number of unfavorable intermediate risk factors below:
* 2-3 intermediate risk factors
* T2b-T2c
* Gleason 7
* PSA 10-20 ng/mL
* Gleason 4+3 disease
* Percent positive cores ≥ 50%
* Tissue available for submission for Decipher genomic score from archived tissue. Patients who had tissue sent to Decipher but did not have sufficient tissue for processing will not be excluded. Patients who already have a Decipher score must present official report documentation.
* Able to undergo radiation therapy with curative intent
* Age ≥ 18 at the time of consent.
* Demonstrate adequate organ function (hematologic, renal, hepatic) within 3 months of registration
* System Laboratory Value
* Hematological:
* Platelet count (plt) ≥ 100,000/ µL
* Hemoglobin (Hgb) ≥ 9 g/dL
* Absolute neutrophil count (ANC) ≥ 1000 cells/µL
* Renal:
* Glomerular filtration rate (GFR) ≥ 45 mL/min
* CKD-EPI equation will be used to calculate GFR
* Hepatic and Other:
* Bilirubin ≤ 1.5 × upper limit of normal (ULN)
* In subjects with Gilbert's syndrome, if total bilirubin is \>1.5 × ULN, measure direct and indirect bilirubin; if direct bilirubin is ≤1.5 × ULN, subject may be eligible
* Aspartate aminotransferase (AST) ≤ 2.5 × ULN
* Alanine aminotransferase (ALT) ≤ 2.5 × ULN
* Serum Albumin \> 3.0 g/dL
* Serum potassium ≥ 3.5 mmol/L
* Endocrine:
* Testosterone ≥ 150 ng/dL
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Good erectile function, as assessed by 'firm enough for masturbation or foreplay' or 'firm enough for intercourse' response to the question "How would you describe the usual quality of your erections during the past 4 weeks" on the EPIC-26 questionnaire
* Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential (defined as a premenopausal female capable of becoming pregnant) OR agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. It is recommended that men who have had a vasectomy more than a year prior to trial registration use a condom. Must also agree not to donate sperm.
* Ability to understand and comply with study procedures for the entire length of the study as determined by the site investigator or protocol designee
* Written informed consent and HIPAA authorization for release of personal health information prior to registration. Note: HIPAA authorization may be included in the informed consent or obtained separately. Subject must have the ability to understand and willingness to sign the written informed consent document.
* Ability to swallow pills.
* For patients in whom SBRT/combination RT stratification is pre-specified, prostate volume as determined by MRI, CT, or ultrasound to be less than 90 cc.
Exclusion Criteria:
* Prior surgical, cryotherapy, or high-intensity focused ultrasound for prostate cancer
* Prior orchiectomy or hormonal therapy (gonadotropin releasing hormone (GnRH) agonists, non-steroidal anti-androgens)
* Prior treatment with a first generation AR inhibitor (e.g. bicalutamide, flutamide, nilutamide, cyproterone acetate) or second generation AR inhibitor (e.g.Enzalutamide, Apalutamide, or Darolutamide)
* Prior treatment with other investigational AR inhibitors, CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700, or oral ketoconazole longer than 28 days
* Prior use of estrogens; patients who have used testosterone injections must have ceased utilization within 90 days prior to screening testosterone. Patients who have used any other type of testosterone supplementation (e.g. patches) must have ceased utilization within 45 days prior to screening testosterone.
* Use of 5-α reductase inhibitors (finasteride, dutasteride) within 28 days of randomization.
* Prior radiation therapy that would result in overlap of current radiation therapy fields
* Prior chemotherapy for prostate cancer
* Clinically positive lymph nodes by imaging, sampling, or dissection. Patients with lymph nodes greater than 1.5 cm on short axis will require a negative biopsy for eligibility.
* Metastatic disease, as assessed by abdominal or pelvic computed tomography (CT) or other imaging modality. Patients with 3 intermediate risk factors will require a CT abdomen/pelvis and a bone scan or PET imaging (PSMA PET/CT, fluciclovine PET/CT, etc.).
* Erectile aids other than oral phosphodiesterase (PDE)-5 inhibitors
* History of any of the following: Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure New York Heart Association (NYHA) class III or IV, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), clinically significant ventricular arrhythmias, moderate or severe hepatic impairment (Child Pugh Class B or C), viral hepatitis, or human immunodeficiency virus within 6 months prior to randomization.
* Current untreated hypertension (systolic \>= 160 mmHg or diastolic \>= 100 mmHg). Patients with one blood pressure reading with systolic \< 160 mmHg and diastolic \< 100 mmHg within 90 days of registration would be eligible for study.
* Individuals with a history of another malignancy are not eligible if:
* The cancer is under active treatment
* The cancer can be seen on radiology scans
* If they are off cancer treatment, but in the opinion of their oncologist, have a high risk of relapse within 5 years.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (NCI-CTCAE version 5.0 Grade 2), psychiatric illness or social situations that would limit compliance with study requirement
* Any condition that, in the opinion of the site investigator, would preclude participation in this study
