This phase II trial investigates the effect of high dose-rate brachytherapy and stereotactic body radiotherapy in treating patients with prostate adenocarcinoma. Brachytherapy, also known as internal radiation therapy, uses radioactive material placed directly into or near a tumor to kill tumor cells. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue.

PRIMARY OBJECTIVES:

I. To estimate the biochemical progression-free survival (b-PFS) at the 5-year time point after combination therapy of stereotactic body radiotherapy (SBRT) and high dose rate (HDR)-brachytherapy (BT) boost stratified by patients with intermediate and high-risk prostate cancer.

II. To estimate the rate of acute >= grade 3 patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms determined within 90 days after treatment completion, respectively.

SECONDARY OBJECTIVES:

I. To estimate patient-reported GU symptoms at the end of radiotherapy and within 6, 12, 24, and 60 months from radiotherapy completion.

II. To estimate patient reported GI symptoms at the end of radiotherapy and within 6, 12, 24, and 60 months from radiotherapy completion.

III. To estimate the cumulative incidence of acute grade >= 2 GU physician-scored toxicity, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scale.

IV. To estimate the cumulative incidence of acute grade >= 2 GI physician-scored toxicity, as assessed by the CTCAE version 5.0 scale.

V. To estimate the cumulative incidence of late >= 2 GU physician-scored toxicity, as assessed by the CTCAE version 5.0 scale.

VI. To estimate the cumulative incidence of late >= 2 GI physician-scored toxicity, as assessed by the CTCAE version 5.0 scale.

VII. To determine the prostate specific antigen (PSA) complete response rate (PSA nadir =< 0.3ng/mL) at 3 months following treatment of combination SBRT and HDR-BT boost regardless of testosterone recovery.

VIII. To determine clinical progression-free survival at 5-years. IX. To determine distant metastasis-free survival at 5-years. X. To determine overall survival at 5-years.

OUTLINE:

Patients undergo HDR-BT for up to 24 hours and undergo SBRT every other day or consecutive days for up to 14 consecutive chronologic days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 90 days, every 3 months for 24 months, and then every 6 months for up to 5 years.

Inclusion Criteria:

• Ability to understand a written informed consent document, and the willingness to sign it
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• History/physical examination with digital rectal examination of the prostate within 8 weeks prior to registration
• Histologically confirmed intermediate- to high-risk prostate adenocarcinoma (T1c-T3b, PSA > 10, and/or Gleason score >= 7
• No evidence of disease beyond the prostate and/or seminal vesicles (i.e., no suspicious pelvic lymph nodes or presence of metastatic disease outside the pelvis)
• Prostate size =< 60cc
• International Prognostic Scoring System (IPSS) score =< 15
• Able to safely receive moderate sedation or general anesthesia

Exclusion Criteria:

• Patients with neuroendocrine or small cell carcinoma of the prostate
• Prior or concurrent invasive malignancy (except non-melanomatous skin cancer) or lymphomatous/hematogenous malignancy unless continually disease free for a minimum of 5 years
• Regional lymph node involvement
• Evidence of distant metastases
• Previous radical surgery (prostatectomy) or cryosurgery or high-intensity focused ultrasound for prostate cancer
• Previous pelvic irradiation or prostate brachytherapy
• Previous or concurrent cytotoxic chemotherapy for prostate cancer
• Patients with history of inflammatory bowel disease (i.e., Crohn's disease, ulcerative colitis), high predisposition for radio-toxicity compared to general population (i.e., ataxia telangiectasia), or at risk for major bowel surgery
• Transurethral resection of the prostate (TURP) procedure within 6 months of radiation treatment