This clinical trial studies the side effects of computed tomography (CT)-guided stereotactic body radiation therapy (SBRT) with intrafraction motion monitoring and to see how well it works in treating patients with prostate cancer that has not spread to other parts of the body (localized). In CT-guided SBRT, x-ray-based imaging and cone-beam CTs are used to define and localize the area to be treated with SBRT. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. A recent randomized trial showed that while SBRT is associated with less urinary incontinence and erectile dysfunction than complete surgical removal of the prostate, there are more urinary irritative side effects and more bowel side effects than with surgery. One source of uncertainty in SBRT that may contribute to genitourinary (GU) and gastrointestinal (GI) side effects is the necessity of treating a "margin" of volume around the prostate to account for its movement during SBRT. Intrafraction motion monitoring is any technique or system designed to track the movement of the body and target during fractions of external beam radiation to keep the beam on target. This allows for the patient to be repositioned, if needed, to ensure delivery of the SBRT to only the planned treatment area. CT-guided SBRT with intrafraction motion monitoring may lower GU and GI side effects by allowing tighter margins, as has been demonstrated with magnetic resonance imaging (MRI)-guided SBRT.

PRIMARY OBJECTIVE:

I. To determine the acute physician-scored GU toxicity associated with CT-guided SBRT utilizing a 2mm prostate ± seminal vesicles planning target volume (PTV) margin for localized prostate cancer.

SECONDARY OBJECTIVES:

I. To determine the acute physician-scored GI toxicity associated with the intervention.

II. To determine the late physician-scored toxicity associated with the intervention.

III. To determine the patient-reported quality of life outcomes associated with the intervention.

IV. To determine the 5-year biochemical recurrence-free survival (BCRFS) associated with the intervention.

V. To evaluate intrafraction prostate motion using on-board imaging data acquired during this trial in conjunction with prior data, described above.

OUTLINE:

Patients undergo CT-guided SBRT with intrafraction motion monitoring over 5 fractions every other day, or on consecutive days, if necessary, in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI on study and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for the first year, every 6 months for a minimum of 5 years, and then annually thereafter.

Inclusion Criteria:

• Histologically confirmed, clinically localized adenocarcinoma of the prostate
• No evidence of metastatic disease in lymph nodes above the bifurcation of the renal arteries, or in bones or visceral organs (nodal disease identified on a prostate-specific membrane antigen [PSMA] positron emission tomography [PET]/CT scan below the bifurcation of the renal arteries are amenable)
• Staging workup as recommended by the National Comprehensive Cancer Network (NCCN) on the basis of risk grouping
• Advanced imaging studies (i.e. PSMA PET/CT and fluciclovine PET/CT scan) can supplant a bone scan if performed first
• Age ≥ 18
• Written informed consent obtained from participant or participant's legal representative and ability for participant to comply with the requirements of the study

Exclusion Criteria:

• Patients with neuroendocrine or small cell carcinoma of the prostate
• Patients with any evidence of distant metastases except that evidence of lymphadenopathy below the level of the renal arteries can be deemed locoregional per the discretion of the investigator
• Prior whole gland cryosurgery, high-intensity focused ultrasound (HIFU) or brachytherapy of the prostate
• Prior pelvic radiotherapy
• History of Crohn's Disease, ulcerative colitis, or ataxia telangiectasia
• Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the participant or the quality of the data