This clinical trial studies the side effects of image-guidance and online adaptation with stereotactic body radiation therapy (SBRT) for the treatment of patients with prostate adenocarcinoma that has not spread to other parts of the body (localized). Image-guided SBRT is a standard treatment for localized prostate cancer. This treatment uses imaging of the cancer within the body to define and localize the area to be treated with the radiation. Imaging can be obtained using either computed tomography (CT), magnetic resonance imaging (MRI), or a combination of the two. Typically, with SBRT, a radiation plan is developed based on the CT or MRI images obtained before treatment begins and adjustments are not made to the plan during treatment. However, anatomy can be different from day-to-day which may cause radiation to be delivered to the normal surrounding structures and possibly more side effects. During image-guided SBRT with online adaptation, the initial radiation plan is designed similarly; however, when the patient presents for radiation, the attending radiation oncologist, a dosimetrist, and a medical physicist "re-optimize" the radiation plan using the current anatomy of the day, meaning the changes in bladder and prostate size/shape are taken into account. The initial plan and the re-optimized plan are then compared, and the plan that has the optimal balance between delivering a tumor killing dose of radiation and minimizing radiation dose to normal surrounding structures is delivered. Image-guidance and online adaptation with SBRT may lower side effects and be a safer way to treat localized prostate adenocarcinoma.

PRIMARY OBJECTIVE:

I. To determine whether daily, real-time adaptive SBRT to the prostate improves acute patient-reported genitourinary (GU) toxicity when compared with conventional, non-adaptive SBRT to the prostate for localized prostate cancer.

SECONDARY OBJECTIVES:

I. To determine whether there are differences in the acute, patient-reported other toxicity following daily, real-time adaptive versus conventional, non-adaptive SBRT for localized prostate cancer.

II. To determine whether there are chronic differences in patient-reported quality of life (QOL) outcomes following daily, real-time adaptive versus conventional, non-adaptive SBRT for localized prostate cancer.

III. To determine whether there are differences in the acute and late physician-scored GU and gastrointestinal (GI) toxicity following daily, real-time adaptive versus conventional, non-adaptive SBRT for localized prostate cancer.

IV. To determine whether there are differences in the 5-year biochemical recurrence-free survival (BCRFS) following daily, real-time adaptive versus conventional, non-adaptive SBRT for localized prostate cancer.

CORRELATIVE OBJECTIVE:

I. To correlate patient-reported and physician-scored toxicity with a commercially available genetic biomarker (PROSTOX trademark, MiraDx, Los Angeles, CA).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo MRI or CT-guided SBRT without daily plan adaptation once every other day or once daily (QD) for a total of 5 treatments over 18 days in the absence of disease progression or unacceptable toxicity.

ARM 2: Patients undergo MRI or CT-guided SBRT with daily plan adaptation once every other day or QD for a total of 5 treatments over 18 days in the absence of disease progression or unacceptable toxicity.

Additionally, all patients undergo MRI and CT during screening and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at months 1, 3, 6, 9, 12, 24, 36, 48, and 60.

Inclusion Criteria:

• Age ≥ 18

• Histologically confirmed, clinically localized adenocarcinoma of the prostate

• Staging workup as recommended by the National Comprehensive Cancer Network (NCCN) on the basis of risk grouping

  • Advanced imaging studies (i.e. prostate-specific membrane antigen [PSMA] positron emission tomography [PET]/CT and fluciclovine PET/CT scan) can supplant a bone scan if performed first

• 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 PSMA PET/CT scan below the bifurcation of the renal arteries are amenable)

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• No indication for urgent or emergent radiation

• 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 cryosurgery, high-intensity focused ultrasound (HIFU), brachytherapy, or other ablative treatments of the whole 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

This block size will be blinded to the radiation oncology research team when enrolling a patient. The arm allocation will be masked until after the screening/baseline data are entered and filled out in Research Electronic Data Capture (REDCap) (no anticipation of the group assignment will be possible).