This clinical trial evaluates changes in quality of life after two treatments with near margin-less adaptive radiation therapy (ART) compared to five treatments with standard stereotactic ablative body radiotherapy (SABR) in patients with prostate cancer that has not spread to other parts of the body (localized). ART is a type of radiation therapy that uses information gathered during the treatment cycle to inform, guide, and alter future radiation treatments with respect to location and dose. It may be able to deliver radiation to the site of disease over a shorter time and with smaller margins (less treatment delivered to nearby healthy tissues). SABR 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. Shorter duration near margin-less ART may be just as effective at treating patients with localized prostate cancer but have less quality of life side effects than standard SABR.

PRIMARY OBJECTIVE:

I. To evaluate treatment-related, patient-reported early quality of life (QOL) changes between near "margin-less" ART in 2 fractions versus standard of care 3-5mm SABR in 5 fractions, using the Expanded Prostate Cancer Index Composite (EPIC)-26 bowel and urinary irritative/obstructive domains.

SECONDARY OBJECTIVES:

I. To assess treatment-related, patient-reported late QOL changes after SABR using the EPIC-26 bowel and urinary irritative/obstructive domains.

II. To assess and compare early physician-reported grade ≥ 2 gastrointestinal (GI) and/or genitourinary (GU) toxicities of interest within 3 months after SABR using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

III. To assess and compare patient-reported financial toxicities, using the Functional Assessment of Chronic Illness Therapy-Comprehensive Score for Financial Toxicity (FACIT-COST) assessment tool.

IV. To assess and compare late physician-reported grade ≥ 2 GI and/or GU toxicities of interest within 24 months after SABR using the CTCAE v5.0.

V. To assess and compare change in International Index of Erectile Function (IIEF-15) and International Prostate Symptom Score (IPSS).

VI. To explore the association of fiducial-free treatment on dosimetry, patient reported outcomes (PROs), and toxicity.

VII. To explore the association of bladder filling on dosimetry, PROs, and toxicity.

VIII. To assess and compare the cumulative incidence of biochemical failure, local progression, distant metastasis, and metastasis-free survival within 60 months after SABR.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo near margin-less adaptive radiation therapy (ART) for 2 treatments at least 3 days apart in the absence of disease progression or unacceptable toxicity. Patients also undergo cone beam computed tomography (CBCT) and may undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) on study.

ARM II: Patients undergo standard SABR for 5 treatments at least 2 days apart in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI on study.

After completion of study treatment, patients are followed up at months 1, 3, and 6, and then every 6 months for up to 60 months.

Inclusion Criteria:

• Gender assigned male at birth: age ≥ 18 years
• Histological confirmation of prostate adenocarcinoma
• National Comprehensive Cancer Network (NCCN) (Prostate Cancer version 4.2022) low- to intermediate-risk prostate adenocarcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Ability to complete questionnaire(s) by themselves or with assistance
• Signed informed consent
• Willing to complete requirements for follow-up (during active monitoring phase)

Exclusion Criteria:

• NCCN (Prostate Cancer version 4.2022) very low-, high-, or very high-risk prostate adenocarcinoma
• Prior definitive treatment of prostate cancer including radiotherapy, prostatectomy, cryotherapy, or high intensity focused ultrasound (HIFU)
• Prior bladder outlet obstruction procedures including transurethral resection of the prostate (TURP), Holmium laser enucleation of the prostate (HoLEP), transurethral vaporesection of the prostate (TUVRP), etc.
• Metastatic disease by conventional or molecular imaging
• Contraindications to radiation therapy (RT) including uncontrolled inflammatory bowel disease, ATM mutation, and Xeroderma pigmentosum mutation
• Concurrent antineoplastic agents (chemotherapy)
• Previous or concurrent malignancy other than non-melanoma skin cancer, indolent lymphoma, or chronic myelogenous leukemia, unless continuously disease-free ≥ 5 years
• Medical or psychiatric conditions that preclude informed decision-making or adherence with the protocol-defined treatment or follow-up
• Prostate gland volume > 80 cc based on magnetic resonance imaging (MRI), and/or International Prostate Symptom Score (IPSS) composite score > 17
• Body weight > 200 kilogram
• Known allergy or sensitivity to polyethylene glycol (PEG) or iodine