This study is a large, prospective, pragmatic, controlled comparison of patient-centric outcomes [quality of life (QOL), toxicity, and disease control] between parallel cohorts of men with prostate cancer treated simultaneously at proton therapy facilities and at geographically similar conventional (photon-based) radiation facilities using intensity-modulated radiation therapy (IMRT) techniques.

This study is a large, prospective, pragmatic, controlled comparison of patient-centric outcomes [quality of life (QOL), toxicity, and disease control] between parallel cohorts of men with prostate cancer treated simultaneously at proton therapy facilities and at geographically similar conventional (photon-based) radiation facilities using intensity-modulated radiation therapy (IMRT) techniques. This study includes a pre-specified randomized comparison of standard fractionation and moderate hypofractionation dose schemes within the proton therapy cohort. In addition, subgroup analyses will include a comparison of outcomes by race (Black vs. White), comorbidity score (0 vs. 1+), age (<65 vs. ≥65), fractionation schedule (standard, moderate, ultra-hypofractionation), and prostate cancer aggressiveness (very low and low, intermediate, and high risk) for all objectives.

All interventions will be standard of care (SOC) radiation strategies using either IMRT or proton therapy. All patient-reported QOL, patient-scored and patient-reported toxicity, and disease control assessments will be SOC. Participants will also complete pretreatment surveys regarding demographic data, personal treatment goals, factors affecting treatment decision-making, and sources of information used in treatment selection.

Inclusion Criteria:

• Diagnosis of adenocarcinoma of the prostate.
• 30-85 years of age at the time of consent with a life expectancy estimation (LEE) of ≥ 8 years.
• Localized prostate cancer, as confirmed by staging with PSA, biopsy, Gleason score, DRE with or without mpMRI, and clinical stage.
• Very low-risk, low-risk, intermediate-risk, or high-risk disease based on NCCN Prostate Cancer Risk Group Guidelines and Joint AUA/ASTRO/SUO Guidelines.
• If patient has high-risk disease, nuclear medicine bone imaging must be performed to document the absence of overt metastatic disease in bones.
• ECOG/Zubrod Performance Status 0 - 2.
• Candidate for definitive prostate radiotherapy (either IMRT or proton).
• If patient is to be treated with IMRT, all treatment must be planned with IMRT; if patient is to be treated with protons, all treatment must be planned with protons (including pelvic nodes if treated).

Exclusion Criteria:

• Findings of metastatic disease (nodal or distant, N1 or M1).
• Very high-risk prostate cancer based on NCCN Prostate Cancer Risk Group Guidelines and Joint AUA/ASTRO/SUO Guidelines.
• Prior procedures for treatment of prostate cancer, such as radical or robotic prostatectomy, high-intensity focused ultrasound, cryosurgery, or focal prostatectomy [note that procedures used for benign prostatic hyperplasia symptoms, such as transurethral resection of the prostate (TURP) and GreenLight Laser Therapy, are acceptable].
• Previous prostate cancer treatment with the exception of ADT according to NCCN guidelines.
• History of invasive rectal malignancy or other malignancy in the true pelvis (e.g. bladder, rectum, or reproductive organs), regardless of disease-free interval.
• Active inflammatory bowel disease (i.e., patients requiring medical interventions or who are symptomatic).
• Prior pelvic RT for any reason.
• Documented lack of psychological ability or general health permitting completion of the study requirements and required follow-up.
• Documented diminished capacity to understand the risks and benefits of participation in research and to autonomously provide informed consent.

In addition, because the embedded randomized controlled trial compares fractionation schemes, patients who are receiving pelvic node irradiation may not be enrolled on the randomized controlled trial.