PRORAD-5 PROstate RADiation in 5 Fractions: Phase II Five Fraction Radiotherapy for Patients With Advanced Prostate Cancer.

1. Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of prostate within one year of study entry. Evaluation can happen outside of MD Anderson as long as histological confirmation takes place at MD Anderson.

1. cT1c-T3a by digital exam or imaging (AJCC 8th Ed.). No cT3b-4 by digital exam or imaging (AJCC 8th Ed.)

2. Gleason Grade Group 2-5 (Gleason 7, 8, 9, 10).

3. If Gleason Grade 2, must meet definition of unfavorable intermediate risk (at least one of the following: cT2b, PSA >10 ng/mL prior to starting androgen deprivation therapy (ADT).

If a participant is taking 5-alpha reductase inhibitors the measured PSA may be doubled).

2. Node negative by conventional imaging.

3. Be ≥ 18 years of age on the day of signing informed consent.

4. Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both LHRH agonist and oral anti-androgen) is ≤ 185 days prior to registration; Please note: baseline PSA must be obtained prior to the start of any ADT.

5. ECOG performance status 0-2.

1. Diagnosis of active scleroderma, lupus, or other rheumatologic disease which in the opinion of the treating radiation oncologist precludes safe RT.

2. Prior prostatectomy, cryosurgery, or HIFU for adenocarcinoma of the prostate

3. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation fields

4. Distant metastatic disease on conventional imaging, which by the discretion of the treating physician cannot be treated definitively.