This trial is a prospective clinical trial designed to demonstrate the safety and feasibility of whole-pelvis adaptive prostate stereotactic body radiation therapy (SBRT) with a tumor boost to the magnetic resonance (MR)-detected sites of disease. The hypothesis is that this treatment approach will be safe and feasible with <15% of patients experiencing an acute CTCAEv5 grade ≥3 genitourinary (GU) or gastrointestinal (GI) adverse event.

Inclusion Criteria:

• Pathologically proven adenocarcinoma of the prostate with NCCN high-risk disease or NCCN unfavorable intermediate-risk disease.

• Patients with unfavorable intermediate-risk disease must meet the following criteria:

  • At least one intermediate risk factor (IRF):

    • PSA 10-20 ng/mL
    • cT2b-c (AJCC 8th ed.)
    • Gleason score 7

  • At least one "unfavorable" intermediate-risk identifier:

    • > 1 IRF
    • Gleason score 4+3
    • ≥ 50% of biopsy cores positive

  • NO high-risk features

• Patients with high-risk disease must meet at least one of the following criteria:

  • cT3a-T3b
  • PSA > 20
  • Gleason score ≥ 8

• MRI scan of the prostate with at least one MR-detectable lesion in the prostate/seminal vesicles. PET/CT which is found to display activity n the prostate consistent with prostate cancer may be substituted per investigator discretion.

• Planning to undergo concurrent whole-pelvis SBRT and androgen deprivation therapy (ADT). ADT may be initiated at any time per institutional standard, so long as ADT begins within 60 days of the start of radiotherapy.

• At least 18 years of age.

• ECOG performance status ≤ 1

• Agreement to adhere to Lifestyle Considerations throughout study duration

• Able to complete relevant patient-reported quality-of-life questionnaires in the opinion of the treating physician.

• Able to understand and willing to sign an IRB approved written informed consent document.

Exclusion Criteria:

• Definitive radiologic evidence of nodal (cN+) or metastatic (cM1) disease on conventional imaging (bone scan) or prostate cancer-specific PET/CT scan (NaF PET/CT, Axumin PET/CT, fluciclovine, choline, or PSMA PET/CT scan). Patients with lymph nodes ≥ 1 cm on short axis are ineligible unless the lymph node is read as benign by Radiology.
• Prior androgen deprivation therapy. (If the onset of androgen ablation is ≤ 60 days prior to treatment start, the patient is eligible.) Baseline PSA and testosterone must be obtained prior to start of treatment.
• Systemic chemotherapy within 3 years prior to treatment start.
• Prior radical prostatectomy, pelvic lymph node dissection, prostate cryotherapy, or high-intensity focused ultrasound (HIFU) to the prostate.
• Prior pelvic radiotherapy.
• Presence of baseline CTCAE grade ≥ 2 GI or GU toxicity that does not resolve to grade 1 or less with appropriate intervention.
• cT4 disease.
• American Urologic Association (AUA) urinary symptom score ≥ 20
• Prostate gland measuring >90 cc.
• Unable to get prostate fiducial markers placed for image guided radiation treatment. Rectal hydrogel is optional and is left to the discretion of the treating physician.
• Hip prosthetic that does not allow for treatment planning visualization.
• Prior malignancy (except for non-melanoma skin cancer) unless disease-free for at least 2 years. Patients are not eligible if they have had a prior pelvic malignancy (e.g. bladder cancer, rectal cancer).
• Prior transurethral resection of the prostate (TURP) within 3 months prior to registration.
• Uncontrolled intercurrent illness precluding RT and/or ADT including, but not limited to, seizures, myocardial infarction in the past 6 months, current severe or unstable angina pectoris, congestive heart failure requiring hospitalization in the past 6 months, uncontrolled active infection, uncontrolled hypertension, or any condition that in the opinion of the investigator would preclude participation in the study.
• History of uncontrolled inflammatory bowel disease, including ulcerative colitis and Crohn's disease.
• Presence of anal fissure or history of bowel or bladder fistula.
• Scleroderma. Patients who are moderately symptomatic from other autoimmune diseases or patients on biologic therapies for autoimmune diseases are also excluded.
• Known history of HIV or chronic hepatitis B or C. Testing to evaluate for the presence of HIV and/or hepatitis B or C is not required in patients who do not carry the diagnosis.
• Poorly visualized bladder and bowel on diagnostic CT or CT simulation (either due to body habitus or artifact).
• Unable to spend 30 minutes lying on the radiation therapy treatment couch due to significant urinary frequency/urgency or other comorbidities.