Adaptive Stereotactic Body Radiation Therapy to the Prostate and Pelvic Nodes With Simultaneous Integrated Boost to the MR-detected Nodule for Patients With High-risk and Unfavorable Intermediate-risk Prostate Cancer

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 Predicted risk of lymph node involvement ≥ 10% using the Memorial Sloan-Kettering prostate cancer nomogram (Appendix A) OR high-risk Decipher score (0.60 - 1.0). For patients with <10% risk of lymph node involvement by the MSKCC nomogram, Decipher testing is required. Patients with high-risk disease must meet at least one of the following criteria: cT3a-T3b PSA > 20 Gleason score ≥ 8 3T MRI scan of the prostate with at least one MR-detectable lesion in the prostate/seminal vesicles (PIRADS 4 or 5) or at least one MR-detectable PIRADS 3 lesion provided there is pathologic correlation from the prostate biopsy. 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 > 15 Prostate gland measuring >90 cc. Unable to get a prostate MRI. 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. More than 50% of the prostate is involved with cancer on MRI as determined by the treating physician. Patients with only PIRADS score of 3 lesions and no MR-fusion biopsy pathologic correlation. Hip prosthetic. 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 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.