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
* 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.