Adaptive Radiation Therapy for Men With Intermediate- or High-Risk Prostate Cancer

Inclusion Criteria: 1. Subjects must have histologically confirmed intermediate- and favorable high risk (AJCC 8th ed stage IIA-IIC) adenocarcinoma of the prostate. 2. Age \> 18 years. 3. ECOG performance status ≤ 2 4. Prostate volume (segmented) ≤ 100 cc determined by MRI and/or US within 24 mo of treatment for patients not on ADT and within 6 mo for patients on prior ADT. A simulation MRI is acceptable. 5. Subjects must have had a pre-treatment diagnostic multiparametric MRI prostate (mpMRI) showing a PI-RADS3, 4 or 5 lesion or a 68Ga- or 18F-PSMA (TLX591-CDx or piflufolastat F18) PET/CT within 12 mo of study registration. 6. Baseline International Prostate Symptom Score (IPSS) is ≤ 15. Baseline alpha blocker use is allowed. 7. Subjects must have full capacity to understand and be willing to sign the informed consent document. Exclusion Criteria: 1. Subjects must not be experiencing toxicity CTCAE grade ≥ 3 GU or GI toxicity at baseline. 2. Subjects must not be receiving any other investigational agents. 3. Subjects must not have had prior pelvic radiation therapy. 4. Subjects must not have node-positive disease. 5. Subjects must not have extraprostatic extension determined by MRI prostate within 24 mo of treatment. For patients receiving ADT, the prostate MRI must have been obtained prior to the start of ADT. 6. Subjects must not have had prior ablative therapies for prostate cancer including cryosurgery, HIFU and nanoknife. 7. Subjects with prior TURP or laser enucleation are eligible. However, patients that have undergone prior simple prostatectomy are excluded. 8. Subjects that are receiving other antineoplastic agents including methotrexate are ineligible. Subjects that have received prior ADT are eligible if they have received \< 6 mo total of ADT, if last administration of ADT was \> 6 mo prior to registration and serum total testosterone levels have recovered to at least 100 ng/dL. Subjects with prior cancer diagnoses are eligible provided that treatment was completed and no evidence of disease status achieved at least 2 years prior to study registration. 9. Subjects must not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 10. Any condition or significant co-morbidity that prevents safe delivery of SBRT per the discretion of the treating physician(s). 11. Subjects with active inflammatory bowel disease or active collagen vascular disorder. 12. Subjects that cannot undergo prostate fiducial placement. 13. Subjects that cannot undergo rectal spacer placement are excluded. Please, note that a rectal spacer incorporating iodine or similar CT contrast is preferred. However, patients that are able to only have a non-contrast rectal spacer due to iodine allergy or similar contraindication remain eligible. 14. Subjects that cannot undergo prostate MRI. 15. Subjects with bilateral prosthetic hips will be excluded. Subjects with unilateral prosthetic hips will be eligible only if the initial treatment plan meets all target and normal tissue constraints without protocol violation.