EBRT and HDR Brachytherapy for Unfavorable-intermediate, High, and Very High-risk Prostate Cancer

Inclusion Criteria: 1. Provision of signed and dated informed consent form. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Male, aged 18 or above. 4. Histologic proven diagnosis of cancer of the prostate up to one year before registration. 5. Unfavorable-intermediate risk, high risk, or very high-risk prostate cancer as determined by the NCCN Guidelines Version 4.2019 (Section 12.4). 6. History and physical exam completed up to 6 months before registration. 7. PSA value \< 50 ng/mL prior to androgen deprivation therapy and up to 12 months before registration. Subjects who do not meet this criteria's timeframe due to extenuating circumstances (i.e. COVID-19 quarantine, changes to their treatment plan, etc) but meet all other eligibility criteria may still be eligible. The PI will review each case and decide 8. ECOG performance status 0 or 1. 9. Pelvic MRI obtained up to 12 months before registration. 10. Candidate for receiving the combination of HDR brachytherapy and EBRT, with or without ADT. The ADT may have begun prior to study enrollment. Exclusion Criteria: 1. Evidence of bone metastases. 2. Diagnosis of a prior invasive malignancy (except for non-melanoma skin cancer), unless the participant has been disease-free for at least 3 years. 3. Patient has had previous radical surgery (prostatectomy) or cryosurgery for prostate cancer. 4. Patient has had previous pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy. 5. Patient has had prior radiotherapy, including brachytherapy, to the region of this study cancer that would result in overlap of radiation therapy fields. 6. Patient has had previous or concurrent cytotoxic chemotherapy for prostate cancer (prior chemotherapy for different cancer is allowed). 7. Patient has MRI incompatible metallic implant(s) that cannot be removed. 8. The patient has severe or active co-morbidities as defined by the following: * Unstable angina and/or congestive heart failure requiring hospitalization up to 6 months (180 days) before registration * Transmural myocardial infarction up to 6 months (180 days) before registration * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration * Hepatic insufficiency resulting in clinical jaundice and/or coagulation effects or severe liver dysfunction. * Acquired immune deficiency syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be slightly immunosuppressive. Protocol- specific requirements may also exclude immuno-compromised patients.