The purpose of this study is to assess the impact of prostate-specific membrane antigen/positron emission tomography (PSMA/PET)-informed magnetic resonance (MR)-guided radiation therapy on serious toxicity outcomes in patients with biopsy-proven locally radiorecurrent prostate cancer. The primary aim is to evaluate the safety of delivering MR-Linac-guided stereotactic body radiotherapy (SBRT) after prior prostate external beam radiotherapy for recurrent disease, and assess urinary toxicity outcomes at 2 years.

Inclusion Criteria:

1. 18 years of age or older male participants

2. Biopsy proven intraprostatic prostate cancer after prior definitive external beam radiotherapy (moderate hypofractionation or Stereotactic Body Radiation Therapy (SBRT) acceptable).

   a. NOTE: Seminal vesicle involvement allowed

3. Pathology confirming recurrent disease must have evidence of viable cancer as indicated with pathology interpretation where a Gleason score can be assigned

4. Serum testosterone ≥ 50 ng/dL determined within 2 months prior to enrollment

   a. Prior Androgen Deprivation Therapy (ADT) use acceptable if testosterone level >50ng/dL

5. At least 4 weeks must have elapsed from major surgery

6. Karnofsky Performance Scale (KPS) ≥ 80% or Eastern Cooperative Oncology Group (ECOG) 0-1

7. Prostate size as determined on MRI to be < 90 cc.

8. International Prostatism Symptom Score (IPSS) ≤ 20

9. Patient must be available for follow-up. After 2 years of follow-up, upon completion of post-treatment biopsy, telephone, and chart review-based follow-up will be acceptable for up to 5 years

10. Presence of a T2 and/or DWI-visible prostatic lesion on mpMRI

    a. NOTE: Lesion visible on MRI required for enrollment but PSMA/PET avid lesion not required

11. Satisfy all MRI screening criteria and be willing to fill out the standard MRI screening form

Exclusion Criteria:

1. History of prostate brachytherapy (low dose rate or high dose rate)
2. Actively undergoing androgen deprivation therapy and/or anti-androgens at time of enrollment
3. CT or MRI or PET scan evidence of extraprostatic disease
4. Patients with one or more positive lymph nodes considered suspicious as determined by clinical assessment on MRI or CT or PET scan
5. History of another malignancy within the previous 2 years except for the following: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, currently in complete remission, or any other cancer that has been in complete remission for at least 3 years
6. Patients with Crohn's disease or ulcerative colitis
7. MRI ineligibility due to: the presence of a cardiac pacemaker, defibrillator, or other implanted metallic or electronic device which is considered MR unsafe; severe claustrophobia; inability to lie flat for the duration of the study; etc.
8. Metallic implant or device in the pelvis that might distort the local magnetic field and compromise quality of mp-MRI
9. Lateral pelvic separation greater than 50 cm and/or anterior-posterior separation greater than 35 cm which are incompatible with MRCAT reconstruction
10. Contra-indications to receiving gadolinium contrast or PSMA radioligand
11. Karnofsky Performance Scale (KPS) < 80 or ECOG 2+
12. Grade 3 or higher toxicity experienced after the initial course of External Beam Radiation Therapy (EBRT)
13. Disease free interval < 2 years
14. Hx of Transurethral Resection Of Prostate (TURP) within the year
15. Prior high-intensity focused ultrasound (HIFU) or Cryotherapy
16. Prior history of urethral stricture
17. Unable to give informed consent
18. Unable to complete quality of life questionnaires

The de-identified participant data from the final research dataset will be shared upon reasonable request beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's Data Sharing Strategy Board (DSSB). Requests should be directed to: Michael.zelefsky@nyulangone. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

The investigator who proposed to use the data will be granted access upon reasonable request. Requests should be directed to Michael.zelefsky@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.