Lu-PSMA and Stereotactic Radiotherapy Versus Radiotherapy Alone for Prostate Cancer (LUST)

Inclusion Criteria:

1. Patients with prostate cancer must have 1-3 asymptomatic metastatic lesions that are ≤ 5.0 cm or < 250 cm3 documented at CT/MRI or WBD-MRI.

2. PSMA-PET/CT positive scan matching with lesions documented on baseline CT/MRI orWBD-MRI.

3. Patients must have had their primary tumor treated with surgery and/or radiation andprevious salvage radiation to the prostate bed or pelvis is allowed.

4. Patients will be admitted to the therapeutic phase only if diagnostic PET/CT PSMASUV max is ≥ 3.

5. Histologic confirmation of malignancy (primary or metastatic tumor).

6. Prostate specific antigen (PSA) ≥ 0.2 ng/mL but ≤ 50 ng/mL and Testosterone ≥ 125ng/dL.

7. PSA doubling time (PSADT) < 15 months. PSADT will be calculated using as many PSAvalues that are available from time of relapse (PSA > 0.2 ng/dL).

8. Patients unfit or refusing ADT.

9. Patients may have had prior systemic therapy and/or ADT associated with treatment oftheir primary prostate cancer. Patients may have had ADT associated with salvageradiation therapy.

10. Patients must be ≥ 18 years of age.

11. Patient understands the purpose of the study and the procedures required for it; thepatient is willing to participate in the study and to sign a written informedconsent document.

12. Patients must have an Eastern Cooperative Oncology Group performance status ≤ 2.

13. Patients should have a life expectancy of at least 6 months.

14. Patients must have normal organ and marrow function as defined as:

• Leukocytes >2,000/μL;

• Absolute neutrophil count >1,000/μL;

• Platelets >75,000/μL;

• total bilirubin within normal institutional limits (this will not apply topatients with confirmed Gilbert's syndrome);

• AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal;

• Creatinine within normal institutional limits.

15. If the participant engages in sexual activity with a woman of childbearingpotential, a condom must be used together with another highly effective method ofcontraception during the Treatment Period and for 6 months after the last dose ofstudy intervention. The participant must agree not to donate sperm for the purposeof reproduction during the Treatment Phase and for a minimum of 6 months afterreceiving the last dose of study intervention.

16. Highly effective birth control methods are required beginning at the screening visitand continuing until 6 months following last treatment with study drug. Patients andfemale partner who is of childbearing potential must use 2 acceptable methods ofbirth control (1 of which must include a condom as a barrier method ofcontraception, see Appendix F) starting at screening and continuing throughout thestudy period and for 6 months after final study drug administration. Two acceptablemethods of birth control thus include Condom (barrier method of contraception) andone of the following is required ( established use of oral, or injected or implantedhormonal method of contraception by the female partner; placement of an intrauterinedevice (IUD) or intrauterine system (IUS) by the female partner; additional barriermethod like occlusive cap with spermicidal foam/gel/film/cream/suppository in thefemale partner; tubal ligation in the female partner; vasectomy or other procedureresulting in infertility (eg., bilateral orchiectomy), for more than 6 months.

17. Highly effective birth control methods are required beginning at the screening visit and continuing until 6 months following last treatment with study drug. Patients and female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception, starting at screening and continuing throughout the study period and for 6 months after final study drug administration.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:

1. No more than 3 years of ADT is allowed, with the most recent ADT treatment havingoccurred more than 6 months prior to enrollment.

2. PSMA -PET/CT scan more than 3 months.

3. Spinal cord compression or impending spinal cord compression.

4. Suspected pulmonary and/or liver metastases.

5. Bone metastasis in a femoral bone.

6. Previous radiation therapy on the metastatic site.

7. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from adverse events due to agents administered more than 4 weeks earlier.A window of 3 days is permitted.

8. Participation in another clinical trial with any investigational agents within 30days prior to study screening. A window of 3 days is permitted.

9. Any condition for which, in the opinion of the investigator, participation would notbe in the best interest of the participant.

10. Patients with known brain metastases should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events.

11. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to 177-Lu-PSMA- I & T or other agents used in the study.

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

13. Unable to lie flat during or tolerable SABR.

14. Other known malignant neoplastic diseases in the patient's medical history with adisease-free interval of less than 3 years (except for previously treated basal cellcarcinoma);

15. Known HIV-positivity, whether or not symptomatic.