177Lu-PSMA-I&T for Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

1. Male 18 years or older able to understand and provide signed written informedconsent.

2. Histologically or pathologically confirmed prostate adenocarcinoma withoutpredominant small cell component.

3. Progressive disease by one or more of the following criteria:

4. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over aprevious reference value measured at least 1 week apart with a minimum startvalue of >2 ng/mL.

5. Progression of measurable disease (RECIST 1.1) or presence of at least two newbone lesions (PCWG3 criteria).

6. Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g. abiraterone, enzalutamide, apalutamide, darolutamide).

7. Must have received no more than one previous AR-directed therapy.

8. Must have been administered ARAT (abiraterone, enzalutamide, darolutamide, orapalutamide) in the castration-sensitive or castration-resistant setting.

9. Must have progressed while on ARAT.

10. PSMA-PET scan (e.g., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by centralreader.

11. Effective castration with serum testosterone level of <50 ng/dL and plan to continuewith chronic medical or surgical castration.

12. Ability to attend required study visits and return for adequate follow-up, asrequired by this protocol.

13. Patients with HIV that are healthy and with a low risk of acquired immune deficiencysyndrome related outcomes may participate in the trial at the investigators'discretion.

14. Patients with HBV and HCV may also participate if symptoms are sufficiently managed.

15. Life expectancy of at least 6 months as assessed by investigator.

16. Willing to initiate ARAT therapy determined by investigator.

17. For patients who have partners of childbearing potential: The patient and/or partnermust use a method of birth control with adequate barrier protection, deemedacceptable by the principal investigator during the study and for 6 months after thelast study drug administration.

Exclusion Criteria:

1. Prior treatment with radioligand therapy including other lutetium-labeled compounds.

2. Prior treatment with radium-223 (Xofigo) within the past 12 weeks.

3. Prior chemotherapy treatment for castration-resistant prostate cancer. Priordocetaxel use in the hormone-sensitive setting is permitted, as long as no more than 6 doses were received, the last dose was administered >1 year prior to consent, anddisease progression did not occur during docetaxel treatment.

4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2

5. Patients with known HRR gene-mutation (BRCA 1/2 encompassing both germline andsomatic) who have not been previously treated with olaparib or rucaparib.

6. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, orinvestigational therapy.

7. Inadequate organ and bone marrow function as evidenced by:

8. Hemoglobin < 8 g/dL.

9. Absolute neutrophil count < 1.5 x 109/L.

10. Platelet count < 100 x 109/L.

11. AST/SGOT and/or ALT/SGPT > 3.0 x ULN.

12. Total bilirubin > 2 x ULN unless patient has known Gilbert's syndrome and thenmay be 3 x ULN.

13. Creatinine clearance (CrCl) < 50 mL/min based on the Cockcroft-Gault equation.

14. Albumin ≤ 2.75 g/dL

15. Patients who undergo a transfusion for the sole purpose of meeting eligibility forthis trial will be excluded.

16. Assessment by the Investigator as unable or unwilling to comply with therequirements of the protocol.

17. Use of an investigational therapeutic drug within the last 4 weeks prior to start ofstudy treatment or scheduled to receive one during the study period.

18. Known CNS metastasis unless received therapy, asymptomatic and neurologicallystable.

19. Patients receiving zoledronic acid for bone-targeted therapy must be on stable dosefor 4 weeks prior to randomization.

20. Major surgery within 30 days of randomization as determined by the Investigator.

21. Patients with active significant cardiac disease defined by any of the following:

22. New York Heart Association class 3 or 4 congestive heart failure within 6months of signing the ICF unless treated with improvement.

23. Current diagnosis of electrocardiogram abnormalities with significant cardiacarrhythmias

24. History of long QT syndrome or know history of Torsades de Pointe

25. History of myocardial infarction, angina pectoris, or coronary artery bypassgraft within 6 months of ICF signature

26. Participants with symptomatic cord compression or clinical/radiological findingsindicating impending spinal cord compression

27. Patients with a superscan seen on baseline bone scan as determined by investigator.

28. Active malignancy other than low-grade non-muscle-invasive bladder cancer andnon-melanoma skin cancer

29. Previous use of G-CSF for persistent neutropenia after standard of care treatment.

30. Participants who have a pregnant partner or are capable of fathering a child and whoare unwilling to take precautions to prevent potential harm to the fetus or preventpregnancy.

31. Participants with active Covid19. Recovered patients may be included when completelyrecovered (no symptoms at least 28 days before study medication and a negative Covidtest within 72 hours).