Targeted Alpha Therapy with 225Actinium-Prostate Specific Membrane Antigen (PSMA)-I&T of Castration-resISTant Prostate Cancer (TATCIST).

Inclusion Criteria:

1. Participants aged ≥ 18 years.

2. Participants must have the ability to understand and sign an approved informedconsent (ICF).

3. Participants must have the ability to understand and comply with all protocolrequirements.

4. Adenocarcinoma of prostate proven by histopathology.

5. Life expectancy of 6 months or more.

6. Unresectable metastases.

7. Documented progressive disease (PD); progressive mCRPC will be based on at least 1of the following criteria:

8. Serum PSA progression is defined as 2 consecutive increases in PSA over aprevious reference value measured at least 1 week prior. The minimal startingvalue is 1.0 ng/mL, if PSA is the only indication of progression.

9. Soft-tissue progression defined as an increase ≥ 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of alltarget lesions based on the smallest SOD since treatment started or theappearance of one or more new lesions.

10. Progression of bone disease: evaluable disease or new bone lesions(s) by bonescan (2+2 PCWG3 criteria).

11. If known Breast Cancer gene (BRCA) mutations are present, participants should havereceived FDA approved therapies such as poly-ADP ribose polymerase (PARP) inhibitorsand progressed.

12. Castration resistant disease with confirmed testosterone level ≤ 50 ng/dL underprior androgen deprivation therapy (ADT). Must have a castrate level of serumtestosterone (< 50 ng/dL or < 1.7 nmol/L).

13. Positive PSMA PET/CT scans, obtained with approved PSMA-ligands, defined as at leastone PSMA-positive metastatic lesion and no PSMA-negative lesions.

14. ECOG-PS 0 to 1.

15. Hemoglobin (Hgb) concentration ≥ 9.0 g/dL.

16. Platelet counts ≥ 100 × 10^9/L.

17. White blood cell (WBC) count ≥ 2.0 × 10^9/L, absolute neutrophil count (ANC) > 1.5 × 10^9/L. a. Hematological criteria cannot be met with ongoing or recent blood transfusions (within 7 days prior to the scheduled first dose of study treatment) or requiregrowth factor support (within 21 days prior to the scheduled first dose of studytreatment).

18. Alanine aminotransferase or aspartate aminotransferase ≤ 3.0 × upper limit of normal (ULN).

19. Serum total bilirubin ≤ 1.5 × ULN; in participants with Gilbert's syndrome, a totalbilirubin ≤ 3 times ULN and direct bilirubin within normal limits are permitted.

20. Albumin ≥ 2.5 g/dL.

21. Serum/plasma creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min based on theCockcroft-Gault formula.

22. Prothrombin time, international normalized ratio or prothrombin time test < 1.5 ×ULN.

23. Received ≥ 1 androgen receptor axis-targeted therapies (ARAT).

24. Participants on anti-androgen therapy are allowed to continue their treatment at thediscretion of their treating physician.

Exclusion Criteria:

1. Less than 6 weeks from enrollment since last myelosuppressive therapy (includingDocetaxel, Cabazitaxel, 223Ra, 153Sm, 177Lu-PSMA-617/other Lu-PSMA RLT or any otherradionuclide therapy). Participants who received previous treatment with Ac-225 areexcluded.

2. Participants who received more than 4 prior lines of systemic therapy for CRPC.

3. Urinary tract obstruction as evidenced by Tc-99m DTPA renal scan with diuretics.

4. Participants with skeletal metastases presenting as a superscan on a 99m Tc MDP BoneScan. Superscan is defined as a bone scan which demonstrates markedly increased skeletalradioisotope uptake relative to soft tissues in association with absent or faintrenal activity (absent kidney sign).

5. Persistent baseline dry eye or dry mouth > Grade 1 from prior RLT.

6. Persistent prior AEs > Grade 1 from prior anti-cancer therapies.

7. Abnormal renal function (estimated glomerular filtration rate < 60 mL/min), baselineHgb < 9g/dL, ANC < 1.5 ×10^9/L, platelets < 100 ×10^9/L, and prothrombin time,international normalized ratio or prothrombin time test ≥ 1.5 × ULN.

8. Administration of an investigational agent ≤ 60 days or 5 half-lives, whichever isshorter, prior to Cycle 1, Week 0.

9. Known presence of central nervous system (CNS) metastases or liver metastases.

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

11. Concurrent illness that may jeopardize the participant's ability to undergo studyprocedures as determined by the Investigator.

12. Symptomatic cord compression, or clinical or radiologic findings indicative ofimpending cord compression.

13. Concurrent serious (as determined by the investigator) medical conditions,including, but not limited to, New York Heart Association Class III or IV congestiveheart failure, unstable ischemia, uncontrolled symptomatic arrhythmia, history ofcongenital prolonged QT syndrome, uncontrolled infection, known active hepatitis Bor C, or other significant co-morbid conditions that in the opinion of theInvestigator would impair study participation or cooperation.

14. Major surgery ≤ 30 days prior to enrollment.

15. Planning to conceive pregnancy during the treatment and up to 6 months after thelast treatment.