TATCIST: This trial is recruiting people with metastatic castration-resistant prostate cancer (mCRPC) to investigate a targeted radiation treatment called FPI-2265PSMA-directed Targeted Alpha Therapy With FPI-2265 (225Ac-PSMA-I&T) for the Treatment of Metastatic Castration-resISTant Prostate Cancer (TATCIST). A Phase II Clinical Trial.

Inclusion

1. Participants aged ≥ 18 years.
2. Participants must have the ability to understand and sign an approved informed consent (ICF).
3. Participants must have the ability to understand and comply with all protocol requirements.
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 1 of the following criteria:

   1. Serum PSA progression is defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal starting value is 1.0 ng/mL, if PSA is the only indication of progression.
   2. 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 all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions.
   3. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria).
8. If known Breast Cancer gene (BRCA) mutations are present, participants should have received FDA approved therapies such as poly-ADP ribose polymerase (PARP) inhibitors and progressed.
9. Castration resistant disease with confirmed testosterone level ≤ 50 ng/dL under prior androgen deprivation therapy (ADT). Must have a castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L).
10. Positive PSMA PET/CT scans, obtained with approved PSMA-ligands, defined as at least one PSMA-positive metastatic lesion and no PSMA-negative lesions.
11. ECOG-PS 0 to 1.
12. Hemoglobin (Hgb) concentration ≥ 9.0 g/dL.
13. Platelet counts ≥ 100 × 10^9/L.

14. 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 require growth factor support (within 21 days prior to the scheduled first dose of study treatment).

15. Alanine aminotransferase or aspartate aminotransferase ≤ 3.0 × upper limit of normal (ULN).
16. Serum total bilirubin ≤ 1.5 × ULN; in participants with Gilbert's syndrome, a total bilirubin ≤ 3 times ULN and direct bilirubin within normal limits are permitted.
17. Albumin ≥ 2.5 g/dL.
18. Serum/plasma creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min based on the Cockcroft-Gault formula.
19. Prothrombin time, international normalized ratio or prothrombin time test < 1.5 × ULN.
20. Received ≥ 1 androgen receptor axis-targeted therapies (ARAT).
21. Participants on anti-androgen therapy are allowed to continue their treatment at the discretion of their treating physician.