Targeted Alpha Therapy With 225Actinium-PSMA-I&T of Castration-resISTant Prostate Cancer (TATCIST).

Inclusion Criteria:

Signing informed consent
Adenocarcinoma of Prostate proven by histopathology
Life expectancy of 6 months or more
Unresectable metastases
Progressive disease, with docetaxel/cabazitaxel or declined taxane therapy by the patient
177Lu-PSMA-617 naive or 177Lu-PSMA-617/177Lu-PSMA-I&T treated
If BRCA mutations or microsatellite instability is present, patients should have received FDA approved therapies such as PARP inhibitors and pembrolizumab, and progressed
Castration-resistant disease with confirmed testosterone level ≤50 ng/ml under prior androgen deprivation therapy (ADT)
Positive 68Ga-PSMA-11 PET/CT for the majority of measurable diseases defined as SUV ≥2.0
ECOG 0-2
Hemoglobin concentration ≥ 9.0 g/dL
Platelet counts ≥100 × 109/L
White blood cell count ≥ 2.0 × 109/L), ANC>1.5 x109/L
Glomerular Filtration Rate (GFR) ≥ 60 ml/min
AST and ALT ≤ 5xULN
Billirubin ≤ 3x ULN
Albumin ≥ 25 g/L
Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula
Received at least one ARAT in the past
Patients on anti-androgen therapy are allowed to continue their treatment at the discretion of their oncologists

Exclusion Criteria:

Inclusion Criteria:
Signing informed consent.
Adenocarcinoma of Prostate proven by histopathology
Life expectancy of 6 months or more.
Unresectable metastases.
Progressive disease, with docetaxel/cabazitaxel or declined taxane therapy by the patient.
177Lu-PSMA-617 naive or 177Lu-PSMA-617/177Lu-PSMA-I&T treated.
If BRCA mutations or microsatellite instability is present, patients should have received FDA approved therapies such as PARP inhibitors and pembrolizumab, and progressed
Castration resistant disease with confirmed testosterone level ≤50 ng/mlunder prior androgen deprivation therapy (ADT)
Positive 68Ga-PSMA-11 PET/CT for the majority of measurable disease defined as SUV ≥2.0.
ECOG 0-2
Hemoglobin concentration ≥ 9.0 g/dL
Platelet counts ≥100 × 109/L
White blood cell count ≥ 2.0 × 109/L), ANC>1.5 x109/L
Glomerular Filtration Rate (GFR) ≥ 60 ml/min
AST and ALT ≤ 5xULN
Billirubin ≤ 3x ULN
Albumin ≥ 25 g/L.
Serum/plasma creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based on Cockcroft-Gault formula
Received at least one ARAT in the past.
Patients on anti-androgen therapy are allowed to continue their treatment at the discretion of their oncologists.

Exclusion Criteria:

Less than 6 weeks since last myelosuppressive therapy (including Docetaxel, Cabazitaxel, 223Ra, 153Sm, 177Lu-PSMA-617, 177Lu-PSMA-I&T) or other radionuclide therapy permitted (including 223Ra, 153Sm)
Urinary tract obstruction as evidenced by Tc-99m DTPA renal scan with diuretics
Abnormal renal function (eGFR <60 mL/min), baseline Hgb <9g/dL, ANC<1.5 x109/L, platelets <100 x109/L, and PT, INR or PTT ≥1.5xULN
Persistent baseline dry eye or dry mouth from prior RLT
Persistent prior AEs >Grade 1 from prior anti-cancer therapies
Administration of an investigational agent ≤60 days or 5 half-lives, whichever is shorter, prior to randomization
The known presence of central nervous system metastases
Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer
Concurrent illness that may jeopardize the patient's ability to undergo study procedures.
Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
Concurrent serious (as determined by the investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure
Major surgery ≤30 days prior to randomization
Planning to conceive pregnancy during the treatment and up to 6 months after the last treatment