Comparison of 177Lu-PSMA-617 and 225Ac-PSMA-617

Inclusion Criteria:

1. Age ≥18 years.
2. Histologically confirmed prostate adenocarcinoma.
3. High-risk disease as defined as meeting 1 or more of the 3 following criteria:

   1. Gleason score of 4+4 disease or higher, Or Gleason 4+3 with large cribriform component (defined as \>0.25 mm in short diameter)
   2. Pelvic nodal metastases on PSMA PET.
   3. Extracapsular extension or seminal vesicle invasion on MRI or PSMA PET.
4. No evidence of distant metastatic disease as determined by PSMA PET. Nodal disease at or below the iliac bifurcation (clinical stage N1) is allowed.
5. Maximum Standardized Uptake Value (SUVmax) in the primary tumor greater than 10 on PSMA PET using Gallium-68 (68Ga)-PSMA-11 or piflufolastat F 18 (18F-DCFPyL).

   \*Note: this applies to treatment cohorts only; there are no SUV requirements for tissue-only cohorts (Control Group).
6. Target tumor in the prostate measuring greater than 1.0 cm on MRI.
7. Willing to undergo prostatectomy with or without lymph node dissection, and candidate for prostatectomy as determined by urologic oncology.
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%),
9. Demonstrates adequate organ function as defined below:

   1. Platelets ≥100,000/mcL, independent of transfusions or growth factors within 3 months of treatment start.
   2. Hemoglobin ≥10 g/dL, independent of transfusions or growth factors within 3 months of treatment start.
   3. Absolute Neutrophil Count (ANC) ≥1,500/microliter (mcL).
   4. Creatinine clearance Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 , calculated using the Cockcroft-Gault equation.
   5. Albumin ≥2.5 g/dL.
   6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN.
   7. Total bilirubin (TBIL) ≤2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted.

      * Note: this applies to treatment cohorts only; there are no requirements for tissue-only cohorts (Control Group)
10. Ability to understand and the willingness to sign a written informed consent document.
11. Participants must provide consent to comply to recommended radioprotection precautions during study.
12. Participants must use adequate contraception and not donate sperm while on study drug and for at least 14 weeks after the last study treatment.

Exclusion Criteria:

1. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease- free, treatment- free for more than 3 years prior to randomization, or participants with adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible.
2. Individuals with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
3. Concurrent and serious (as determined by the principal investigator) medical conditions, including, but not limited to New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
4. Has received prior prostate cancer therapy.

   a. Prior 5-alpha reductase inhibitors (e.g. finasteride, dutasteride) allowed if discontinued at least 3 weeks prior to treatment start.
5. Has participated in a study of an investigational therapeutic product and received study treatment or used an investigational device within four weeks of the first dose of treatment.
6. Prior external beam radiation therapy (EBRT) to the prostate or prostate bed.
7. Dry mouth that impacts the eating of food (i.e., requiring fluids prior to eating)

Additional exclusion criteria applicable only to participants undergoing intraarterial administration of PSMA RLT:

1. Severe allergy to iodinated contrast.
2. Severe atherosclerosis from prior CT imaging study, or greater than 10 pack-year smoking history if no prior imaging available.