There is evidence that Actinium-225 Prostate-Specific Membrane Antigen (225Ac-PSMA) has a potentially higher level of efficacy than 177 Lutetium Prostate-Specific Membrane Antigen (177Lu-PSMA) as a radioligand therapy. This single center, pilot study will compare differences in the mechanisms of actinium-225 and lutetium-177 radioligand therapies (RLT) in participants with high or very high risk localized or locoregional prostate cancer planning on undergoing a prostatectomy.

PRIMARY OBJECTIVES:

1. Compare the tumor absorbed dose between 177Lu-PSMA-617 and 225Ac-PSMA-617.
2. Compare the immunologic priming of 177Lu-PSMA-617 and 225Ac-PSMA-617 with controls in prostatectomy specimens.

SECONDARY OBJECTIVES:

1. Determine the safety and tolerability of neoadjuvant 177Lu-PSMA-617 and 225Ac-PSMA-617 in participants with high or very high-risk prostate cancer planning to undergo radical prostatectomy.
2. Estimate PSA response for 177Lu-PSMA-617 and 225Ac-PSMA-617 treatment.
3. Estimate the rate of pathologic response in participants treated with 177Lu-PSMA-617 and 225Ac-PSMA-617.

EXPLORATORY OBJECTIVES:

1. Determine the relationship between percent cell necrosis and tumor absorbed dose for both 177Lu-PSMA-617 and 225Ac-PSMA-617.
2. Compare the heterogeneity of cell necrosis for 177Lu-PSMA-617 and 225Ac-PSMA-617.
3. Compare messenger ribonucleic acid (mRNA) expression profiles of tumor treated with 177Lu-PSMA-617, 225Ac-PSMA-617, and controls.
4. Compare mRNA expression profiles of tumors in participants who achieve a PSA50 response and those that do not.
5. Compare mRNA expression profiles of tumors from archival tissue and at time of prostatectomy.
6. Compare the percent cell necrosis between participants receiving a single cycle of PSMA RLT versus participants receiving two cycles of PSMA RLT.
7. Compare the change in uptake on PSMA Positron Emission Tomography (PET) to PSA response and percent cell necrosis.
8. Descriptively evaluate cell necrosis at the tumor margins.
9. Evaluate changes in peripheral immune activation markers following radioligand therapy.
10. Compare the kidney absorbed dose (in Gray) between patients receiving 177Lu-PSMA-617 and those receiving 225Ac-PSMA-617, using post-treatment SPECT imaging acquired 7 days after administration of the first dose.
11. Evaluate feasibility of PET for imaging actinium-225.

OUTLINE:

Participants will be assigned to 1 of 2 cohorts to receive 177Lu-PSMA-617 or 225Ac-PSMA-617. Additional participants undergoing prostatectomy without RLT will be enrolled as a control group. Participants enrolled in the RLT cohorts will receive 1 to 2 cycles of PSMA radioligand therapy up to 6 weeks apart before a scheduled, non-investigational, prostatectomy four weeks after PSMA radioligand therapy. Participants receiving RLT will be followed up for a safety assessment 6 weeks after surgery and for up to 60 months after prostatectomy for long term follow-up. Participants in the prostatectomy only cohort will have safety and long-term follow-up performed as part of clinical care up to 24 months after surgery.

Inclusion Criteria:

1. Histologically confirmed prostate adenocarcinoma.

2. Willing to undergo prostatectomy with or without lymph node dissection, and candidate for prostatectomy as determined by urologic oncology.

3. High-risk disease as defined as meeting 1 or more of the 3 following criteria:

   1. Gleason score of 4+5 disease or higher.
   2. Pelvic nodal metastases on PSMA PET.
   3. Extracapsular extension or seminal vesicle invasion on MRI.

4. No evidence of distant metastatic disease as determined by PSMA PET. Nodal disease 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).

6. Target tumor in the prostate measuring greater than 1.5 cm on MRI.

7. Age ≥18 years.

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.

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. 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.

2. 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.

3. Dry mouth that impacts the eating of food (i. e. requiring mouthwash prior to eating).

4. Concurrent 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.

5. 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.

6. 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.

7. Prior external beam radiation therapy (EBRT) to the prostate or prostate bed.

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.

De-identified data may be shared with study collaborators during the course of the study.