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

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.