The goal of this clinical trial is to is to investigate if it is possible to lower the chance of cancer reoccurrence and also preserve quality of life by using the drug Pluvicto instead of androgen-deprivation therapy to the usual radiation therapy for advanced local prostate cancer.

Participants will receive one dose of Pluvicto, followed by radiation about 6 weeks later. Radiation therapy will be completed in 5 treatments over the period of 2 weeks. A second dose of Pluvicto will be given 6 weeks after radiation is complete. Some participants may also receive a third dose of Pluvicto, and this would be given 6 weeks after the second dose of Pluvicto.

Prostate cancer is the most common cancer in men worldwide and second leading cause of cancer death in men. The most common treatment for prostate cancer is radiation therapy (RT) plus long-term androgen deprivation therapy (ADT) for 18-36 months with a consideration for the addition of abiraterone acetate.

With the introduction of abiraterone and other second generation androgen signaling inhibitors (ARSIs) there is great interest in shortening the duration of systemic therapy. This interest stems from the high toxicity rates of ADT and substantial impact on patient-reported quality of life (QoL). The use of ADT is associated with some adverse events. Therefore, the combination of adverse event risks and decrease in quality of life associated with castration have resulted in decreased compliance to long term ADT and even ARSIs, where approximately 50% of patients with locally advanced disease either decline any ADT or stop treatment early. The goal of this clinical trial is to is to investigate if it is possible to lower the chance of cancer reoccurrence and also preserve quality of life by using the drug Pluvicto instead of androgen-deprivation therapy to the usual radiation therapy for advanced local prostate cancer.

This clinical trial will evaluate the safety of using Lu-PSMA-617 with SBRT to the prostate and pelvic lymph nodes, and to determine whether Lu-PSMA-617 can replace androgen deprivation therapy (ADT) to improve oncologic outcomes by use of cytotoxic agents, avoid ADT related side effects, and improve compliance for participants to receive systemic therapy.

Inclusion Criteria:

• Participant must be ≥ 18 years of age.

• ECOG performance status ≤ 1

• Histologic confirmation of prostate adenocarcinoma of the prostate

• PSMA avid disease on PSMA PET/CT, where the tumor in the prostate has SUVmax ≥ 10.

  • PSMA PET/CT must be obtained within 4 months.

• Need ≥ 1 criteria:

  • Node positive disease on PSMA PET/CT or conventional imaging, as defined by having any of the following:

    • Pelvic nodal disease (cN1) as defined by LN stations that commence at the bifurcation of the common iliac vessels
    • Regional nodal disease (M1a) as defined by LN stations that commence at the bifurcation of the aorta and bifurcation of the proximal inferior vena cava to the common iliac veins.

  • In the absence of nodal metastasis, must have ≥ 2 of the following

    • i. cT3a or cT3b by conventional imaging (MRI) or PSMA PET/CT
    • ii. Grade group ≥ 4
    • iii. PSA ≥ 40 ng/mL

• Adequate organ and marrow function to receive treatment:

  • Hemoglobin > 10 g/dL

  • White blood cell (WBC) > 3000 / mL

  • Absolute neutrophil count ≥ 1,500 / mcL

  • Platelets ≥ 100,000 / mcL

  • Creatinine ≤ 1.5x ULN

  • Estimated glomerular filtration rate (eGFR)* > 50 mL/min

  • Total bilirubin** < 2× ULN

  • Albumin > 3 g/dL

  • Aspartate aminotransferase (AST) < 3× ULN

    • *based upon Chronic Kidney Disease- Epidemiology Collaboration (CKD-EPI) equation. Participants with estimated GFR between 50 - 60 mL/min will require a 99mTc-TPA GFR test and only participants with non-obstructive pathology will be included in the study.
    • ** Total bilirubin ≤ 2x ULN (except for participants with known Gilbert's Syndrome ≤ 3x ULN is permitted)

• International Prostate Symptoms Score (IPSS) ≤ 15.

• Medically fit for treatment and agreeable to follow-up.

• Ability to understand and the willingness to sign a written informed consent.

• Participants with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 14 weeks from receiving the last dose of Lu-PSMA-617. Participants must also not donate sperm for 14 weeks from receiving the last dose of Lu-PSMA-617.

Exclusion Criteria:

• Clinical or radiographic evidence of distant metastatic disease (M1a above aortic bifurcation, M1b, or M1c) by any imaging. Participants are allowed to M1a nodal disease that is below the aortic bifurcation. Negative PSMA PET/CT is an acceptable substitute to conventional staging.
• Prostate gland size >90 cc measured by CT, ultrasound, or MRI
• Prior head and neck radiation therapy.
• Prior treatment for prostate cancer (incudes chemotherapy, radiation therapy, or anti-androgen therapy).
• Prohibited within 30 days prior to administration to study treatment: spironolactone and other investigational drug therapies.
• Prohibited 3 months before participant registration and during administration of study treatment: oral ketoconazole, , estrogens, and radiopharmaceuticals.
• History of prior pelvic radiation therapy.
• Enrollment concurrently in another investigational drug study within 6 months of registration.
• History of another active malignancy within the previous 3 years except for adequately treated skin cancer or superficial bladder cancer.
• History of prior myelodysplastic syndrome or acute leukemia.
• History of or active Crohn's disease or ulcerative colitis.
• Contraindication to or inability to tolerate PSMA/PET.
• Any condition that in the opinion of the investigator would preclude participation in this study.
• Inability to adhere to radiation safety measures in hospital or at home
• Prior treatment with radionuclide therapies, 177Lu-PSMA-617 or other
• Reduced salivary gland function with baseline CTCAE Gr > 1 dry mouth will be excluded.

All IPD that underlies publication

Compiled and analyzed participant data will be published upon study completion. Publisher may request Protocol and Statistical Analysis Plan.

To be shared with investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.