Table 3.

Inclusion and exclusion criteria.

Inclusion criteria

1. Patient has provided written informed consent. 2. Male patients must be 18 years of age or older at the time of written informed consent. 3. Histologically or cytologically confirmed adenocarcinoma of the prostate OR unequivocal diagnosis of metastatic prostate cancer (i.e., involving bone or pelvic lymph nodes or para-aortic lymph nodes) with an elevated serum prostate specific antigen (PSA). 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 5. Patients must have progressed on a ≥1 second-generation androgen receptor (AR)-targeted agent (e.g., enzalutamide, abiraterone, darolutamide, or apalutamide). 6. Patients must have progressive disease for study entry defined as any one of the following:      • PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement.      • Soft tissue progression as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria.      • Bone progression: ≥ 2 new lesions on bone scan.      • Symptomatic progression e.g., bone pain. 7. At least 3 weeks since the completion of systemic therapy, surgery, or radiotherapy prior to registration. 8. Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist). 9. Serum testosterone levels ≤ 1.75nmol/L within 28 days prior to registration. 10. Significant PSMA avidity on PSMA PET/CT, defined as a minimum uptake of maximum standardized uptake value (SUVmax) of 20 at a site of disease, and SUVmax ≥10 at sites of measurable disease ≥10 mm (unless subject to factors explaining a lower uptake, e.g., respiratory motion, reconstruction artifact). 11. The presence of ≥ 2 bone metastases on bone scintigraphy, which have not been previously treated with radiotherapy. 12. No contraindication to treatment with a bone antiresorptive agent such as denosumab or zoledronic acid. 13. Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:      • Hemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusion in last four weeks)      • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L      • Platelets ≥ 150 x 109/L      • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome, where this applies for the unconjugated bilirubin component      • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases      • Albumin ≥ 25 g/L      • Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 mL/min using the Cockcroft Gault equation. 14. Sexually active patients are willing to use medically acceptable forms of barrier contraception. 15. Willing to undergo biopsies if disease is considered accessible and biopsy is feasible. 16. Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.

Exclusion criteria

1. Superscan on whole body bone scan (WBBS) or diffuse marrow disease on PSMA PET. 2. Prior treatment with 223Ra or [177Lu]Lu-PSMA. 3. Has received more than one previous line of chemotherapy for the treatment of metastatic prostate cancer. 4. Site(s) of discordant FDG positive disease defined by minimal PSMA expression and no uptake on whole body bone scan ([WBBS] for bone metastases). 5. Other malignancies (in addition to the prostate cancer being treated in this study) within the previous 2-years prior to registration other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months. 6. Symptomatic brain metastases or leptomeningeal metastases. 7. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ 4 weeks. 8. Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.