Combination of Radium-223 and Lutetium-177 PSMA-I&T in Men with Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria:

• Patient must be ≥ 18 years of age and must have provided written informed consent.

• Histologically or cytologically confirmed adenocarcinoma of the prostate, ORunequivocal diagnosis of metastatic prostate cancer. (i.e. involving bone or pelviclymph nodes or para-aortic lymph nodes) with an elevated serum PSA.

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

• Patients must have progressed on ≥ 1 second-generation AR-targeted agent (e.g.,enzalutamide, abiraterone, apalutamide, or darolutamide).

• Patients must have progressive disease for study entry. PCWG3 defines this as anyone of the following:

• PSA progression: minimum of two rising PSA values from a baseline measurementwith an interval of ≥ 1 week between each measurement.

• Soft tissue progression as per RECIST 1.1 criteria

• Bone progression: ≥ 2 new lesions on bone scan

• Symptomatic progression eg. Bone pain

• At least three weeks since receiving anti-cancer treatment (other than ADT), thecompletion of surgery or radiotherapy prior to registration.

• Prior surgical orchiectomy or chemical castration maintained on luteinizinghormone-releasing hormone (LHRH) analogue (agonist or antagonist).

• Serum testosterone levels ≤ 1.75nmol/L (≤ 50ng/dL) within 28 days beforeregistration.

• Significant PSMA avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 20 ata site of disease, and SUVmax >10 at sites of measurable disease >10mm (unlesssubject to factors explaining a lower uptake, e.g. respiratory motion,reconstruction artefact).

• ≥ 2 bone metastases must be present on bone scintigraphy which have not beenpreviously treated with radiotherapy.

• No contraindication to treatment with a bone antiresorptive agent such as denosumabor zoledronic acid.

• Patients must have adequate bone marrow, hepatic and renal function documentedwithin 28 days prior to registration, defined as:

• Haemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusionin last four weeks)

• Absolute neutrophil count ≥ 1.5x10^9/L

• Platelets ≥ 150 x10^9/L

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients withknown Gilbert's syndrome, where this applies for the unconjugated bilirubincomponent.

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN ifthere is no evidence of liver metastasis or ≤ 5 x ULN in the presence of livermetastases

• Albumin ≥ 25 g/L

• Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 mL/min using the Cockcroft Gault equation

• Sexually active patients are willing to use medically acceptable forms of barriercontraception.

• Willing to undergo biopsies, if disease is considered accessible and biopsy isfeasible.

• Willing and able to comply with all study requirements, including all treatments andthe timing and nature of all required assessments.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

• Superscan on Bone scan (WBBS) or diffuse marrow involvement on PSMA PET/CT

• Prior treatment with 223Ra or 177Lu-PSMA.

• Has received more than one previous line of chemotherapy for the treatment ofmetastatic prostate cancer.

• Sites of discordant FDG-positive disease defined by minimal PSMA-expression and nouptake on WBBS (for bone metastases).

• Other malignancies within the previous 2 years other than basal cell or squamouscell carcinomas of skin or other cancers that are unlikely to recur within 24months.

• Symptomatic brain metastases or leptomeningeal metastases.

• Patients with symptomatic or impending cord compression unless appropriately treatedbeforehand and clinically stable for ≥ four weeks.

• Concurrent illness, including severe infection that may jeopardise the ability ofthe patient to undergo the procedures outlined in this protocol with reasonablesafety.