The Study of 177Lu-TLX591 Plus SOC Versus SOC Alone in Patients With mCRPC (ProstACT Global

• Drug: 177Lu-TLX591
• Drug: Enzalutamide
• Drug: Abiraterone
• Drug: Docetaxel

Inclusion Criteria:

• Be a male, at least 18 years old, with documented adenocarcinomacancer arising from mucus-producing glands in organs of the prostate defined by histological / pathological confirmation.
• Be of ECOG Performance Status 0, 1, or 2 and have an estimated life expectancy of ≥6 months from Day 1.
• Have metastatic disease (defined as ≥1 metastatic lesion present on baseline CT, MRI or bone scintigraphy).
• Have castration-resistant PC (defined as disease progressing despite castration by orchiectomyremoval of one or both testicles, also known as orchidectomy or ongoing use of luteinizing hormone-releasing hormonea chemical substance produced by glands in the endocrine system that regulates various functions in the body [LHRH] analogues) and must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L) at Screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening
• Must have received a minimum of 12 weeks of prior therapy on their first ARPI (abiraterone, apalutamide, darolutamide or enzalutamide), received in either mCSPC (de novo or recurrent) nmCRPC or first-line mCRPC treatment setting with documented evidence of disease progression while receiving this ARPI. Participants may have received docetaxel in the mCSPC setting following the CHARTERED or STAMPEDE treatment regimens (6 cycles of docetaxel every 3 weeks) provided the last dosethe amount of medication taken of therapy was ≥6 months prior to screening and ≥4 cycles were administered.
• Have a disease that is progressing at study entry, despite a castrate testosterone level (<50 ng/dL or <1.7 nmol/L), by the demonstration of at least one of the following:
• Two consecutive rising PSA values assessed sequentially at least one week apart, with the final measurement required to be a minimum of 2.0 ng/mL for study entry. Only the last measurement must meet or exceed 2.0 ng/mL.
• Progressive disease or new lesion(s) in the viscera or lymph nodessmall bean-shaped structures that filters harmful substances from lymph fluid as per RECIST1.1 or in bone as per PCWG3. Any ambiguous results are to be confirmed by other imagingtests that create detailed images of areas inside the body modalities (e.g., CT or MRI scan).
• Have disease that is PSMA-positive, as demonstrated by a 68Ga-PSMA-11 PET/CT or PET/MRI scan and confirmed as eligible by the Sponsor’s appointed BICR.

Imaging-based eligibility review will be performed in two stages:

1. Presence of metastases for exclusion: Screening CT and MRI will be assessed to exclude participants with brain metastasiswhen the cancer has spread to other parts of the body, also known as mets with long-axis>1cm
2. PSMA PET eligibility: Screening 68Ga-PSMA-11 PET/CT or PET/MRI will be assessed along with CT, MRI, and bone scans utilizing tumor to liver ratio (TLR) for PSMA positivity-based exclusion. TLR is defined as the ratio of tumor lesion SUVmax to liver SUVmean derived from a 3 cm 3D spherical region of interest (ROI).

PSMA positivity is defined as : At least 1 lesion with PSMA TLR≥2.

PSMA exclusion critieria: The presence of any of the following will result in the patient being ineligible for this trial:

i) visceral metastatic lesions that are ≥1 cm that have a PSMA TLR< 1 ii) Lytic bone metastatic lesions with a soft tissuetissue/the material that joins, holds up or surrounds inside body parts such as fat, muscle, ligaments and lining around joints component of at least 1 cm with a TLF <1.

iii) At least one metastatic lymph nodea small lump or mass of tissue in your body lesion with short axis ≥2.5 cm with a TLF<1.

• Must have recovered to ≤ Gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 1 from all clinically significant toxicities related to prior therapies (i.e., surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence, local radiotherapy, ARPI, chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells, etc.) with the exception of alopeciathe partial or complete absence of hair from areas of the body where it normally grows; baldness. Specific conditions may be discussed with the medical monitorto check on, keep track of as needed.
• Have adequate organ function at Screening:

Bone marrowsoft, spongy tissue found in bones that makes blood cells:

• Plateletssmall disc-shaped blood cells that clump together to form clots to stop bleeding ≥150×109/L.
• Absolute neutrophil count ≥1.5 x 109/L.
• Hemoglobin >10g/dL (with no red bloodthe red bodily fluid that transports oxygen and other nutrients around the body cell transfusion in the previous 4 weeks).

Liver function:

• Total bilirubin ≤ 1.5× the upper limit of normal (ULN). For participants with known Gilbert’s Syndrome ≤3× ULN is permitted.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3× ULN.

Renal function:

• Creatinine clearance ≥45 mL/min determined using the Cockcroft-Gault formula.
• Have the capacity to understand the study and be able and willing to comply with all protocol requirements.
• Participants must comply with the radiation protection rules (including hospital admissions and isolation) that are used by the treating institution in order to protect their contacts and the general public, especially if a female partner of the participant is or could be pregnant.
• Must agree to practice adequate precautions to prevent pregnancy in a partner and to avoid potential problems associated with radiation exposure to the unborn child (Recommendations related to contraception and pregnancy testing in clinical trialsresearch studies performed to test new treatments, tests or procedures and evaluate their effectiveness on various diseases Version 1.1, [CTFG (Clinical Trial Facilitation Group), 2020) ].