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

Inclusion Criteria:

• Be a male, at least 18 years old, with documented adenocarcinoma of the prostatedefined by histological / pathological confirmation.

• Be of ECOG Performance Status 0, 1, or 2 and have an estimated life expectancy of ≥6months from Day 1.

• Have metastatic disease (defined as ≥1 metastatic lesion present on baseline CT, MRIor bone scintigraphy).

• Have castration-resistant PC (defined as disease progressing despite castration byorchiectomy or ongoing use of luteinizing hormone-releasing hormone [LHRH]analogues) and must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L) at Screening

• Must have received a minimum of 12 weeks of prior therapy on their first ARPI (abiraterone or enzalutamide), received in either mCSPC (de novo or recurrent) orfirst-line mCRPC treatment setting. Participants may have received docetaxel in themCSPC setting following the CHARTERED or STAMPEDE treatment regimens (6 cycles ofdocetaxel every 3 weeks) provided the last dose of therapy was ≥6 months prior toscreening and ≥4 cycles were administered.

• Have a disease that is progressing at study entry, despite a castrate testosteronelevel (<50 ng/dL or <1.7 nmol/L), by the demonstration of at least one of thefollowing:

• 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 nodes as per RECIST1.1or in bone as per PCWG3. Any ambiguous results are to be confirmed by other imagingmodalities (e.g., CT or MRI scan).

• Have disease that is PSMA-positive, as demonstrated by a 68Ga-PSMA-11 PET/CT orPET/MRI scan and confirmed as eligible by the Sponsor's appointed BICR.

• Must have recovered to ≤ Grade 1 from all clinically significant toxicities relatedto prior therapies (i.e., surgery, local radiotherapy, ARPI, chemotherapy, etc.)with the exception of alopecia. Specific conditions may be discussed with themedical monitor as needed.

• Have adequate organ function at Screening:

Bone marrow:

• Platelets ≥150×109/L.

• Absolute neutrophil count ≥2×109/L.

• Hemoglobin >10g/dL (with no red blood cell transfusion in the previous 4 weeks).

• Lymphocyte count >1.0x109/L

Liver function:

• Total bilirubin ≤ 1.5× the upper limit of normal (ULN). For participants with knownGilbert'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 allprotocol requirements.

• Participants must comply with the radiation protection rules (including hospitaladmissions and isolation) that are used by the treating institution in order toprotect their contacts and the general public, especially if a female partner of theparticipant is or could be pregnant.

• Must agree to practice adequate precautions to prevent pregnancy in a partner and toavoid potential problems associated with radiation exposure to the unborn child (Recommendations related to contraception and pregnancy testing in clinical trialsVersion 1.1, [CTFG (Clinical Trial Facilitation Group), 2020) ].

Exclusion Criteria:

• Is unable to understand or is unwilling to sign a written informed consent documentor to follow investigational procedures in the opinion of the Investigator.

• Has PC associated with pathological findings consistent with small cell or anyhistology other than adenocarcinoma of the prostate. If there are minor (<20%)elements of neuroendocrine histology, this is acceptable.

• Diagnosed with other malignancies that are expected to alter life expectancy or mayinterfere with disease assessment. However, participants with a prior history ofmalignancy that has been adequately treated and who have been disease-free for morethan 3 years are eligible, as are participants with adequately treated non-melanomaskin cancer, and superficial bladder cancer.

• Is at increased risk of hemorrhage or bleeding, or with a recent history (within thelast 6 months) of a thromboembolic event (e.g., deep vein thrombosis [DVT] /pulmonary embolism [PE]) and have been administered long-term anti-coagulant oranti-platelet agents, with the exception of low dose aspirin (75 to 100 mg daily).

• Has received prior treatment with monoclonal antibody (mAb) J591 or HuJ591 or anyother PSMA targeted therapy.

• Have received chemotherapy in the mCRPC or non-metastatic prostate cancer (nmCRPC)settings (note: prior docetaxel use in the mCSPC setting with CHAATERED or STAMPEDEregimens is permitted if the last dose of therapy was ≥6 months prior to screeningand ≥4 cycles of docetaxel were administered).

• Has known allergies, hypersensitivity, or intolerance to the investigational drug orits excipients.

• Has received prior systemic anti-cancer therapy (e.g., chemotherapy, immunotherapy,or biological therapy) and/or radiation therapy within 4 weeks of enrolment (excluding ARPI and/or LHRH analogues).

OR if any significant AEs have not resolved to National Cancer Institute (NCI) AE Criteria ≤ 2.

OR are receiving other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.

• Has received prior treatment with radioisotopes, including but not limited to: 89Strontium, 153Samarium, 186Rhenium, 188Rhenium, 223Radium, or hemi-bodyirradiation within 6 months prior to enrolment.

• Has received other investigational therapy within 4 weeks of enrolment.

• Has known brain metastases with long-axis ≥1cm, or liver metastases with long-axis ≥1cm, or lytic bone metastases with long-axis ≥1cm.

• Has a history of seizure and/or stroke within the past 6 months. Has clinical orradiologic findings indicative of impending spinal cord compression or experiencesymptomatic spinal cord compression.

• Has evidence of a serious active or sub-clinical infection or angina pectoris (NewYork Heart Association [NYHA] Class III or IV), significantly prolonged QT intervalor other serious illness(es) involving the cardiac, respiratory, central nervoussystem, renal, hepatic or hematological organ systems, that might impair the abilityto complete this study or could interfere with determination of causality of anyadverse effects experienced in this study, or which require treatment that couldinteract with study treatment, particularly with enzalutamide.

• Has received treatment with any PARP inhibitors (i.e., Olaparib) or with anyplatinum based anti-neoplastic drugs.