ProstACT Global: A study for people with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on prior treatment that is investigating the effectiveness of adding targeted radionuclide therapy to standard of care treatmentA Multinational, Multicenter, Prospective, Randomized, Controlled, Open-Label, Phase 3 Study of Lutetium (177Lu) Rosopatamab Tetraxetan in Combination With Standard of Care Versus Standard of Care Alone in Patients With PSMA Positive Metastatic Castration-Resistant Prostate Cancer Previously After Androgen Receptor Pathway Inhibitor Treatment

Inclusion

• Be a male, at least 18 years old, with documented adenocarcinoma 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 orchiectomy 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, 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 dose 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 nodes as per RECIST1.1 or in bone as per PCWG3. Any ambiguous results are to be confirmed by other imaging 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 metastasis 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 tissue component of at least 1 cm with a TLF <1.

iii) At least one metastatic lymph node lesion with short axis ≥2.5 cm with a TLF<1.

• Must have recovered to ≤ Grade 1 from all clinically significant toxicities related to prior therapies (i.e., surgery, local radiotherapy, ARPI, chemotherapy, etc.) with the exception of alopecia. Specific conditions may be discussed with the medical monitor as needed.
• Have adequate organ function at Screening:

Bone marrow:

• Platelets ≥150×109/L.
• Absolute neutrophil count ≥1.5 x 109/L.
• Hemoglobin >10g/dL (with no red blood 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 trials Version 1.1, [CTFG (Clinical Trial Facilitation Group), 2020) ].