Study Evaluating Dosimetry, Randomized Dose Optimization, Dose Escalation and Efficacy of Ac-225 Rosopatamab Tetraxetan in Participants With PSMA PET-Positive Castration-Resistant Prostate Cancer (CRPC)

Inclusion Criteria:

• Progressive CRPC defined as castrate levels of testosterone and progressing by atleast one of the following criteria:

1. Serum PSA progression consisting of two consecutive increases in PSA measuredat least 1 week apart. The minimal study baseline value is 2.0 ng/mL

2. Soft tissue progression defined as a ≥20% increase in the sum of the diameter (short axis for nodal lesions and long axis for non-nodal lesions) of alltarget lesions based on the smallest sum of the diameter since the previoustreatment was started or the appearance of one or more new lesions byCT/magnetic resonance imaging (MRI)

3. Progression of bone disease defined by PCWG3 as evaluable disease or new bonelesions by bone scan

4. Identification of new soft tissue or bone lesions on PSMA PET imaging

• Metastatic disease defined as either or both of the following:

1. Parts 1, 2 and 3: Documented M1 disease on conventional imaging (CT/MRI of thechest/abdomen/pelvis and/or Technetium 99m [99mTc] whole-body bone scan)

2. Parts 1 and 2 only: Identification of bone lesion(s), extra-pelvic soft tissuelesion(s), or visceral metastases on PSMA PET imaging with an FDA-approvedimaging agent

• PSMA PET-positive disease, defined as at least one PSMA-positive metastatic lesionand no PSMA-negative lesions

• Progression following treatment with ADT and at least one ARSI (e.g., enzalutamide,apalutamide, darolutamide, and/or abiraterone acetate)

• The standard of care use (in the setting of metastatic CRPC with significant burdenof active bone metastases) of antiresorptive bone-targeted agents (e.g., zoledronicacid, denosumab) is required for all participants without a contraindication, for atleast 4 weeks prior to study drug administration

• Participants with HIV are eligible if they are well-controlled (i.e, an undetectableHIV viral load (<50 copies/mL) within 6 months of enrollment and a stable ARTregimen for at least 6 months prior to enrollment) and at low risk for HIV-relatedillness

Part 3 Only:

• Prior treatment with Lu-177-PSMA-radioligand therapy

• Prior treatment with up to only one taxane-based chemotherapy regimen is allowed

Exclusion Criteria:

• Superscans by nuclear medicine/99mTc bone scan

• A known malignancy that is progressing or has required active treatment within thepast 3 years other than CRPC, which is expected to alter life expectancy or mayinterfere with CRPC disease assessment

• Prior platinum-based chemotherapy

• Prior PARP inhibitors (e.g., olaparib or rucaparib)

• Prior treatment with Radium-223, Actinium-225, Strontium-89, Samarium-153,Rheunium-186, or Rhenium-188

• Participants receiving anti-coagulants or anti-platelet drugs (e.g., aspirin ornonsteroidal anti-inflammatory drugs [NSAIDs]) who cannot discontinue use ifplatelet count decreases to <50,000

Part 2 Only:

• Prior chemotherapy for CRPC. Prior taxane chemotherapy for HSPC is allowed ifdiscontinued ≥1 year prior to randomization

• Prior radiopharmaceutical therapy (e.g., Ra-223, Lu-177-PSMA-617, orLu-177-PSMA-I&T)

• Prior PSMA-targeted therapy

Part 3 Only:

• Prior PSMA-targeted therapy (e.g., antibody-drug conjugates or CAR-T therapy),except for Lu-177-PSMA-radioligand therapy