A Study of JNJ-69086420, an Actinium-225-Labeled Antibody Targeting Human Kallikrein-2 (hK2) for Advanced Prostate Cancer

Inclusion Criteria:

• For Part 1, Part 2, Part 3: Metastatic castration resistant prostate cancer (mCRPC)with histologic confirmation of adenocarcinoma (adenocarcinoma with small-cell orneuroendocrine features is allowed) with prior exposure to at least one androgenreceptor (AR) targeted therapy (for example [e.g.], abiraterone acetate,enzalutamide, apalutamide, darolutamide). In addition: Part 1: prior taxane or otherchemotherapy is acceptable but not required. Part 2a: prior taxane or otherchemotherapy required, Part 2b: no prior taxane or other chemotherapy, Part 2c:mCRPC that has progressed after prior treatment with lutetium Lu-177 vipivotidetetraxetan, with or without prior chemotherapy, Part 3: prior taxane or otherchemotherapy is acceptable but not required & For Part 4a: metastatic HSPC, For Part 4b: disease that can be treated with less than or equal to (<=) 5 radiation fieldsand no visceral metastases

• Parts 1, 2 & 3: Prior orchiectomy or medical castration, or, for participants whohave not undergone orchiectomy, must be receiving ongoing androgen deprivationtherapy with a gonadotropin releasing hormone (GnRH) analog (agonist or antagonist)prior to the first dose of study drug and must continue this therapy throughout thetreatment phase. This criterion does not apply to Part 4

• Palliative radiotherapy (e.g. soft tissue lesions) must be completed greater than (>) 2 weeks prior to start of study drug except for palliative radiotherapy for pain (e.g., bone pain), which may be used any time prior to first dose

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate organ functions as reflected in laboratory parameters

Exclusion Criteria:

• Prior treatment with radium Xofigo (Ra 223 dichloride), strontium, samarium, orother radioconjugate therapy, other systemic anti-neoplastic therapy <=30 days priorto the first dose of study drug except for luteinizing hormone-releasing hormoneagonists/antagonists or GnRH agonists/antagonists. Novel androgen axis drugs <=14days prior to the first dose of study drug. In addition: Part 2b: Must not havereceived prior treatment with chemotherapy (eg, docetaxel) or poly ADP ribosepolymerase (PARP) inhibitors, Part 2c: Prior treatment with lutetium Lu-177vipivotide tetraxetan is required, but must have been completed >42 days prior tofirst dose of study drug, Part 3: Must not have received prior treatment withJNJ-78278343, Part 4: Must not have received ADT or AR-targeted therapy less than orequal to (<=) 56 days prior to first dose of study drug

• Known history of myelodysplastic syndrome, leukemia, or hematological malignancywith features suggestive of myelodysplastic syndrome/acute myeloid leukemia at anytimepoint

• Toxicity from prior anticancer therapy has not resolved to baseline levels or toGrade <= 1 (except alopecia, radiation tissue fibrosis, or peripheral neuropathy)

• Known allergies, hypersensitivity, or intolerance to JNJ-69086420 or its excipientsand protein therapeutics. For Part 3, known allergies, hypersensitivity, orintolerance to JNJ-78278343 or its excipients or protein therapeutics

• Active or chronic hepatitis B or hepatitis C infection