The main purpose of the study is to assess the safety and tolerability of AZD2284, AZD2287, and AZD2275.

This is a first-in-human, Phase I, non-randomized, open-label clinical trial designed to evaluate AZD2284, AZD2287, and AZD2275.

This trial will consist of 2 Parts:

Part A (Imaging):

- Part A (Cold Antibody Exploration): aims to determine the optimal dosing regimen, with or without unconjugated antibody (AZD2275) pre-administration to improve the biodistribution of AZD2287.

Part B (Therapeutic):

• Part B (Actinium-225 Dose Escalation): aims to assess the safety, tolerability, and efficacy of escalating doses of AZD2284 informed by the optimal dosing regimen identified in Part A.
• Part B Expansion Cohorts 1 and 2: aims to explore efficacy of AZD2284.

Main Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

• Histologically confirmed diagnosis of adenocarcinoma of the prostate without strong clinical suspicion of majority neuroendocrine differentiation.

• Must have had prior bilateral orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).

• At least one metastatic lesion present on baseline Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or bone scan obtained ≤ 28 days prior to the first dose of Investigational Medicinal Product (IMP). Participants may have non-measurable lesions including bone only metastases.

• Adequate organ function

• Part A only: Metastatic prostate cancer considered to be stable or progressing metastatic castration resistant prostate cancer (mCRPC).

• Part B only: Progressing mCRPC defined as meeting at least one of following documented criteria -

  1. Serum/plasma PSA progression
  2. Soft-tissue progression
  3. Progression of bone disease

• Part B Dose Escalation: Previously treated with at least 2 prior lines of systemic anti-cancer therapy for mCRPC. Prior lines must include:

  1. At least 1 androgen receptor pathway inhibitor (ARPI)
  2. A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
  3. A checkpoint inhibitor for participants with known microsatellite instability-high (MSI-H), deficient mismatch pair (dMMR), or tumor mutational burden (TMB) ≥ 10 mut/Mb

• Part B Dose Expansion: Previously treated with at least 1 prior line of systemic anti-cancer therapy for mCRPC. Prior lines must include:

  1. At least 1 ARPI
  2. A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
  3. A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
  4. No previous cytotoxic chemotherapy for CRPC. Taxanes for metastatic hormone sensitive prostate cancer (mHSPC) is acceptable if the last cycle Day 1 was > 12 months before first study treatment.
  5. Previous treatment with prostate specific membrane antigen radioligand therapy (PSMA-RLT) or Radium-223 is allowed but not required. Participants who have had prior radiation therapy, including therapeutic radiopharmaceuticals, external bean radiation therapy (EBRT), and/or brachytherapy are eligible, subject to satisfying all other inclusion/exclusion criteria. Therapeutic radiopharmaceuticals will be considered a prior line of systemic therapy.

Main Exclusion Criteria:

• Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
• Radiation therapy (RT) or external beam radiation therapy (EBRT) within 28 days prior to the first dose and all RT-related events have not recovered to Grade ≤ 1.
• Administration of any systemic cytotoxic or investigational therapy ≤ 28 days of the first dose of IMP or 5 half-lives, whichever is shorter.
• All prior treatment-related adverse events must have resolved to Grade ≤ 1.
• Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements.
• Known or suspected allergies or contraindications to any of the investigational drugs or any component of the investigational drug formulation.
• Clinically relevant proteinuria
• Diffuse and intense osseous radiotracer uptake on bone scintigraphy or PSMA imaging characteristic of a superscan.
• Chronic corticosteroid use greater than 10 mg prednisone equivalent daily.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure."Yes",indicatesthat AZ are accepting requests for IPD, but this does not mean all requests will be approved.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment athttps://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.