A Phase I Study of [225Ac]-AZD2284 in Patients With Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria: * eria: * • 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 - * a)Serum/plasma PSA progression * b)Soft-tissue progression * c)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: * a)At least 1 androgen receptor pathway inhibitor (ARPI) * b)A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation * c)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: * (a)At least 1 ARPI * (b)A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision. * (c)A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb. * (d)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. * (e)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.