Study of AZD0516 as Monotherapy and in Combination in Participants With Metastatic Prostate Cancer

Main Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of metastatic adenocarcinoma ofthe prostate. Focal high grade neuroendocrine features are permitted.

• Measurable PSA ≥ 1 μg/L (≥ 1 ng/mL).

• Surgically or medically castrated with serum testosterone levels ≤ 50 ng/dL (≤ 1.75nmol/L) within ≤ 28 days before treatment allocation. Ongoing androgen deprivationtherapy (ADT) with a gonadotropin releasing hormone (GnRH) modulator forparticipants who have not undergone bilateral orchiectomy must be initiated at least 2 weeks prior to consent and must continue throughout the study.

• Eastern cooperative oncology group (ECOG) performance status of 0 or 1.

• Adequate organ and marrow function in the absence of blood transfusion or growthfactor support (within 21 days prior to the scheduled first dose of studyintervention).

• Provision of baseline archival or newly obtained formalin-fixed paraffin-embedded (FFPE) tumour sample is mandatory.

• Documented current evidence of metastatic prostate cancer

• Life expectancy of at least 12 weeks in the opinion of the investigator

• Documented mCRPC progression at screening as assessed by the investigator with atleast one of the following criteria:

1. PSA progression defined by a minimum of 3 rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the screening visitshould be ≥ 1 μg/L (1 ng/mL).

2. Radiographic disease progression in soft tissue based on response evaluationcriteria in solid tumors (RECIST) v1.1 criteria with or without PSA progressionas per prostate cancer working group 3 (PCWG3).

3. Radiographic disease progression in bone defined as the appearance of 2 or morenew bone lesions on a bone scan as per PCWG3 with or without PSA progression.

Main Exclusion Criteria:

• Cancer related spinal cord compression, or brain metastases unless asymptomatic,treated and stable and not requiring continuous corticosteroids at a dose of > 10 mgprednisone/day or equivalent for at least 4 weeks prior to study enrolment.

• History of leptomeningeal carcinomatosis.

• Unresolved toxicities of Grade ≥ 2 (National Cancer Institute Common TerminologyCriteria for Adverse Events v5.0) from prior therapy (excluding vitiligo, alopecia,and endocrine disorders that are controlled with replacement hormone therapy).

• Uncontrolled intercurrent illness within the last 12 months.

• Cardiovascular disorder (History of arrhythmia, uncontrolled hypertension,symptomatic hypotension, history of brain perfusion problems, symptomatic heartfailure, prior or current cardiomyopathy, severe valvular heart disease)

• History of malignancy

• History of non-infectious interstitial lung disease (ILD)/pneumonitis

• Active infection exclusions, including tuberculosis and infections with Hepatitis BVirus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV).

• Any known predisposition to bleeding

• Clinically severe pulmonary compromise

• Participants with Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) orwith features suggestive of MDS/AML.

• Previous treatment with a STEAP2 targeting modality, chemotherapeutic agent thatinhibits topoisomerase activity or metabolic enzymes.