Phase Ib/II Platform Study of Multiple Anti-Cancer Agents in Participants With Metastatic Prostate Cancer

Inclusion criteria

• Participants with a diagnosis of histologically confirmed adenocarcinoma of the prostate (no small cell, neuroendocrine, sarcomatoid, spindle or signet cell).
• Minimum life expectancy of 3 months or more.
• Eastern Cooperative Oncology Group (ECOG) performance status of O or 1 at screening, with no deterioration.
• PCWG3 (Prostate Cancer Working Group 3) modified RECIST Version 1.1 evaluable disease.
• Must have received at least one novel androgen receptor pathway inhibitor (ARPI), such as enzalutamide or darolutamide or apalutamide or abiraterone acetate.
• Must have one or more unresectable metastatic lesions.
• Must have had prior orchiectomy and/or ongoing androgen deprivation therapy, and a castrate level of serum testosterone (\<50ng/dL or \<l.7nmol/L).
• Progressive metastatic castration-resistant prostate cancer (mCRPC) following the most recent treatment at time of study entry.
• Adequate organ and marrow function.
• Non sterilised participants who are sexually active with a partner of childbearing potential must use a condom (plus spermicide, if available), must refrain from fathering a child, freezing or donating sperm, and it is recommended for the partner to also use a highly effective contraceptive method. Inclusion Criteria for Sub study 1:
• Must have received a single line of ARPI, such as enzalutamide, darolutamide, apalutamide or abiraterone acetate.
• PSMA positive mCRPC by computed tomography positron emission tomography, obtained with PSMA ligand defined as at least 1 PSMA positive metastatic lesion with tracer uptake greater than liver, and no PSMA negative lesions. All measurable or intraprostatic lesions must be PSMA positive.
• Capable of self-administering oral formulations.

Exclusion criteria

• Any evidence of non adenocarcinomatous forms of prostate cancer (including small cell, spindle cell, signet cell, neuroendocrine, sarcomatous).
• Known, unresolved urinary tract obstruction.
• Participants with a history of central nervous system metastases.
• Symptomatic malignant spinal cord compression or findings indicative of impending cord compression.
• Participants with a history of leptomeningeal carcinomatosis.
• Previous or concurrent cancer distinct from the cancer under investigation in primary site or histology .
• Concurrent serious medical conditions.
• Previous history of interstitial lung disease or non-infectious pneumonitis.
• Participants with a history or clinical/laboratory features suggestive of myelodysplastic syndrome or acute myeloid leukaemia.
• Persistent toxicities caused by previous therapy.
• Participants unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with absorption.
• Active infection, including tuberculosis, hepatitis C virus, and hepatitis B virus infection.
• Known hypersensitivity to study intervention or any of their excipients. Exclusion Criteria for Sub study 1:
• History of uncontrolled seizures or requirement for \>2 antiepileptic drugs.
• History of severe brain injury or stroke.
• Skeletal metastases demonstrating a superscan appearance on bone scan.
• Participants have received prior therapy with AZD9574 or more than 1 prior line of any other Poly-ADP-ribose polymerase inhibitor (PARPi)-based regimen (either as a treatment or as maintenance).