Phase Ib/II Platform study of Multiple Anti-Cancer Agents in Participants with Metastatic Prostate Cancer - PROSPECTOR

Inclusion Criteria

• Inclusion Criteria:
• 1. Participants with a diagnosis of histologically confirmed adenocarcinoma of the prostate (no small cell, neuroendocrine, sarcomatoid, spindle or signet cell).
• 2. Minimum life expectancy of 3 months or more.
• 3. Eastern Cooperative Oncology Group (ECOG) performance status of O or 1 at screening, with no deterioration.
• 4. PCWG3 (Prostate Cancer Working Group 3) modified RECIST Version 1.1 evaluable disease.
• 5. Must have received at least one novel androgen receptor pathway inhibitor (ARPI), such as enzalutamide or darolutamide or apalutamide or abiraterone acetate.
• 6. Must have one or more unresectable metastatic lesions.
• 7. Must have had prior orchiectomy and/or ongoing androgen deprivation therapy, and a castrate level of serum testosterone (<50ng/dL or
• 8. Progressive metastatic castration-resistant prostate cancer (mCRPC) following the most recent treatment at time of study entry.
• 9. Adequate organ and marrow function.
• 10. 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:
• 1. Must have received a single line of ARPI, such as enzalutamide, darolutamide, apalutamide or abiraterone acetate.
• 2. 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.
• 3. Capable of self-administering oral formulations.
• Exclusion Criteria:
• 1. Any evidence of non adenocarcinomatous forms of prostate cancer (including small cell, spindle cell, signet cell, neuroendocrine, sarcomatous).
• 2. Known, unresolved urinary tract obstruction.
• 3. Participants with a history of central nervous system metastases.
• 4. Symptomatic malignant spinal cord compression or findings indicative of impending cord compression.
• 5. Participants with a history of leptomeningeal carcinomatosis.
• 6. Previous or concurrent cancer distinct from the cancer under investigation in primary site or histology .
• 7. Concurrent serious medical conditions.
• 8. Previous history of interstitial lung disease or non-infectious pneumonitis.
• 9. Participants with a history or clinical/laboratory features suggestive of myelodysplastic syndrome or acute myeloid leukaemia.
• 10. Persistent toxicities caused by previous therapy.
• 11. Participants unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with absorption.
• 12. Active infection, including tuberculosis, hepatitis C virus, and hepatitis B virus infection.
• 13. Known hypersensitivity to study intervention or any of their excipients.
• Exclusion Criteria for Sub study 1:
• 1. History of uncontrolled seizures or requirement for >2 antiepileptic drugs.
• 2. History of severe brain injury or stroke.
• 3. Skeletal metastases demonstrating a superscan appearance on bone scan.
• 4. 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).