Testing Two Oral Drugs Combination (Cediranib and Olaparib) Compared to a Single Drug (Olaparib) for Men With Advanced Prostate Cancer

PRIMARY OBJECTIVE: I. To assess the clinical activity of the combination of cediranib and olaparib, as measured by radiographic progression free survival (rPFS), as compared to olaparib monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC). SECONDARY OBJECTIVES: I. To assess the clinical activity of the combination of cediranib and olaparib, as measured by prostate-specific antigen (PSA) response rate, radiographic response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1, and overall survival (OS), as compared to olaparib monotherapy in patients with mCRPC. II. To evaluate association of homologous recombination deoxyribonucleic acid (DNA) repair deficiency (HRD) with the clinical activity of the combination of cediranib and olaparib or olaparib monotherapy, as measured by rPFS, in mCRPC patients. III. To evaluate the safety the combination of cediranib and olaparib and olaparib monotherapy in patients with metastatic prostate cancer. EXPLORATORY OBJECTIVES: I. To characterize genomic alterations by whole exome sequencing in mCRPC patients and correlate that with clinical activity or resistance to olaparib with or without cediranib. II. To characterize changes in ribonucleic acid (RNA) expression of DNA repair genes, angiogenesis markers, and immune markers, by whole transcriptome sequencing and correlate with clinical activity or resistance to olaparib with or without cediranib. III. To characterize changes in immune tumor microenvironment in mCRPC patients by profiling expression of co-stimulatory and co-inhibitory molecules and tumor infiltrating lymphocytes, and correlate with clinical activity or resistance to olaparib with or without cediranib. IV. To identify baseline predictive biomarkers for rPFS or response and to identify on-treatment markers of acquired resistance in men with mCRPC receiving either olaparib plus cediranib or olaparib alone. V. To explore biomarker signatures that correlate with the clinical activity or resistance to olaparib with or without cediranib, including changes in gene expression or acquired mutations in tumor biopsies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive olaparib orally (PO) twice daily (BID) and cediranib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.