Ceralasertib (AZD6738) Alone and in Combination With Olaparib or Durvalumab in Patients With Solid Tumors

PRIMARY OBJECTIVES: I. To assess objective response rate (ORR) of ceralasertib monotherapy and ceralasertib + olaparib by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria (ARID1A Cohort). II. To assess the composite response rate (objective response and/or PSA50 response) of ceralasertib monotherapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) (N = 5-10) harboring pathogenic ATM mutations and/or loss of ATM expression by Immunohistochemistry (IHC) (ATM Cohort). III. To assess objective response rate of ceralasertib monotherapy in patients with other advanced solid tumor malignancies harboring pathogenic ATM mutations and/or loss of ATM expression by IHC (ATM Cohort). IV. To assess the objective response rate (ORR) of ceralasertib in combination with durvalumab by RECIST 1.1 criteria (Endometrial Cohort) SECONDARY OBJECTIVES: I. To determine the median duration of response (DOR) in each study arm and cohort. II. To determine the median progression-free survival and progression-free survival rate at 6 and 12 months in each study arm and cohort. III. To determine the median overall survival (Endometrial cohort only). IV. To further characterize the safety and tolerability profile of ceralasertib alone and in combination with olaparib and durvalumab, respectively. V. To determine the percent change from baseline in the sum of the longest diameter of target lesions. VI. Prostate cancer patients only: To determine the PSA50 response rate and radiographic progression-free survival by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. OUTLINE: Participants will be assigned to receive one of 3 treatment regimens (ceralasertib monotherapy, ceralasertib plus olaparib combination therapy, or ceralasertib plus durvalumab combination therapy) based on the immunohistochemistry (IHC) and or Chemiluminescent immunoassay (CLIA) and disease type. ARID1A Subgroup: Participants with renal cell carcinoma with predominant clear cell histology, urothelia, all pancreatic cancers, endometrial and ovarian, and other solid tumors (excluding clear cell ovarian cancer and endometrial cancer) will receive either ceralasertib monotherapy if the IHC results for BAF250a is positive or ceralasertib plus olaparib combination therapy IHC results for BAF250a expression is negative. ATM-Loss Subgroup: Participants with metastatic castrate resistant prostate cancer (mCRPC), or other solid tumors with evidence of ATM loss by either pathogenic ATM mutation in CLIA-approved assay and/or loss of ATM expression by IHC will receive ceralasertib monotherapy. Endometrial Cancer Cohort: Participants with the presence of pathogenic ARID1A alteration on CLIA-approved next-generation sequencing panel without evidence of microsatellite instability and/or presence of intact mismatch repair proteins by immunohistochemistry will receive ceralasterib + durvalumab. Participants may continue treatment until disease progression by RECIST 1.1/PCWG3 (when applicable) criteria, unacceptable toxicity, or participant withdrawal from study, whichever occurs first. Participants may be treated beyond disease progression with prior evidence of clinical benefit and only upon approval of Principal Investigator. Participants will be followed for up to 30 days following last dose of protocol therapy, and up to 3 years for the endometrial cohort.