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A Randomized Phase II Study Comparing Single-Agent Olaparib, Single Agent Cediranib, and the Combinations of Cediranib/Olaparib, Olaparib/Durvalumab (MEDI4736), Cediranib/Durvalumab (MEDI4736), Olaparib/AZD5363 (Capivasertib) in Women with Recurrent, Persistent or Metastatic Endometrial Cancer. A Multi-Arm Trial for Women with Recurrent or Persistent Endometrial Cancer

Primary Objective To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms that may be added by subsequent amendment) versus single agent cediranib as measured by progression free survival (PFS), in patients with recurrent, persistent or metastatic endometrial cancer. Secondary Objectives To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms that may be added by subsequent amendment) versus single-agent cediranib as measured by overall survival (OS) in patients with recurrent, persistent or metastatic endometrial cancer. To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment versus single-agent cediranib as measured by response rate in patients with recurrent, persistent or metastatic endometrial cancer. To assess the safety and tolerability of single agent cediranib, single-agent olaparib, and the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment). To assess if mutations in DNA Homologous Repair Genes (assayed prior to all treatment and prior to the study treatment) are predictive of response to olaparib alone or in combination with cediranib. (Integrated Biomarker) To assess if markers of angiogenesis in serial plasma samples are associated with response to cediranib alone or in combination with olaparib. (Integrated Biomarker) Exploratory Objectives To compare the efficacy of the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment) versus single agent olaparib as measured by PFS, response rate and OS, if and only if the combination is superior to the single-agent cediranib arm. To assess if phosphatase and tensin homolog (PTEN) loss as assessed by IHC is predictive of response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) To assess if loss of function of ARID1A assessed by immunohistochemistry (IHC) and mutational profile is predictive of response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) To assess if TP53 mutation status and p53 expression as assessed by IHC is associated with response to olaparib or in combination with cediranib. (Exploratory Biomarker) To assess if markers of angiogenesis in tissue are associated with response to cediranib alone or in combination with olaparib. (Exploratory Biomarker) To assess if microsatellite instability (MSI) as assessed by loss of DNA mismatch repair (MMR) proteins is associated with response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) To assess if surrogate markers for the TCGA molecular subgroups p53 IHC, MSI, and mutational status of the exonuclease domain of polymerase epsilon (POLE) are associated with response to treatment in all arms. (Exploratory Biomarker) To examine the association of the change in mutant allele frequency with response to treatment and to identify resistance mutations at the time of recurrence using ctDNA. (Exploratory Biomarker)

Primary Objective To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms that may be added by subsequent amendment) versus single agent cediranib as measured by progression free survival (PFS), in patients with recurrent, persistent or metastatic endometrial cancer. Secondary Objectives To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms that may be added by subsequent amendment) versus single-agent cediranib as measured by overall survival (OS) in patients with recurrent, persistent or metastatic endometrial cancer. To compare the efficacy of single-agent olaparib and the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment versus single-agent cediranib as measured by response rate in patients with recurrent, persistent or metastatic endometrial cancer. To assess the safety and tolerability of single agent cediranib, single-agent olaparib, and the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment). To assess if mutations in DNA Homologous Repair Genes (assayed prior to all treatment and prior to the study treatment) are predictive of response to olaparib alone or in combination with cediranib. (Integrated Biomarker) To assess if markers of angiogenesis in serial plasma samples are associated with response to cediranib alone or in combination with olaparib. (Integrated Biomarker) Exploratory Objectives To compare the efficacy of the combination of olaparib and cediranib (and potentially other combination arms may be added by subsequent amendment) versus single agent olaparib as measured by PFS, response rate and OS, if and only if the combination is superior to the single-agent cediranib arm. To assess if phosphatase and tensin homolog (PTEN) loss as assessed by IHC is predictive of response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) To assess if loss of function of ARID1A assessed by immunohistochemistry (IHC) and mutational profile is predictive of response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) To assess if TP53 mutation status and p53 expression as assessed by IHC is associated with response to olaparib or in combination with cediranib. (Exploratory Biomarker) To assess if markers of angiogenesis in tissue are associated with response to cediranib alone or in combination with olaparib. (Exploratory Biomarker) To assess if microsatellite instability (MSI) as assessed by loss of DNA mismatch repair (MMR) proteins is associated with response to olaparib alone or in combination with cediranib. (Exploratory Biomarker) To assess if surrogate markers for the TCGA molecular subgroups p53 IHC, MSI, and mutational status of the exonuclease domain of polymerase epsilon (POLE) are associated with response to treatment in all arms. (Exploratory Biomarker) To examine the association of the change in mutant allele frequency with response to treatment and to identify resistance mutations at the time of recurrence using ctDNA. (Exploratory Biomarker)