Last updated on June 2019

PARP-inhibition and CTLA-4 Blockade in BRCA-deficient Ovarian Cancer

Brief description of study

Of the approximately 21,000 cases of ovarian cancer diagnosed annually in the U.S, ten percent are attributed to hereditary syndromes, most commonly the result of mutations in the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Mutation in these genes results in the inability to repair double-stranded breaks in DNA. Treating these tumors with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors results in the specific killing of BRCA negative cells by blocking a second DNA-repair mechanism. Treatment of ovarian cancer patients with PARP inhibitors has resulted in improved progression free survival (PFS), but not overall survival (OS). It's not completely understood why this is the case, but some preclinical studies using ovarian cancer models in mice have suggested that combining PARP inhibitors with immune system modulators like T cell checkpoint inhibitors improves long-term survival.

Therefore, the purpose of this study is to evaluate the safety and efficacy of a combination of a PARP inhibitor (Olaparib) with a T cell checkpoint inhibitor (the anti-CTLA-4 antibody Tremelimumab) in women with recurrent BRCA mutation-associated ovarian cancer.

Detailed Study Description

The mechanism of action of Olaparib, a potent inhibitor of mammalian PARP-1, PARP-2, and PARP-3, has been proposed to involve the trapping of inactivated PARP onto single-stranded breaks preventing their repair and generating a potential block for cellular DNA replication. In tumors with homologous recombination deficiency, such as those with BRCA mutations, single agent treatment with Olaparib can lead to cell death and tumor regressions by a process known as synthetic lethality.

Tremelimumab is a human monoclonal immunoglobulin G2 (IgG2) antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a co-inhibitory receptor expressed on activated T cells. Tremelimumab has been shown to block the inhibitory signal mediated by interaction of human CTLA-4 on activated T cells with B7-1 and B7-2 on antigen-presenting cells. This is thought to maintain T cell activation in the tumor microenvironment and promote the establishment of tumor-specific immune responses.

Like melanoma, ovarian cancer is associated with significant tumor heterogeneity, and is also a rational target for immune therapy. Although antitumor effects have been observed in patients with epithelial ovarian cancer in response to anti-CTLA-4 antibody treatment, evidence of clinical disease regression has not been demonstrated. Based on data indicating that a subset of ovarian cancers associated with germline mutations in BRCA1/2 genes may be more immunogenic, we hypothesized that BRCA-negative tumors would be particularly vulnerable to checkpoint blockade, and that immune priming with targeted cytotoxic therapy using a PARP-inhibitor would sensitize ovarian tumors to immune therapy and optimize patient survival. We have demonstrated this in pre-clinical models of high grade BRCA1-negative ovarian cancer.

Based on significant therapeutic benefit demonstrated in pre-clinical models, this clinical trial evaluates the combination of Olaparib and Tremelimumab in women with recurrent BRCA-deficient ovarian cancers.

Clinical Study Identifier: NCT02571725

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University of Virginia Cancer Center

Charlottesville, VA United States
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