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The role of PARP inhibitor combination therapy in ovarian cancer.

ABSTRACT: The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind developing combination therapies, to work synergistically with PARPi and overcome mechanisms of resistance to restore drug sensitivity, and clinical evidence of their efficacy to date.

SUBMITTER: Hockings H

PROVIDER: S-EPMC10196552 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The role of PARP inhibitor combination therapy in ovarian cancer.

Hockings Helen H Miller Rowan E RE

Therapeutic advances in medical oncology 20230516

The use of PARP inhibitors (PARPi) has transformed the care of advanced high-grade serous/endometrioid ovarian cancer. PARPi are now available to patients in both the first-line and recurrent platinum-sensitive disease settings; therefore, most patients will receive PARPi at some point in their treatment pathway. The majority of this expanding population of patients eventually acquire resistance to PARPi, in addition to those with primary PARPi resistance. We discuss the rationale behind develop ...[more]

PMID: 37215065

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Project description:PurposePreclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.Patients and methodsIn a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor-naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment.ResultsThirty-five patients with ovarian cancer [median, four prior therapies (IQR, 2-5.5), predominantly platinum-resistant (86%), BRCA wild-type (77%)] received at least one full cycle of treatment. ORR was 14% [5/35; 95% confidence interval (CI), 4.8%-30.3%]. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%-85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS [HR, 0.37 (95% CI, 0.16-0.87), P = 0.023], while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23-8.40), P = 0.017].ConclusionsThe PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.

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The role of PARP inhibitor combination therapy in ovarian cancer.

Publications

The role of PARP inhibitor combination therapy in ovarian cancer.

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