Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study.

Autor:	Lampert EJ; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Zimmer A; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Padget M; Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Cimino-Mathews A; Department of Pathology, The Johns Hopkins Medical Institution, Baltimore, Maryland., Nair JR; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Liu Y; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Swisher EM; Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology, University of Washington, Seattle, Washington., Hodge JW; Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Nixon AB; Department of Medicine, Duke University Medical Center, Durham, North Carolina., Nichols E; Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Bethesda, Maryland., Bagheri MH; Department of Radiology and Imaging Sciences, Clinical Center, National Cancer Institute, Bethesda, Maryland., Levy E; Interventional Radiology, NIH Clinical Center, Bethesda, Maryland., Radke MR; Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology, University of Washington, Seattle, Washington., Lipkowitz S; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Annunziata CM; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Taube JM; Department of Dermatopathology, The Johns Hopkins Medical Institution, Baltimore, Maryland., Steinberg SM; Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Lee JM; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. leej6@mail.nih.gov.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Aug 15; Vol. 26 (16), pp. 4268-4279. Date of Electronic Publication: 2020 May 12.
DOI:	10.1158/1078-0432.CCR-20-0056
Abstrakt:	Purpose: Preclinical 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 Methods: In 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. Results: Thirty-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]. Conclusions: The 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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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