Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase II study
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Abstract
Abstract 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.
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In platinum-resistant ovarian cancer patients given PARP inhibitors plus ICIs, higher circulating type I IFN- and IFNG-related cytokines and malignant-cell PD-L1 expression are associated with better disease outcome.
“Moreover, increased circulating levels of type I IFN- and IFNG-related cytokines as well as PD-L1 expression in malignant cells have been associated with favorable disease outcome in patients with platinum-resistant ovarian cancer receiving PARP inhibitors plus ICIs (F € arkkil € a et al., 2020; Lampert et al., 2020).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Lampert et al., 2020
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- Authors
- Lampert, E. J., Zimmer, A., Padget, M., Cimino-Mathews, A., Nair, J. R., Liu, Y., Swisher, E. M., Hodge, J. W., Nixon, A. B., Nichols, E., Bagheri, M. H., Levy, E., Radke, M. R., Lipkowitz, S., Annunziata, C. M., Taube, J. M., Steinberg, S. M., & Lee, J.-M.
- Affiliations
- National Cancer Institute (US)
- 3Department of Pathology, The Johns Hopkins Medical Institution, Baltimore, Maryland.
- Duke Medical Center (US)
- University of Washington (US)
- Frederick National Laboratory for Cancer Research (US)
- 7Department of Radiology and Imaging Sciences, Clinical Center, National Cancer Institute, Bethesda, Maryland.
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Corresponding author
- Lee, Jung-Min
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-08-14
- Volume
- 26
- Issue
- 16
- Pages
- 4268-4279
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7442720
- OpenAlex
- W3025130660
- Cited by
- 220
- References
- 40
- Citations by year
- 2026: 22 · 2025: 37 · 2024: 32 · 2023: 46 · 2022: 34 · 2021: 37 · 2020: 12
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI CCR (#ZIA BC011525)
- National Ovarian Cancer Coalition (SU2C-AACRDT16-15)
- DDCF (#2014194)
- NCI NIH (HHSN261200800001E)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- recurrent ovarian cancer, olaparib, durvalumab, PARP inhibitors, PD-L1 inhibitors, immune checkpoint blockade, combination therapy, tumor immunology, interferon-gamma, VEGFR-3, tumor-infiltrating lymphocytes, platinum-resistant ovarian cancer, BRCA wild-type, progression-free survival, biomarkers, translational biomarkers
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Progression-Free Survival, Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Female, Humans, Interferon-gamma, Middle Aged, Neoplasm Recurrence, Local, Ovarian Neoplasms, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerases, Gene Expression Regulation, Neoplastic, Vascular Endothelial Growth Factor A, Chemokine CXCL10, Chemokine CXCL9, B7-H1 Antigen
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