The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study
Open accessPublished version of a preprint
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21492 · Cited by 84,109
IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Ayers, M., Lunceford, J., Nebozhyn, M., Murphy, E., Loboda, A., Kaufman, D. R., Albright, A., Cheng, J. D., Kang, S. P., Shankaran, V., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci91190 · Cited by 3,788
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic
Chan, T. A., Yarchoan, M., Jaffee, E., Swanton, C., Quezada, S. A., Stenzinger, A., & Peters, S. (2019) · Annals of Oncology · doi:10.1093/annonc/mdy495 · Cited by 2,683
Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G., & Jain, R. K. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.29 · Cited by 2,027
Coleman, R. L., Oza, A. M., Lorusso, D., Aghajanian, C. A., Oaknin, A., Dean, A. P., Colombo, N., Weberpals, J. I., Clamp, A. R., Scambia, G., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32440-6 · Cited by 1,699
Self-citationPredictive biomarkers for checkpoint inhibitor-based immunotherapy
Gibney, G. T., Weiner, L. M., & Atkins, M. B. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30406-5 · Cited by 1,635
CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - a target for novel cancer therapy
Tokunaga, R., Zhang, W., Naseem, M., Puccini, A., Berger, M. D., Soni, S., McSkane, M., Baba, H., & Lenz, H.-J. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.11.007 · Cited by 1,627
Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
Shin, D. S., Zaretsky, J. M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C. S., Hugo, W., Sandoval, S., Torrejon, D. Y., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1223 · Cited by 1,337
Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion
Castro, F., Cardoso, A. P., Gonçalves, R. M., Serre, K., & Oliveira, M. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00847 · Cited by 1,224
Swisher, E. M., Lin, K. K., Oza, A. M., Scott, C. L., Giordano, H., Sun, J., Konecny, G. E., Coleman, R. L., Tinker, A. V., O'Malley, D. M., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30559-9 · Cited by 1,196
Self-citationGelmon, K. A., Tischkowitz, M. D., MacKay, H. J., Swenerton, K. D., Robidoux, A., Tonkin, K. S., Hirte, H. W., Huntsman, D. D., Clemons, M. J., Gilks, C. B., et al. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70214-5 · Cited by 1,130
Chen, P.-L., Roh, W., Reuben, A., Cooper, Z. A., Spencer, C. N., Prieto, P. A., Miller, J. P., Bassett, R. L., Gopalakrishnan, V., Wani, K., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1545 · Cited by 988
PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression
Jiao, S., Xia, W., Yamaguchi, H., Wei, Y., Chen, M.-K., Hsu, J.-M., Hsu, J. L., Yu, W.-H., Du, Y., Lee, H.-H., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3215 · Cited by 981
Walsh, T., Casadei, S., Lee, M. K., Pennil, C. C., Nord, A. S., Thornton, A., Roeb, W., Agnew, K. J., Stray, S. M., Wickramanayake, A., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115052108 · Cited by 960
Self-citationSen, T., Rodriguez, B. L., Chen, L., Corte, C. M. D., Morikawa, N., Fujimoto, J., Cristea, S., Nguyen, T., Diao, L., Li, L., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1020 · Cited by 902
Clinical significance of tumor-infiltrating lymphocytes in breast cancer
Stanton, S. E., & Disis, M. L. (2016) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-016-0165-6 · Cited by 854
Pantelidou, C., Sonzogni, O., De Oliveria Taveira, M., Mehta, A. K., Kothari, A., Wang, D., Visal, T., Li, M. K., Pinto, J., Castrillon, J. A., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1218 · Cited by 743
Shen, J., Zhao, W., Ju, Z., Wang, L., Peng, Y., Labrie, M., Yap, T. A., Mills, G. B., & Peng, G. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-1003 · Cited by 614
Konstantinopoulos, P. A., Waggoner, S. E., Vidal, G. A., Mita, M. M., Moroney, J. W., Holloway, R. W., Le, L. V., Sachdev, J. C., Chapman‐Davis, E., Colón‐Otero, G., et al. (2019) · JAMA Oncology · doi:10.1001/jamaoncol.2019.1048 · Cited by 577
Self-citationPARP inhibition elicits STING-dependent antitumor immunity in brca1-deficient ovarian cancer
Ding, L., Kim, H.-J., Wang, Q., Kearns, M., Jiang, T., Ohlson, C. E., Li, B. B., Xie, S., Liu, J. F., Stover, E. H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.054 · Cited by 572
STING: a master regulator in the cancer-immunity cycle
Zhu, Y., An, X., Zhang, X., Qiao, Y., Zheng, T., & Li, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1087-y · Cited by 431
Prognostic and Therapeutic Relevance of Molecular Subtypes in High-Grade Serous Ovarian Cancer
Konecny, G. E., Wang, C., Hamidi, H., Winterhoff, B. J. N., Kalli, K. R., Dering, J., Ginther, C., Chen, H., Dowdy, S. C., Cliby, W. A., et al. (2014) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju249 · Cited by 405
PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer
Chabanon, R. M., Muirhead, G., Krastev, D. B., Adam, J., Morel, D., Garrido, M., Lamb, A., Hénon, C., Dorvault, N., Rouanne, M., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci123319 · Cited by 332
CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer
Higuchi, T., Flies, D. B., Marjon, N. A., Mantia-Smaldone, G. M., Ronner, L., Gimotty, P. A., & Adams, S. F. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0044 · Cited by 287
Lee, J.-M., Cimino‐Mathews, A., Peer, C. J., Zimmer, A. S., Lipkowitz, S., Annunziata, C. M., Cao, L., Harrell, M. I., Swisher, E. M., Houston, N. D., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.72.1340 · Cited by 243
Self-citationCombining DNA damaging therapeutics with immunotherapy: more haste, less speed
Brown, J. S., Sundar, R., & Lopez, J. S. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.376 · Cited by 243
PARP inhibitors in ovarian cancer
Franzese, E., Centonze, S., Diana, A., Carlino, F., Guerrera, L. P., Napoli, M. D., Vita, F. D., Pignata, S., Ciardiello, F., & Orditura, M. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.12.002 · Cited by 220
Zhang, S., Kohli, K., Black, G., Lu, Y., Spadinger, S. M., He, Q., Pillarisetty, V. G., Cranmer, L. D., Tine, B. A. V., Yee, C., et al. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0940 · Cited by 158
Management strategies for recurrent platinum-resistant ovarian cancer
Naumann, R. W., & Coleman, R. L. (2011) · Drugs · doi:10.2165/11591720-000000000-00000 · Cited by 152
Drew, Y., de Jonge, M., Hong, S. H., Park, Y. H., Wolfer, A., Brown, J., Ferguson, M., Gore, M. E., Alvarez, R. H., Gresty, C., et al. (2018) · Gynecologic Oncology · doi:10.1016/j.ygyno.2018.04.555 · Cited by 131
TGF-β Inhibition and Immunotherapy: Checkmate
Ganesh, K., & Massagué, J. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.037 · Cited by 126
O'Sullivan, C. C., Moon, D. H., Kohn, E. C., & Lee, J. M. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00042 · Cited by 106
Self-citationDrew, Y., Kaufman, B., Banerjee, S. N., Lortholary, A. H., Hong, S. H., Park, Y. H., Zimmermann, S., Roxburgh, P., Ferguson, M., Álvarez, R. H., et al. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz253.016 · Cited by 96
Wu, X., Feng, Q., Wang, Y., Shi, J., Ge, H., & Di, W. J. (2009) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-009-0749-9 · Cited by 83
Fenerty, K. E., Padget, M., Wolfson, B., Gameiro, S. R., Su, Z., Lee, J. H., Rabizadeh, S., Soon-Shiong, P., & Hodge, J. W. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0445-4 · Cited by 68
Self-citationRobustness and Information Transfer within IL-6-induced JAK/STAT Signalling
Billing, U., Jetka, T., Nortmann, L., Wundrack, N., Komorowski, M., Waldherr, S., Schaper, F., & Dittrich, A. (2019) · Communications Biology · doi:10.1038/s42003-018-0259-4 · Cited by 64
Pujade-Lauraine, É., Fujiwara, K., Ledermann, J. A., Oza, A. M., Kristeleit, R. S., Ray-Coquard, I., Richardson, G. E., Sessa, C., Yonemori, K., Banerjee, S. N., et al. (2019) · Gynecologic Oncology · doi:10.1016/j.ygyno.2019.04.053 · Cited by 63
Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?
González-Martı́n, A., & Sánchez‐Lorenzo, L. (2019) · Cancer · doi:10.1002/cncr.32520 · Cited by 52
Póti, Á., Berta, K., Xiao, Y., Pipek, O., Klus, G. T., Ried, T., Csabai, I., Wilcoxen, K., Mikule, K. W., Szállási, Z., et al. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0312-6 · Cited by 27
Challenges and Opportunities for Immunotherapies in Gynecologic Cancers.
Jm, L., Ivy, S. P., & Kohn, E. C. (2016) · PubMed · Cited by 7
Cited by
Sorted by citations
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer
Labrie, M., Brugge, J. S., Mills, G. B., & Zervantonakis, I. K. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00454-5 · Cited by 410
Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant
Yang, C. Q., Xia, B.-R., Zhang, Z.-C., Zhang, Y., Lou, G., & Jin, W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.577869 · Cited by 358
Nakamura, Y., Kawazoe, A., Lordick, F., Janjigian, Y. Y., & Shitara, K. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00492-2 · Cited by 307
Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier
Vafaei, S., Zekiy, A. O., Khanamir, R. A., Zaman, B. A., Ghayourvahdat, A., Azimizonuzi, H., & Zamani, M. (2022) · Cancer Cell International · doi:10.1186/s12935-021-02407-8 · Cited by 284
Pang, K., Shi, Z., Wei, L., Yang, D. F., Ma, Y.-Y., Wang, W., Wang, G.-Y., Cao, M.-Y., Dong, J., Chen, Y.-A., et al. (2022) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100907 · Cited by 268
Metadata
- 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 › Oncology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
