TY - JOUR
T1 - Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer
T2 - a Proof-of-Concept Phase II Study
AU - Lampert, Erika J.
AU - Zimmer, Alexandra
AU - Padget, Michelle
AU - Cimino-Mathews, Ashley
AU - Nair, Jayakumar R.
AU - Liu, Yingmiao
AU - Swisher, Elizabeth M.
AU - Hodge, James W.
AU - Nixon, Andrew B.
AU - Nichols, Erin
AU - Bagheri, Mohammad H.
AU - Levy, Elliott
AU - Radke, Marc R.
AU - Lipkowitz, Stanley
AU - Annunziata, Christina M.
AU - Taube, Janis M.
AU - Steinberg, Seth M.
AU - Lee, Jung Min
N1 - Funding Information:
Association for Cancer Research, the scientific partner of Stand Up To Cancer. This research was made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (DDCF grant #2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, Elsevier, and other private donors (to E.J. Lampert). This project has also been funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E (to E. Nichols).
Funding Information:
We thank Drs. Elise C. Kohn, Bernard Parker, Lori Minasian and Farah Zia, Irene Ekwede RN, Nicole Houston RN, Kathryn Trewhitt NP, and Ms. Mireya Gomez for their contributions in clinic. We thank Bao Tran, Maggie Cam, and Xiongfong Chen for their expertise in generating the RNA and WES data used in this study. We also thank Drs. Kohn and Steeg for their invaluable comments concerning the manuscript. This research was supported by the Intramural Research Program of the NCI, CCR (grant number: #ZIA BC011525; to J.-M. Lee). Durvalumab and olaparib were supplied to the CCR, NCI under a Cooperative Research and Development Agreement between the CCR/NCI and Astra-Zeneca. Research funding was also provided by AstraZeneca and Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number: SU2C-AACR-DT16-15; to E. Swisher). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American
Funding Information:
A. Cimino-Mathews is an employee/paid consultant for and reports receiving commercial research grants from Bristol-Myers Squibb and reports receiving speakers bureau honoraria from Roche Diagnostics. A.B. Nixon is an employee/paid consultant for Eli Lilly, Kanghong Pharma, GlaxoSmithKline, and Promega, and reports receiving commercial research grants from Acceleron Pharma, Amgen, AstraZeneca/MedImmune, Eureka Therapeutics, Genentech, HTG Molecular Diagnostics, Leadiant Biosciences, MedPacto Inc., Novartis, Tracon Pharma. J.M. Taube is an employee/paid consultant for Bristol-Myers Squibb and Akoya Biosciences, and reports receiving commercial research grants from Bristol-Myers Squibb, Akoya Biosciences, AstraZeneca, Merck, and Compugen. J-M. Lee is an advisory board member/unpaid consultant for AstraZeneca. C.M. Annunziata received research funding from Precision Biologics. J.-M. Lee received research funding from AstraZeneca and Eli Lilly. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
1Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. 2Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. 3Department of Pathology, The Johns Hopkins Medical Institution, Baltimore, Maryland. 4Department of Medicine, Duke University Medical Center, Durham, North Carolina. 5Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology, University of Washington, Seattle, Washington. 6Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Bethesda, Maryland. 7Department of Radiology and Imaging Sciences, Clinical Center, National Cancer Institute, Bethesda, Maryland. 8Interventional Radiology, NIH Clinical Center, Bethesda, Maryland. 9Department of Dermatopathology, The Johns Hopkins Medical Institution, Baltimore, Maryland. 10Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/8/15
Y1 - 2020/8/15
N2 - 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–nave 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 IFNg and CXCL9/CXCL10 expression, systemic IFNg/TNFa production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNg 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.
AB - 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–nave 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 IFNg and CXCL9/CXCL10 expression, systemic IFNg/TNFa production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNg 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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U2 - 10.1158/1078-0432.CCR-20-0056
DO - 10.1158/1078-0432.CCR-20-0056
M3 - Article
C2 - 32398324
AN - SCOPUS:85086334949
VL - 26
SP - 4268
EP - 47279
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 16
ER -