Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial

Lajos Pusztai, Christina Yau, Denise M. Wolf, Hyo S. Han, Lili Du, Anne M. Wallace, Erica String-Reasor, Judy C. Boughey, A. Jo Chien, Anthony D. Elias, Heather Beckwith, Rita Nanda, Kathy S. Albain, Amy S. Clark, Kathleen Kemmer, Kevin Kalinsky, Claudine Isaacs, Alexandra Thomas, Rebecca Shatsky, Theresa L. HelstenAndres Forero-Torres, Minetta C. Liu, Lamorna Brown-Swigart, Emmanuel F. Petricoin, Julia D. Wulfkuhle, Smita M. Asare, Amy Wilson, Ruby Singhrao, Laura Sit, Gillian L. Hirst, Scott Berry, Ashish Sanil, Adam L. Asare, Jeffrey B. Matthews, Jane Perlmutter, Michelle Melisko, Hope S. Rugo, Richard B. Schwab, W. Fraser Symmans, Doug Yee, Laura J. van't Veer, Nola M. Hylton, Angela M. DeMichele, Donald A. Berry, Laura J. Esserman

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%–37%), hormone receptor (HR)-positive/HER2-negative (14%–28%), and triple-negative breast cancer (TNBC) (27%–47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.

Original languageEnglish (US)
Pages (from-to)989-998.e5
JournalCancer Cell
Volume39
Issue number7
DOIs
StatePublished - Jul 12 2021

Bibliographical note

Funding Information:
A.S. Clark: research funding from Novartis .

Funding Information:
L.J. Esserman is an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative, and received grant funding from QLHC for the I-SPY TRIAL; and is a member of the Blue Cross/Blue Shield Medical Advisory Panel and receives reimbursement for her time and travel. She has a grant from Merck for an Investigator initiated trial of DCIS.

Funding Information:
K. Kalinsky has disclosed advisory/consulting funding from Eli-Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Immunomedics, Merck, Seattle Genetics, OncoSec, 4D Pharma, DaicchiSankyo, and Cyclocel. Dr. Kalinsky also reports financial disclosures for his spouse (stock): Grail, Array BioPharma and Pfizer (prior employee).

Funding Information:
A.J. Chien: institutional research funding from Seagen , Merck , Amgen , and Puma .

Funding Information:
R. Nanda: research funding from Arvinas , AstraZeneca , Celgene , Corcept Therapeutics , Genentech/Roche , Immunomedics/Gilead , Merck , OBI Pharm, Inc. , Odonate Therapeutics , OncoSec , Pfizer , Taiho , SeaGen .

Funding Information:
Supported by Quantum Leap Healthcare Collaborative (2013 to present) and the Foundation for the National Institutes of Health (2010?2012), a grant from the Gateway for Cancer Research (G-16-900), and by a grant (28XS197) from the National Cancer Institute Center for Biomedical Informatics and Information Technology. The authors sincerely appreciate the ongoing support for the I-SPY2 TRIAL from the Safeway Foundation, the William K. Bowes, Jr. Foundation, and Give Breast Cancer the Boot. Initial support was provided by Quintiles Transnational Corporation, Johnson & Johnson, Genentech, Amgen, the San Francisco Foundation, Eli Lilly, Pfizer, Eisai, Side Out Foundation, Harlan Family, the Avon Foundation for Women, Alexandria Real Estate Equities, and private individuals and family foundations. We thank Anna Barker for leadership in helping to launch the I-SPY2 trial, the members of the data and safety monitoring committee, the trial coordinators, Ken Buetow and the staff of caBIG for input with the informatics design, the entire project oversight committee and the many investigators who have contributed. We are grateful for the input of our wonderful patient advocates: Susie Brain, Thelma Brown, Elly Cohen, Deborah Collyar, Coleen Crespo, Amy Delson, Peggy Devine, Sandra Finestone, Elizabeth Frank, Diane Heditsian, Patricia Haugen, Deborah Laxague, Marisa Leonardelli, Barbara LeStage, Beverly Parker, Susan Samson, and Patty Spears. Thank you to all the patients who volunteered to participate in I-SPY2. All authors have reviewed the data analyses, contributed to data interpretation, contributed to the intellectual content of the manuscript, approved the final version to be published, and agree to be accountable for all aspects of the work. Conceptualization: L.J.E. D.A.B. A.M.D. N.M.H. L.J.v.V. D.Y. W.F.S. and J.P.; methodology: L.J.E. D.A.B. L.J.v.V. C.Y. D.M.W. L.P. H.S.H. L.D. L.S. E.F.P. J.D.W. M.C. and S.B.; formal analysis: C.Y. D.M.W. L.P. A.S. S.B. and D.A.B.; investigation: L.P. C.Y. D.M.W. H.S.H. L.D. A.M.W. E.S.-R. J.C.B. A.J.C. A.D.E. H.B. R.N. K.S.A. A.S.C. K. Kemmer, K. Kalinsky, C.I. A.T. R. Sanghrio, T.L.H. A.F.-T. M.C.L. L.B.-S. E.F.P. J.D.W. M.C. G.L.H. W.F.S. D.Y. L.J.v.V. N.M.H. A.M.D. and L.J.E.; data curation: C.Y. D.M.W. A.M.W. N.O. R. Sanghrio, A.S. A.L.A.; original draft: L.P. C.Y. D.M.W. H.S.H. R.N. D.Y. and J.B.M.; visualization: L.P. C.Y. B.Y. D.M.W. L.D. and A.S.; supervision: L.J.E. D.A.B. A.M.D. N.M.H. L.J.v.V. D.Y. W.F.S.R. Sanghrio, H.S.R. M.M. L.P. and H.S.H.; project administration: S.M.A. R. Sanghrio, L.S. G.L.H. A.L.A. and J.B.M.; funding acquisition: L.J.E. and J.B.M. L. Pusztai has received consulting fees and honoraria from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Clovis, Syndax, H3Bio, and Daiichi, and Nanostring research support to his institution from AstraZeneca, Pfizer, Merck, Seagen, and Bristol Myers Squibb. H.S. Han: research funding to institution from GlaxoSmithKline, Abbvie, Prescient, G1 Therapeutics, Marker Therapeutics, Novartis, Horizon Pharma, Quantum Leap Healthcare Collaborative, Pfizer, Seattle Genetics, Arvinas, Zymeworks; grants from the Department of Defense, Speaker's Bureau - Lilly. E. String-Reasor: Consulting Lilly; Susan G. Komen, BCRFA, V Foundation research funding. J.C. Boughey: research funding from Eli Lilly. A.J. Chien: institutional research funding from Seagen, Merck, Amgen, and Puma. R. Nanda: research funding from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics/Gilead, Merck, OBI Pharm, Inc., Odonate Therapeutics, OncoSec, Pfizer, Taiho, SeaGen. A.S. Clark: research funding from Novartis. K. Kalinsky has disclosed advisory/consulting funding from Eli-Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Immunomedics, Merck, Seattle Genetics, OncoSec, 4D Pharma, DaicchiSankyo, and Cyclocel. Dr. Kalinsky also reports financial disclosures for his spouse (stock): Grail, Array BioPharma and Pfizer (prior employee). C. Isaacs has received consulting fees from Seattle Genetics, Genentech, AstraZeneca, Novartis, PUMA, Pfizer, and Esai. A. Thomas declares research support (paid to the institution) from Seattle Genetics, Sanofi; stock ownership in Johnson and Johnson, Bristol Myers Squibb, Pfizer, and Gilead; and participation in DSMB (BeyondSpring Pharmaceuticals; and royalties from Up-to-Date). A. Forero-Torres became a Seattle Genetics employee in 2018, and holds stock option from this employment. M.C. Liu received clinical trial research support from Eisai, Genentech, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro. M. Melisko received research funding to the institution from AstraZeneca, Novartis, KCRN Research, and Puma, and consulting fees from Biotheranostics, their spouse received honoraria from Genentech and has stock ownership in Merrimack. E.F. Petricoin: leadership roles in Perthera, Ceres Nanosciences; stock and other ownership interests in Perthera, Ceres Nanosciences, Avant Diagnostics; consulting or advisory roles in Perthera, Ceres Nanosciences, AZGen, Avant Diagnostics; research funding from Ceres Nanosciences (Inst), GlaxoSmithKline (Inst), Abbvie (Inst), Symphogen (Inst), Genentech (Inst); patents, royalties, other intellectual property (National Institutes of Health patents licensing fee distribution/royalty; co-inventor on filed George Mason University?assigned patents related to phosphorylated HER2 and EGFR response predictors for HER family-directed therapeutics, as such can receive royalties and licensing distribution on any licensed IP; travel, accommodations, and expenses from Perthera, Ceres Nanosciences. J.D. Wulfkuhle received honoraria from DAVA Oncology and consults for Baylor College of Medicine, and has disclosed stock ownership in Theralink Technologies, Inc. H.S. Rugo has received research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Lilly, Genentech, Odonate, Daiichi, Seattle Genetics, Eisai, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, and Immunomedics; and Honoraria from Puma, Mylan, and Samsung. L.J. van't Veer is employed by and a stockholder of Agendia NV. L.J. Esserman is an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative, and received grant funding from QLHC for the I-SPY TRIAL; and is a member of the Blue Cross/Blue Shield Medical Advisory Panel and receives reimbursement for her time and travel. She has a grant from Merck for an Investigator initiated trial of DCIS. The following authors declare no competing interests: C.Y. D.M.W. L.D. A.M.W. A.D. E.H.B. K.S.A. R. Shatsky, L.S. S.M.A. A.W. R. Singhrao, L.S. G.L.H. S.M.B. A.A. J.P. R.B.S. D.Y. N.M.H. K. Kemmer, T.L.H. A.S. J.B.M. W.F.S. A.M.D. and D.A.B. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. The trial was designed by the I-SPY2 study investigators. AstraZeneca provided the study drug and funding, but played no role in the study design, collection/analysis of data, or in manuscript preparation. The I-SPY2 trial is sponsored by Quantum Leap Healthcare Collaborative (2013 to present) and the Foundation for the National Institutes of Health (2010 to 2012) and by a grant (28XS197) from the National Cancer Institute Center for Biomedical Informatics and Information Technology. The authors of the manuscript vouch for the accuracy and completeness of the data.

Funding Information:
H.S. Han: research funding to institution from GlaxoSmithKline, Abbvie, Prescient, G1 Therapeutics, Marker Therapeutics, Novartis, Horizon Pharma, Quantum Leap Healthcare Collaborative, Pfizer, Seattle Genetics, Arvinas, Zymeworks; grants from the Department of Defense , Speaker’s Bureau - Lilly .

Funding Information:
Supported by Quantum Leap Healthcare Collaborative (2013 to present) and the Foundation for the National Institutes of Health (2010–2012), a grant from the Gateway for Cancer Research ( G-16-900 ), and by a grant ( 28XS197 ) from the National Cancer Institute Center for Biomedical Informatics and Information Technology. The authors sincerely appreciate the ongoing support for the I-SPY2 TRIAL from the Safeway Foundation , the William K. Bowes, Jr. Foundation , and Give Breast Cancer the Boot . Initial support was provided by Quintiles Transnational Corporation , Johnson & Johnson , Genentech , Amgen , the San Francisco Foundation , Eli Lilly , Pfizer , Eisai , Side Out Foundation , Harlan Family , the Avon Foundation for Women , Alexandria Real Estate Equities , and private individuals and family foundations.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • breast cancer
  • clinical trial
  • DNA repair inhibitor
  • immunotherapy

PubMed: MeSH publication types

  • Journal Article
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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