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Pusztai L, Yau C, Wolf DM, et al. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer Cell. 2021;39(7):989-998.e5doi: 10.1016/j.ccell.2021.05.009.
Pusztai, L., Yau, C., Wolf, D. M., Han, H. S., Du, L., Wallace, A. M., String-Reasor, E., Boughey, J. C., Chien, A. J., Elias, A. D., Beckwith, H., Nanda, R., Albain, K. S., Clark, A. S., Kemmer, K., Kalinsky, K., Isaacs, C., Thomas, A., Shatsky, R., Helsten, T. L., Forero-Torres, A., Liu, M. C., Brown-Swigart, L., Petricoin, E. F., Wulfkuhle, J. D., Asare, S. M., Wilson, A., Singhrao, R., Sit, L., Hirst, G. L., Berry, S., Sanil, A., Asare, A. L., Matthews, J. B., Perlmutter, J., Melisko, M., Rugo, H. S., Schwab, R. B., Symmans, W. F., Yee, D., Van't Veer, L. J., Hylton, N. M., DeMichele, A. M., Berry, D. A., & Esserman, L. J. (2021). Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer cell, 39(7), 989-998.e5. https://doi.org/10.1016/j.ccell.2021.05.009
Pusztai, Lajos, et al. "Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial." Cancer cell vol. 39,7 (2021): 989-998.e5. doi: https://doi.org/10.1016/j.ccell.2021.05.009
Pusztai L, Yau C, Wolf DM, Han HS, Du L, Wallace AM, String-Reasor E, Boughey JC, Chien AJ, Elias AD, Beckwith H, Nanda R, Albain KS, Clark AS, Kemmer K, Kalinsky K, Isaacs C, Thomas A, Shatsky R, Helsten TL, Forero-Torres A, Liu MC, Brown-Swigart L, Petricoin EF, Wulfkuhle JD, Asare SM, Wilson A, Singhrao R, Sit L, Hirst GL, Berry S, Sanil A, Asare AL, Matthews JB, Perlmutter J, Melisko M, Rugo HS, Schwab RB, Symmans WF, Yee D, Van't Veer LJ, Hylton NM, DeMichele AM, Berry DA, Esserman LJ. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Cancer Cell. 2021 Jul 12;39(7):989-998.e5. doi: 10.1016/j.ccell.2021.05.009. Epub 2021 Jun 17. PMID: 34143979.
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Cancer Cell. 2021 Jul 12;39(7):989-998.e5. doi: 10.1016/j.ccell.2021.05.009. Epub 2021 Jun 17.

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

Cancer cell

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 Helsten, Andres 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

Affiliations

  1. Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, 333 Cedar Steet, PO Box 208032, New Haven, CT 06510, USA. Electronic address: [email protected].
  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
  3. Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA.
  4. Medical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
  5. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  6. Comprehensive Breast Health Center, University of California San Diego, La Jolla, CA 92037, USA.
  7. Department of Hematology & Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  8. Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
  9. Department of Internal Medicine, University of Colorado, Aurora, CO 80045, USA.
  10. Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
  11. Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  12. Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Chicago, IL 60153, USA.
  13. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
  14. Knight Cancer Institute, Oregon Health & Sciences University, Portland, OR 97239, USA.
  15. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
  16. Lombardi Comprehensive Care Center, Georgetown University, Washington, DC 20007, USA.
  17. Medical Oncology and Hematology, Wake Forest University, Winston-Salem, NC 27157, USA.
  18. Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA.
  19. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
  20. Quantum Leap Healthcare Collaborative, San Francisco, CA 94118, USA.
  21. Berry Consultants, LLC, Austin, TX 78746, USA.
  22. Gemini Group, Ann Arbor, MI 48107, USA.

PMID: 34143979 DOI: 10.1016/j.ccell.2021.05.009

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.

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: DNA repair inhibitor; breast cancer; clinical trial; immunotherapy

Conflict of interest statement

Declaration of interests L. Pusztai has received consulting fees and honoraria from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics,

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