Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 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

Lajos Pusztai  1 , Christina Yau  2 , Denise M Wolf  3 , Hyo S Han  4 , Lili Du  5 , Anne M Wallace  6 , Erica String-Reasor  7 , Judy C Boughey  8 , A Jo Chien  2 , Anthony D Elias  9 , Heather Beckwith  10 , Rita Nanda  11 , Kathy S Albain  12 , Amy S Clark  13 , Kathleen Kemmer  14 , Kevin Kalinsky  15 , Claudine Isaacs  16 , Alexandra Thomas  17 , Rebecca Shatsky  6 , Theresa L Helsten  18 , Andres Forero-Torres  7 , Minetta C Liu  8 , Lamorna Brown-Swigart  3 , Emmanuel F Petricoin  19 , Julia D Wulfkuhle  19 , Smita M Asare  20 , Amy Wilson  20 , Ruby Singhrao  2 , Laura Sit  2 , Gillian L Hirst  2 , Scott Berry  21 , Ashish Sanil  21 , Adam L Asare  20 , Jeffrey B Matthews  2 , Jane Perlmutter  22 , Michelle Melisko  2 , Hope S Rugo  2 , Richard B Schwab  18 , W Fraser Symmans  5 , Doug Yee  10 , Laura J Van't Veer  2 , Nola M Hylton  2 , Angela M DeMichele  13 , Donald A Berry  21 , Laura J Esserman  2
Affiliations
Clinical Trial

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 et al. Cancer Cell. .

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.

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

PubMed Disclaimer

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, 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.

Figures

Figure 1.
Figure 1.. Bayesian probability distributions for achieving pathologic complete response (pCR) and residual cancer burden (RCB) distributions by treatment arm in the three a priori defined biomarker subsets.
A. Estimated pCR rates and the corresponding 95% probability intervals (X -axes) for the experimental and control arms. Final predictive probabilities of success in a future 300 patient phase 3 trial (Prob(Ph3)), and the probabilities that the experimental arm is superior to the control (Prob(>Ctl)) are also shown. B. RCB categories and distribution of RCB scores by treatment arm in the 3 biomarker subsets.
Figure 2.
Figure 2.. Predictive function of 13 mRNA markers in all HER2-negative, triple negative cancers, and HER2 negative/hormone receptor positive cancers.
Red dots indicate a positive association with pathologic complete response (pCR), blue indicates association with residual disease. The size of the dots is inversely proportional to the p-values; statistically significant associations are highlighted by the white rectangles. P-values and associations were derived from logistic regression models as indicated by the numbers (1 through 4) on the figure.
Figure 3.
Figure 3.. Bayesian probability distribution of pCR, and expression of proliferation, tumor inflammation, and sensitivity to endocrine therapy (SET) gene signatures in MP1 and MP2 ER+/HER2− cancers.
Estimated pCR rates and the corresponding 95% probability intervals (X -axes) for the experimental and control arms in MP1 (A) and MP2 (B) cancers. Final predictive probabilities of success in a future 300 patient phase 3 trial (Prob(Ph3)), and the probabilities that the experimental arm is superior to the control (Prob(>Ctl)) are also shown. Expression of the SET gene signature (C), and proliferation (D), and tumor inflammation (E) signatures in MP1 and MP2 cancers.
See this image and copyright information in PMC

Comment in

References

    1. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, et al. (2017). IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127, 2930–2940. - PMC - PubMed
    1. Barker A, Sigman C, Kelloff G, Hylton N, Berry D, and Esserman L (2009). ISPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy. Clin Pharmacol Ther 86, 97–100. - PubMed
    1. Berry DA (2011). Adaptive clinical trials in oncology. Nature Reviews Clinical Oncology 9, 199–207. - PubMed
    1. Berry SM, Reese CS, and Larkey PD (2012). Bridging Different Eras in Sports. J Am Stat Assoc 94, 661–676.
    1. Bianchini G, Pusztai L, Karn T, Iwamoto T, Rody A, Kelly CM, Müller V, Schmidt M, Qi Y, Holtrich U, et al. (2013). Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers. Breast Cancer Res 15, R86. - PMC - PubMed

Publication types

MeSH terms