TY - JOUR
T1 - TBCRC 032 IB/II Multicenter Study
T2 - Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer
AU - Translational Breast Cancer Research Consortium
AU - Lehmann, Brian D.
AU - Abramson, Vandana G.
AU - Sanders, Melinda E.
AU - Mayer, Erica L.
AU - Haddad, Tufia C.
AU - Nanda, Rita
AU - Van Poznak, Catherine
AU - Storniolo, Anna Maria
AU - Nangia, Julie R.
AU - Gonzalez-Ericsson, Paula I.
AU - Sanchez, Violeta
AU - Johnson, Kimberly N.
AU - Abramson, Richard G.
AU - Chen, Sheau Chiann
AU - Shyr, Yu
AU - Arteaga, Carlos L.
AU - Wolff, Antonio C.
AU - Pietenpol, Jennifer A.
N1 - Funding Information:
B.D. Lehman is listed as an inventor of intellectual property (TNBCtype) licensed by Insight Genetics, Inc. V.G. Abramson is a paid consultant for AbbVie, Daiichi Sankyo, and Novartis. E.L. Mayer is a paid consultant for Pfizer, Lilly, and Novartis. T.C. Haddad is a paid consultant for TerSera. R. Nanda is a paid consultant for and reports receiving commercial research grants from Genentech. C.L. Arteaga reports receiving commercial research grants from Pfizer, Lilly, Takeda, and RADIUS; holds ownership interest (including patents) in Provista and Y-TRAP; is an unpaid consultant/advisory board member for Novartis, Merck, Lilly, Symphogen, Daiichi Sankyo, RADIUS, Taiho Oncology, PUMA Biotechnology, Sanofi, H3Biomedicine, Immunomedics, Petra Pharma, G1 Therapeutics, Athenex, and OrigiMed; and reports receiving other remuneration from the Komen Foundation. J.A. Pietenpol holds ownership interest (including patents) in Insight Genetics, Inc. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors thank all the patients who generously volunteered to participate in this study and the TBCRC investigators, research nurses, and study coordinators for their efforts on behalf of the patients. The authors are grateful to Thomas Stout, PhD, for critical review of the manuscript. The authors also thank the Translational Breast Cancer Research Consortium and Susan G. Komen for the funding support. This research was supported by NCI/NCI grants CA098131 and CA068485 (J.A. Pieten-pol) and Susan G. Komen grants SAC110030 (J.A. Pietenpol) and CCR13262005 (B. D. Lehmann). We would like to thank Vanderbilt Technologies for Advanced Genomics (VANTAGE) and the Translational Pathology Shared Resources for providing technologies supported by NIH S10 instrumentation grants RR028106, RR027764, and OD023475.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Purpose: Preclinical data demonstrating androgen receptor (AR)-positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. Patients and Methods: Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine doselimiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks. Results: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P= 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants. Conclusions: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.
AB - Purpose: Preclinical data demonstrating androgen receptor (AR)-positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer. Patients and Methods: Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine doselimiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks. Results: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P= 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants. Conclusions: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.
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U2 - 10.1158/1078-0432.CCR-19-2170
DO - 10.1158/1078-0432.CCR-19-2170
M3 - Article
C2 - 31822498
AN - SCOPUS:85084960965
SN - 1078-0432
VL - 26
SP - 2111
EP - 2123
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -