TY - JOUR
T1 - Targeting androgen receptor and DNA repair in metastatic castration-resistant prostate cancer
T2 - Results from NCI 9012
AU - Hussain, Maha
AU - Daignault-Newton, Stephanie
AU - Twardowski, Przemyslaw W.
AU - Albany, Costantine
AU - Stein, Mark N.
AU - Kunju, Lakshmi P.
AU - Siddiqui, Javed
AU - Wu, Yi Mi
AU - Robinson, Dan
AU - Lonigro, Robert J.
AU - Cao, Xuhong
AU - Tomlins, Scott A.
AU - Mehra, Rohit
AU - Cooney, Kathleen A.
AU - Montgomery, Bruce
AU - Antonarakis, Emmanuel S.
AU - Shevrin, Daniel H.
AU - Corn, Paul G.
AU - Whang, Young E.
AU - Smith, David C.
AU - Caram, Megan V.
AU - Knudsen, Karen E.
AU - Stadler, Walter M.
AU - Feng, Felix Y.
AU - Chinnaiyan, Arul M.
N1 - Funding Information:
Supported by Grants No. N01-CM-2011-00071C from the National Cancer Institute (NCI), SU2C-AACR-DT0712 from Stand up to Cancer and American Association for Cancer Research, P50CA186786 from NCI, PC080189 from the US Department of Defense, and the Prostate Cancer Foundation. We thank Stephanie Ellison for assistance in formatting and writing this manuscript as well as the Mi-Oncoseq clinical sequencing laboratory for sequence analysis of samples in this study. We are especially grateful to all the patients who participated in this investigational study. We would also like to thank the Michigan Center for Translational Pathology.
Publisher Copyright:
© 2017 by American Society of Clinical Oncology.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline $ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
AB - Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline $ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
UR - http://www.scopus.com/inward/record.url?scp=85044560634&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044560634&partnerID=8YFLogxK
U2 - 10.1200/JCO.2017.75.7310
DO - 10.1200/JCO.2017.75.7310
M3 - Article
C2 - 29261439
AN - SCOPUS:85044560634
SN - 0732-183X
VL - 36
SP - 991
EP - 999
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 10
ER -
