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Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012.

Publication ,  Journal Article
Hussain, M; Daignault-Newton, S; Twardowski, PW; Albany, C; Stein, MN; Kunju, LP; Siddiqui, J; Wu, Y-M; Robinson, D; Lonigro, RJ; Cao, X ...
Published in: J Clin Oncol
April 1, 2018

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.

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Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

April 1, 2018

Volume

36

Issue

10

Start / End Page

991 / 999

Location

United States

Related Subject Headings

  • Receptors, Androgen
  • Proto-Oncogene Proteins c-ets
  • Prostatic Neoplasms, Castration-Resistant
  • Prednisone
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Molecular Targeted Therapy
  • Middle Aged
  • Male
 

Citation

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Hussain, M., Daignault-Newton, S., Twardowski, P. W., Albany, C., Stein, M. N., Kunju, L. P., … Chinnaiyan, A. M. (2018). Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol, 36(10), 991–999. https://doi.org/10.1200/JCO.2017.75.7310
Hussain, Maha, Stephanie Daignault-Newton, Przemyslaw W. Twardowski, Costantine Albany, Mark N. Stein, Lakshmi P. Kunju, Javed Siddiqui, et al. “Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012.J Clin Oncol 36, no. 10 (April 1, 2018): 991–99. https://doi.org/10.1200/JCO.2017.75.7310.
Hussain M, Daignault-Newton S, Twardowski PW, Albany C, Stein MN, Kunju LP, et al. Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol. 2018 Apr 1;36(10):991–9.
Hussain, Maha, et al. “Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012.J Clin Oncol, vol. 36, no. 10, Apr. 2018, pp. 991–99. Pubmed, doi:10.1200/JCO.2017.75.7310.
Hussain M, Daignault-Newton S, Twardowski PW, Albany C, Stein MN, Kunju LP, Siddiqui J, Wu Y-M, Robinson D, Lonigro RJ, Cao X, Tomlins SA, Mehra R, Cooney KA, Montgomery B, Antonarakis ES, Shevrin DH, Corn PG, Whang YE, Smith DC, Caram MV, Knudsen KE, Stadler WM, Feng FY, Chinnaiyan AM. Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol. 2018 Apr 1;36(10):991–999.

Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

April 1, 2018

Volume

36

Issue

10

Start / End Page

991 / 999

Location

United States

Related Subject Headings

  • Receptors, Androgen
  • Proto-Oncogene Proteins c-ets
  • Prostatic Neoplasms, Castration-Resistant
  • Prednisone
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasm Metastasis
  • Molecular Targeted Therapy
  • Middle Aged
  • Male