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Updated: Feb 16, 2026
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012
Maha Hussain1, Stephanie Daignault-Newton1, Przemyslaw W Twardowski1
1Maha Hussain, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Walter M. Stadler, University of Chicago, Chicago; Daniel H. Shevrin, NorthShore University Health System, Evanston, IL; Maha Hussain, Stephanie Daignault-Newton, Lakshmi P. Kunju, Javed Siddiqui, Yi-Mi Wu, Dan Robinson, Robert J. Lonigro, Xuhong Cao, Scott A. Tomlins, Rohit Mehra, David C. Smith, Megan V. Caram, and Arul M. Chinnaiyan, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Przemyslaw W. Twardowski, City of Hope Cancer Center, Duarte; Felix Y. Feng, University of California San Francisco, San Francisco, CA; Costantine Albany, Simon Cancer Center, Indiana University, Indianapolis, IN; Mark N. Stein, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; Kathleen A. Cooney, University of Utah, Salt Lake City, UT; Bruce Montgomery, University of Washington, Seattle, WA; Emmanuel S. Antonarakis, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Paul G. Corn, University of Texas MD Anderson Cancer Center, Houston, TX; Young E. Whang, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and Karen E. Knudsen, Thomas Jefferson University, Philadelphia, PA.
Abstract:
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.
Insights
Adding veliparib to abiraterone did not improve outcomes for metastatic castration-resistant prostate cancer (mCRPC). However, DNA damage repair defects (DRD) were linked to better responses and longer progression-free survival in mCRPC patients.
Area of Science:
- Oncology
- Genitourinary Cancers
- Prostate Cancer Research
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge.
- Androgen receptor (AR) inhibition is a standard treatment, but novel therapeutic strategies are needed.
- Poly (ADP-ribose) polymerase-1 (PARP1) inhibitors are being investigated for their potential in cancer therapy.
Purpose of the Study:
- To evaluate the efficacy of cotargeting poly (ADP-ribose) polymerase-1 (PARP1) with androgen receptor (AR) inhibition versus AR inhibition alone in mCRPC.
- To determine if ETS gene fusions predict treatment response in mCRPC patients.
- To explore molecular biomarkers associated with treatment outcomes in mCRPC.
Main Methods:
- A randomized clinical trial involving 148 patients with mCRPC who underwent metastatic site biopsy.
- Patients were stratified by ETS fusion status and randomized to receive abiraterone plus prednisone with or without veliparib (a PARP1 inhibitor).
- Primary endpoints included confirmed prostate-specific antigen (PSA) response rate (RR) and ETS fusion predictive value; secondary endpoints included safety, measurable disease RR (mRR), and progression-free survival (PFS).
Main Results:
- No significant differences were observed in PSA RR, mRR, or median PFS between the abiraterone plus prednisone arm and the veliparib combination arm.
- ETS fusions did not predict treatment response in this patient cohort.
- Exploratory analysis revealed that patients with DNA damage repair defects (DRD) exhibited significantly higher PSA RR, mRR, PSA decline, and longer median PFS compared to those with wild-type tumors. Similar improvements were noted for patients with normal PTEN, TP53, and PIK3CA status.
Conclusions:
- Cotargeting PARP1 with veliparib did not enhance the efficacy of abiraterone plus prednisone in mCRPC.
- ETS fusion status was not found to be a predictive biomarker for response to this treatment strategy.
- The presence of DNA damage repair defects (DRD) emerged as a significant positive predictive biomarker for improved clinical outcomes in mCRPC, warranting further investigation.
