Oncotarget

Research Papers:

Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer

Karim Boudadi, Daniel L. Suzman, Valsamo Anagnostou, Wei Fu, Brandon Luber, Hao Wang, Noushin Niknafs, James R. White, John L. Silberstein, Rana Sullivan, Donna Dowling, Rana Harb, Thomas R. Nirschl, Brendan A. Veeneman, Scott A. Tomlins, Yipeng Wang, Adam Jendrisak, Ryon P. Graf, Ryan Dittamore, Michael A. Carducci, Mario A. Eisenberger, Michael C. Haffner, Alan K. Meeker, James R. Eshleman, Jun Luo, Victor E. Velculescu, Charles G. Drake, Emmanuel S. Antonarakis _

PDF  |  HTML  |  Supplementary Files  |  Order a Reprint

Oncotarget. 2018; 9:28561-28571. https://doi.org/10.18632/oncotarget.25564

Metrics: PDF 581 views  |   HTML 725 views  |   ?  


Abstract

Karim Boudadi1, Daniel L. Suzman4, Valsamo Anagnostou1, Wei Fu1, Brandon Luber1, Hao Wang1, Noushin Niknafs1, James R. White1, John L. Silberstein3, Rana Sullivan1, Donna Dowling1, Rana Harb1, Thomas R. Nirschl1, Brendan A. Veeneman5,9, Scott A. Tomlins5,6, Yipeng Wang7, Adam Jendrisak7, Ryon P. Graf7, Ryan Dittamore7, Michael A. Carducci1, Mario A. Eisenberger1, Michael C. Haffner2, Alan K. Meeker2, James R. Eshleman2, Jun Luo3, Victor E. Velculescu1, Charles G. Drake8 and Emmanuel S. Antonarakis1,3

1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

4Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

5Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

6Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA

7Epic Sciences Inc., San Diego, CA, USA

8Department of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA

9Present address: Pfizer Inc., Pearl River, NY, USA

Correspondence to:

Emmanuel S. Antonarakis, email: eantona1@jhmi.edu

Keywords: AR-V7; DNA repair; ipilimumab; nivolumab; prostate cancer

Received: April 19, 2018     Accepted: May 17, 2018     Published: June 19, 2018

ABSTRACT

AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had ≥4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in BRCA2, two in ATM, one in ERCC4; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA-PFS was 3.0 (95%CI 2.1–NR) months, PFS was 3.7 (95%CI 2.8–7.5) months, and OS was 8.2 (95%CI 5.5–10.4) months. Outcomes appeared generally better in DRD+ vs. DRD– tumors with respect to PSA responses (33% vs. 0%; P=0.14, nonsignificant), ORR (40% vs. 0%; P=0.46, nonsignificant), PSA-PFS (HR 0.19; P<0.01, significant), PFS (HR 0.31; P=0.01, significant), and OS (HR 0.41; P=0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 25564