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. CarducciMario A. Eisenberger, Michael C. Haffner, Alan K. Meeker, James R. Eshleman, Jun Luo, Victor E. Velculescu, Charles G. Drake, Emmanuel S. Antonarakis

Research output: Contribution to journalArticle

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 DNArepair 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.

Original languageEnglish (US)
Pages (from-to)28561-28571
Number of pages11
JournalOncotarget
Volume9
Issue number47
DOIs
StatePublished - Jun 19 2018

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Keywords

  • AR-V7
  • DNA repair
  • Ipilimumab
  • Nivolumab
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Boudadi, K., Suzman, D. L., Anagnostou, V., Fu, W., Luber, B., Wang, H., Niknafs, N., White, J. R., Silberstein, J. L., Sullivan, R., Dowling, D., Harb, R., Nirschl, T. R., Veeneman, B. A., Tomlins, S. A., Wang, Y., Jendrisak, A., Graf, R. P., Dittamore, R., ... Antonarakis, E. S. (2018). Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Oncotarget, 9(47), 28561-28571. https://doi.org/10.18632/oncotarget.25564