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Oncotarget. 2018 Jun 19;9(47):28561-28571. doi: 10.18632/oncotarget.25564. eCollection 2018 Jun 19.

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

Author information

1
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
3
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
5
Present address: Pfizer Inc., Pearl River, NY, USA.
6
Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
7
Epic Sciences Inc., San Diego, CA, USA.
8
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
9
Department of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA.

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.

KEYWORDS:

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

Conflict of interest statement

CONFLICTS OF INTEREST E.S.A. is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Clovis and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and is the co-inventor of a biomarker technology that has been licensed to Qiagen. S.A.T. has served as a consultant and received honoraria from Roche/ Ventana Medical Systems, Almac Diagnostics, Janssen, AbbVie and Astellas/Medivation; he is also a co-founder of, consultant for and Laboratory Director of Strata Oncology. Y.W., A.J., R.P.G. and R.D. are employees of Epic Sciences. V.E.V. is a founder of Personal Genome Diagnostics (PGDx), is a member of its Scientific Advisory Board and Board of Directors, and owns PGDx stock, which is subject to certain restrictions under university policy; he is also on the Scientific Advisory Board for Ignyta; the terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors disclose no relevant conflicts of interest.

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