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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.

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


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.


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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