Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer
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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
Emmanuel S. Antonarakis, email: [email protected]
Keywords: AR-V7; DNA repair; ipilimumab; nivolumab; prostate cancer
Received: April 19, 2018 Accepted: May 17, 2018 Published: June 19, 2018
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.
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