Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer
2018
// Karim Boudadi 1 , Daniel L. Suzman 4 , Valsamo Anagnostou 1 , Wei Fu 1 , Brandon Luber 1 , Hao Wang 1 , Noushin Niknafs 1 , James R. White 1 , John L. Silberstein 3 , Rana Sullivan 1 , Donna Dowling 1 , Rana Harb 1 , Thomas R. Nirschl 1 , Brendan A. Veeneman 5, 9 , Scott A. Tomlins 5, 6 , Yipeng Wang 7 , Adam Jendrisak 7 , Ryon P. Graf 7 , Ryan Dittamore 7 , Michael A. Carducci 1 , Mario A. Eisenberger 1 , Michael C. Haffner 2 , Alan K. Meeker 2 , James R. Eshleman 2 , Jun Luo 3 , Victor E. Velculescu 1 , Charles G. Drake 8 and Emmanuel S. Antonarakis 1, 3 1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA 5 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 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 Hematology/Oncology, Columbia University Medical Center, New York, NY, USA 9 Present 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.
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