TY - JOUR
T1 - Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer
AU - Boudadi, Karim
AU - Suzman, Daniel L.
AU - Anagnostou, Valsamo
AU - Fu, Wei
AU - Luber, Brandon
AU - Wang, Hao
AU - Niknafs, Noushin
AU - White, James R.
AU - Silberstein, John L.
AU - Sullivan, Rana
AU - Dowling, Donna
AU - Harb, Rana
AU - Nirschl, Thomas R.
AU - Veeneman, Brendan A.
AU - Tomlins, Scott A.
AU - Wang, Yipeng
AU - Jendrisak, Adam
AU - Graf, Ryon P.
AU - Dittamore, Ryan
AU - Carducci, Michael A.
AU - Eisenberger, Mario A.
AU - Haffner, Michael C.
AU - Meeker, Alan K.
AU - Eshleman, James R.
AU - Luo, Jun
AU - Velculescu, Victor E.
AU - Drake, Charles G.
AU - Antonarakis, Emmanuel S.
N1 - Publisher Copyright:
©Boudadi et al.
PY - 2018/6/19
Y1 - 2018/6/19
N2 - 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.
AB - 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.
KW - AR-V7
KW - DNA repair
KW - Ipilimumab
KW - Nivolumab
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85048747017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048747017&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25564
DO - 10.18632/oncotarget.25564
M3 - Article
C2 - 29983880
AN - SCOPUS:85048747017
SN - 1949-2553
VL - 9
SP - 28561
EP - 28571
JO - Oncotarget
JF - Oncotarget
IS - 47
ER -