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.
Bibliographical noteFunding Information:
This research was sponsored by Bristol-Myers Squibb (Princeton, NJ) who also provided both study drugs free of cost. This research was also partially supported by National Institutes of Health grants P30 CA006973 (E.S.A) and R01 CA185297 (J.L. and E.S.A.), Department of Defense grants W81XWH-13-PCRP-CCA (M.A.C. and E.S.A) and W81XWH-15-2-0050 (J.L.), and the Bloomberg-Kimmel Institute for Cancer Immunotherapy (E.S.A.). Genomic studies were partially supported by National Institutes of Health grant R01 CA121113 (V.A. and V.E.V.), and the Commonwealth Foundation (V.E.V.).
©Boudadi et al.
- DNA repair
- Prostate cancer