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.
Highlights
Androgen-receptor splice variant 7 (AR-V7) is a constitutively-active isoform of the androgen receptor that is associated with a aggressive form of advanced prostate cancer [1]
Prostate cancer expressing AR-V7 represents a lethal phenotype with inadequate treatment options
Sufficient clinical activity was not observed in the overall study population, encouraging clinical activity using combined immune-checkpoint blockade was seen in the subset of patients harboring germline and/or somatic mutations in DNA-repair genes
Summary
Androgen-receptor splice variant 7 (AR-V7) is a constitutively-active isoform of the androgen receptor that is associated with a aggressive form of advanced prostate cancer [1]. Prostate cancers expressing AR-V7 often show poor responses to taxane chemotherapies including docetaxel and cabazitaxel [4, 5]. To this end, patients with AR-V7-positive prostate cancer generally have a median progression-free survival (PFS) of only 3-4 months and a median overall survival (OS) of 7-9 months. While prostate cancer is generally regarded as a low–mutation-burden tumor [11] and immune-checkpoint blockade has resulted in only modest benefits as a monotherapy [12, 13], recent data have suggested that ARV7-expressing prostate cancers may be associated with a greater number of DNA-repair gene mutations and a higher mutation load [14]
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