Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer

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.

Keywords: AR-V7; DNA repair; ipilimumab; nivolumab; prostate cancer.

Conflict of interest statement

CONFLICTS OF INTEREST E.S.A. is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, ESSA, AstraZeneca, Clovis and Merck; has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and is the co-inventor of a biomarker technology that has been licensed to Qiagen. S.A.T. has served as a consultant and received honoraria from Roche/ Ventana Medical Systems, Almac Diagnostics, Janssen, AbbVie and Astellas/Medivation; he is also a co-founder of, consultant for and Laboratory Director of Strata Oncology. Y.W., A.J., R.P.G. and R.D. are employees of Epic Sciences. V.E.V. is a founder of Personal Genome Diagnostics (PGDx), is a member of its Scientific Advisory Board and Board of Directors, and owns PGDx stock, which is subject to certain restrictions under university policy; he is also on the Scientific Advisory Board for Ignyta; the terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors disclose no relevant conflicts of interest.

Figures

Figure 1. PSA responses and radiographic responses according to DRD status

(A) Waterfall plot showing PSA responses according to DRD status. The two patients with PSA50 responses (#4 and #8) both had biallelic BRCA2 gene mutations. Patient #4 had a mixed soft-tissue response (some measurable lesions decreased while others increased) and achieved a durable PFS. Patient #8 did not have any measurable disease, but also achieved a durable PFS, and experienced complete resolution of malignant bone pain (pain score 7/10 decreased to 0/10 after 12 weeks of therapy); he is still alive after 17.5+ months of follow-up. (B) Waterfall plot showing objective RECIST responses according to DRD status. The two patients with soft-tissue responses (#6 and #14) had mutations in ATM and ERCC4, respectively. Patient #6 achieved a durable PFS, and is still alive after 17.9+ months of follow-up. (C) CT scan of radiographic response for patient #6 (with somatic ATM mutation) at baseline and after 24 weeks of treatment. The sum diameter of his target lesions decreased by 52% at the time of his best response. (D). CT scan of radiographic response for patient #14 (with somatic ERCC4 mutation) at baseline and after 9 weeks of treatment. The sum diameter of his target lesions decreased by 75% at the time of his best response.

Figure 2. Time-to-event outcomes, according to DRD status

(A) PSA-PFS, according to DRD status [HR 0.19, 95%CI 0.06–0.62, P=0.0003]. (B) PFS, according to DRD status [HR 0.31, 95%CI 0.10–0.92, P=0.014]. (C) OS, according to DRD status [HR 0.41, 95%CI 0.14–1.21, P=0.11].

Figure 3. Clinical outcomes, according to Shannon index (low vs. high)

(A) PSA responses, according to Shannon Index. (B) RECIST responses, according to Shannon index. (C) PSA-PFS, according to Shannon index [HR 0.67, 95%CI 0.23–1.99, P=0.44]. (D) PFS, according to Shannon index [HR 0.43, 95%CI 0.15–1.22, P=0.11]. (E) OS, according to Shannon index [HR 0.34, 95%CI 0.11–0.99, P=0.07].