Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Karim Boudadi , Daniel L. Suzman , Brandon Luber , Hao Wang , John Silberstein , Rana Sullivan , Donna Dowling , Rana Harb , Thomas Nirschl , Ryan Vance Dittamore , Michael Anthony Carducci , Mario A. Eisenberger , Michael Haffner , Alan Meeker , James R. Eshleman , Jun Luo , Charles G. Drake , Emmanuel S. Antonarakis
Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations (BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014
DRD+ Tumors (N=6) | DRD– Tumors (N=9) | HR (95%CI) | P | |
---|---|---|---|---|
PSA50 | 17% | 0% | 0.400 | |
ORR | 40% (2/5) | 0% (0/3) | 0.464 | |
Durable PFS | 50% | 0% | 0.044 | |
PSA-PFS (mo) | 4.9 (95%CI 3.0–4.9) | 2.1 (95%CI 1.7–2.3) | 0.14 (0.04–0.46) | 0.001 |
rPFS (mo) | 7.5 (95%CI 3.9–7.5) | 2.9 (95%CI 1.9–4.0) | 0.28 (0.09–0.86) | 0.027 |
OS (mo) | 9.5 (95%CI 8.2–NA) | 7.2 (95%CI 3.5–9.5) | 0.61 (0.15–2.44) | 0.421 |
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