Association of circulating immune and metabolic markers with clinical outcomes in the ENZAMET trial (ANZUP 1304).

Abstract

5093 Background: ENZAMET showed that enzalutamide (ENZ) significantly improves overall survival (OS) of metastatic hormone-sensitive prostate cancer (mHSPC) compared to conventional non-steroidal anti-androgen (NSAA). However, intrinsic and acquired resistance to ENZ are ongoing problems. In the CHAARTED mHSPC cohort, elevated circulating IL8 and IGFBP1, and a low IGF1:IGFBP1 ratio, were associated with shorter OS and shorter time to castration-resistance. The aim of this study was to confirm the prognostic association of IL8, IGFBP1, and IGF1:IGFBP1 in mHSPC, and also explore the relationship of a set of immune markers with ENZ treatment by post-hoc analysis of ENZAMET. Methods: Baseline plasma levels of IL8, IGF1, IGFBP1, C-reactive protein (CRP), and 14 other cytokines were profiled in 852 participants of ENZAMET (ENZ n=420; NSAA n=432) using Milliplex antibody assays (Merck). The association of these markers with OS and clinical progression-free survival (cPFS) was assessed by Cox regression. Results: In the whole study cohort, we confirmed that high IGFBP1 and IL8, and low IGF1:IGFBP1 were significantly associated with shorter OS and shorter cPFS (p≤0.029). High CRP, CXCL16, IL6, MIC1 and YKL40, and low IL28A were also associated with shorter OS (p≤0.015). These markers were independently associated with OS in multivariable analysis with treatment arm, volume of disease, concurrent docetaxel, and presence of visceral metastases (p≤0.047, Table). None of these markers were predictive of ENZ response. In subgroup analyses by treatment arm, IGFBP1 and IGF1:IGFBP1 were prognostic in the ENZ arm (OS p≤0.042, cPFS p≤0.02) but not in NSAA (OS p=0.08, cPFS p≥0.2). IL8 was prognostic in the NSAA arm (OS p=0.02, cPFS p=0.006) but not in ENZ (OS p=0.5, cPFS p=0.5). MIC1 was the only marker that was prognostic in both treatment arms (OS & cPFS p≤0.002). Conclusions: These data validate IL8, IGFBP1, and IGF1:IGFBP1 as prognostic biomarkers in mHSPC. Furthermore, pro-inflammatory and macrophage-associated cytokines are associated with poorer clinical outcomes. Clinical trial information: NCT02446405 . Hazard ratio (HR) for OS from univariable analyses and multivariable analyses with clinical variables. Variable (log2) HR (95% CI) from univariable analysis P-value HR (95% CI) from multivariable analysis with clinical variables P-value IL8 1.10 (1.01-1.19) 0.029 1.09 (1.00-1.18) 0.047 IGFBP1 1.12 (1.04-1.21) 0.004 1.10 (1.02-1.18) 0.018 IGF1/IGFBP1 0.94 (0.90-0.98) 0.008 0.94 (0.90-0.98) 0.004 CXCL16 1.43 (1.10-1.84) 0.007 1.31 (1.04-1.65) 0.020 CRP 1.10 (1.05-1.16) <0.001 1.08 (1.03-1.14) 0.002 IL6 1.13 (1.07-1.20) <0.001 1.10 (1.04-1.17) 0.001 MIC1 1.39 (1.23-1.58) <0.001 1.23 (1.08-1.40) 0.002 YKL40 1.19 (1.08-1.32) <0.001 1.17 (1.06-1.29) 0.001 IL28A 0.93 (0.88-0.99) 0.015 0.91 (0.86-0.97) 0.002