Impact of Baseline Serum IL-8 on Metastatic Hormone-Sensitive Prostate Cancer Outcomes in the Phase 3 CHAARTED Trial (E3805) - Beyond the Abstract

In recent years, large randomized Phase III clinical trials have demonstrated significant prolongation in overall survival (OS) of men with metastatic hormone-sensitive prostate cancer (mHSPC) by combining agents to the long-held standard of androgen deprivation therapy (ADT). Despite these advances, mHSPC remains a lethal disease with a typical life expectancy of fewer than five years. Additionally, while there are clinical factors that are clearly associated with prognosis such as the presence of high-volume metastatic disease, there remain no validated prognostic and predictive biological biomarkers in this disease space.

The ECOG-ACRIN 3805 CHAARTED trial, initially reported in 2014, transformed the standard of care for men with mHSPC. This Phase III trial randomized patients with newly-diagnosed mHSPC to ADT versus the addition of six cycles of docetaxel chemotherapy. The study met its primary endpoint by demonstrating a significant improvement in OS at initial and long-term follow-up. As a secondary endpoint, chemohormonal therapy also significantly delayed the emergence of castration-resistant prostate cancer (CRPC). What is clear from CHAARTED and other trials of mHSPC is that patient outcomes can vary considerably based on clinical factors. In the ADT arm, median OS ranged from 34 to 60 months depending on the presence of high volume disease and presentation with de novo metastatic disease. Interest in elucidating the intrinsic drivers of aggressive disease has spurred significant activity among the prostate cancer scientific world particularly in understanding the factors that determine early castration resistance, therapy failure, or poorer survival. This work has led to the emergence of putative biomarkers – for example, AR alterations and resistance to AR-targeted therapy; RB1 loss and shorter survival in metastatic CRPC— as well an evolving understanding of the role of chronic inflammation.

Much interest has been directed to understanding the role of inflammation and the immune response in advanced prostate cancer. Mounting evidence suggests that inflammation may mediate the progression of prostate cancer, castration resistance as well as resistance to newer hormonal therapies. Of particular interest is the pro-inflammatory cytokine IL-8, which is produced by a number of cell types including tumor cells. Regulation of IL-8 is complex with various factors, both intrinsic and external, influencing secretion. Furthermore, IL-8 has multiple functions beyond modulating inflammation and is frequently implicated in cancer-promoting effects such as angiogenesis and enhanced metastatic potential across cancer. In prostate cancer, prior studies (pre-clinical and clinical) have demonstrated increased levels of IL-8 in advanced and castration-resistant disease. On this basis, our group previously investigated the role of IL-8 as a potential serum biomarker in 122 men with mHSPC using institutional biorepositories which served as our discovery set. In multivariable analyses adjusting for age, patient performance status, prostate-specific antigen (PSA) level and extent of metastases, patients with higher serum IL-8 levels experienced significantly shorter OS and showed a trend to earlier time to CRPC. To validate the prognostic role of IL-8 in mHSPC, we leveraged the CHAARTED database as our validation cohort, and serum samples taken ≤28 days from therapy initiation were available from 233 patients.

The median IL-8 level in the CHAARTED cohort was 10pg/ml. Tested as continuous and binary (high vs low) variable, IL-8 was prognostic for OS, and this effect was independent of receipt of docetaxel, disease volume, and metachronous vs. de novo metastatic presentation. It is important to note that a binary cut-off of 9.3pg/ml was chosen as the binary threshold based on the median level of IL-8 determined in the discovery dataset. In the overall cohort, for OS, the adjusted hazard ratios were 1.7 and 2.2 for binary and continuous IL-8, respectively. A similar prognostic effect was seen with time to CRPC. Elevated IL-8, continuous or binary, was associated with significantly shorter time to CRPC in multivariable analyses. In a fixed-effects meta-analysis of IL-8 as a binary variable in the discovery and ADT monotherapy CHAARTED cohorts, there was a clear association with worse OS: hazard ratio (HR) 1.7, 95% confidence interval (CI) 1.2-2.7, p = 0.007.

This study adds to accumulating evidence of the deleterious role of IL-8 in prostate cancer, previously shown to drive both an androgen-independent phenotype and resistance to docetaxel. The prognostic impact of high IL-8 naturally raises the idea of therapeutic targeting in metastatic prostate cancer. There are several IL-8-targeting therapies in development as monotherapy and in combination with immune checkpoint (PD-1) blockade. Other therapeutics including anti-IL8 antibodies as well as NF-kB inhibitors are also in development given their potential to decrease IL-8 and other pro-inflammatory factors thought to drive tumor proliferation and therapy resistance. As a biomarker, serum IL-8 shows promise in defining a patient subgroup at-risk for poorer outcomes and who may benefit from these targeted strategies. In parallel to therapy development, our team intends to further validate these findings in independent trial cohorts of mHSPC.

Written by: Anis Hamid, MD, Research Fellow, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts; Christopher Sweeney, MBBS, Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts; Lauren Harshman, MD, Medical Director, Surface Oncology, Cambridge, Massachusetts.
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