Abstract 4901: Short-course enzalutamide reveals immune activating properties in patients with biochemically recurrent prostate cancer

Abstract

Abstract Background: Enazalutamide (enz) is an androgen receptor signaling molecule approved by the FDA for the treatment of patients with metastatic castration-resistant prostate cancer; however, trials are evaluating this agent in earlier stages of disease. Here, we have investigated the effect of enz on peripheral immunity in patients with biochemically recurrent prostate cancer enrolled in a clinical trial of enz with/without a therapeutic vaccine (NCT01875250). Methods: Patients from the arm receiving enz alone (160 mg daily for 84 days, without ADT) were assessed in this study. Peripheral blood mononuclear cells (PBMCs) collected from 12 patients pre and post enz (days 14, 28, 84, and 100) were analyzed by flow cytometry to identify 123 immune cell subsets, including 9 standard subsets (CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cell (MDSC)), and 114 subsets relating to maturation and function. PBMCs were also assessed for T-cell receptor excision circles (TREC) to identify recent thymic emigrants, and by microarray to determine changes in global gene expression. Results: Treatment with enz induced several notable alterations in peripheral immune cells, suggesting that it has potential immune activating properties. These changes occurred early following treatment, and included an increase of NK cells, decreased frequencies of MDSCs with a suppressive phenotype (e.g. PDL1+ MDSC, gMDSC, and CD16+ MDSC), and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enz increased TREC levels by >75% in 7 out of 12 patients compared to pre-therapy levels (p = 0.012); naïve CD4+ and CD8+ T-lymphocytes were also elevated by >25% in those patients demonstrating the greatest increase in TREC. Gene expression analysis of PBMCs corroborated these findings, showing that enz increased activation of interferon-gamma signaling and related immune activating pathways. Conclusions. These findings show that short-course enz has immune activating properties in cancer patients, and support the combination of enz with immunotherapy. Citation Format: Renee N. Donahue, Ravi A. Madan, Jacob Richards, Italia Grenga, Lauren M. Lepone, Christopher R. Heery, James L. Gulley, Jeffrey Schlom. Short-course enzalutamide reveals immune activating properties in patients with biochemically recurrent prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4901.