1). Prostate cancer is commonly thought of as non-responsive to immunotherapy, other than to sipuleucel-T, and generally resistant to immune checkpoint blockade, and this manuscript has a potential epidemiologic association that may help explain this immune evasion.
2). This is the first adverse event to my knowledge that is reduced by hormonal therapy other than disease-related symptoms.
In Liu’s epidemiologic analysis of 17,168 patients with newly diagnosed prostate cancer in Taiwan, they compared the risks of autoimmune disease diagnoses between men who received ADT and those who did not receive ADT, propensity adjusted for potential confounders such as other comorbidities and age, duration of therapy, and competing risks. All forms of hormonal therapy were combined, and subset analyses by type of ADT or antiandrogen was not reported. In their analysis of 5590 cases and 5590 matched controls, 457 autoimmune conditions were diagnosed over 3.82 years, 2.8% in ADT users and 5.4% in non-ADT users. The incidence rate ratio differed between these two groups, particularly for psoriasis, uveitis, Graves’ disease, and possibly inflammatory bowel disease (Crohn’s). Overall the adjusted hazard ratio for autoimmune disease was 0.62 (95% confidence interval (CI) 0.51-0.75, p<0.001), and the risks of autoimmunity at 1, 2, and 3 years of follow up were significantly lower in ADT users. Men on ADT for more than a year had the lowest risk as compared to shorter durations (hazard ratio (HR) 0.61 vs 0.67). As a control, no differences in the risk of other common infections or other medically unrelated conditions were observed such as pneumonia, TB, anaphylaxis, or appendicitis. The authors speculate that castration may reduce chronic inflammation and the levels of certain cytokines/chemokines such as IL-1/6/17 implicated in prostate cancer pathogenesis and autoimmunity, or that ADT may reduce Th1 responses. ADT could potentially have an impact on thymus biology and peripheral T cell maturation and effector vs suppressor function. While the present work did not include correlative studies, this epidemiologic work, if confirmed in other populations, could support further research to understand how ADT itself impacts anti-tumor immunity and immune function in general. Certainly, such knowledge could help in designing improved immunotherapy approaches to men with metastatic prostate cancer, where the ADT itself may be impairing responsiveness.
Based on this study, further research is warranted both at the epidemiologic and population level and in translational studies to address these provocative questions. Perhaps anti-PD-1 based therapies should be used without ADT in the future as one example, or with bipolar androgen therapy where androgens are given in a rapid cycling manner and prolonged responses have been observed in men with metastatic castration-resistant prostate cancer1.
Written by: Andrew John Armstrong, MD, ScM, FACP, Professor of Medicine, Surgery, Pharmacology and Cancer Biology, Director of Research, the Duke Cancer Institute Center for Prostate and Urologic Cancers, Divisions of Medical Oncology and Urology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
1. Teply, Benjamin A., Hao Wang, Brandon Luber, Rana Sullivan, Irina Rifkind, Ashley Bruns, Avery Spitz et al. "Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study." The Lancet Oncology 19, no. 1 (2018): 76-86.
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