Abstract IA09: A phase II trial to promote recovery from COVID-19 with endocrine therapy
Authors: Marshall Catherine H. , Yegnasubramanian Srinivasan , Wang Hao , Durham Jennifer , Wang Ting , Damico Rachel , D'Alessio Franco R. , Sidhaye Venkataramana K. , Pekosz Andrew , Mankowski Joseph L. , Klein Sabra L. , Murli Sumati , Jaffee Elizabeth M. , Denmeade Samuel R. 
Published: December 2020

Abstract
Background: Death from COVID-19 disproportionately affects men, with up to 80% of deaths in severe COVID-19 cases being in men. There are a number of potential differences that might contribute to these sex differences. TMPRSS2 is a serine protease that primes the spike protein of SARS-CoV-2, a critical step in viral entry. TMPRSS2 is most highly expressed in the prostate where it is under androgen control, upregulated by testosterone and downregulated by antiandrogens. ACE2, the receptor used for entry into the host cell, is located on the X chromosome and may also have levels that are altered by hormones, with estradiol downregulating its expression. Previous research on acute lung injury demonstrated that estradiol seems to have beneficial effects on repair of lung injury. Therefore, our central hypothesis is that hormones may partially contribute to the gender disparity seen in COVID-19 patients, with high levels of testosterone being harmful and high levels of estrogen being helpful. Bicalutamide is a nonsteroidal antiandrogen that inhibits the action of androgens and, via feedback on the hypothalamic-pituitary axis, upregulates estradiol. We are conducting a phase II clinical trial to determine if bicalutamide improves the percentage of COVID+ patients with clinical improvement by 7 days.
Methods: We will enroll 40 patients who are hospitalized for COVID-19 with minimal respiratory symptoms (respiratory rate &lt;30 and &lt; 6L oxygen by nasal canula). Patients with more severe symptoms or oxygen requirements, who have taken hormones within the past month, or have pre-existing liver or cardiac disease will be excluded. Patients will be randomized 1:1 (20 in each arm) to bicalutamide or standard of care and will be stratified by gender. The primary outcome is comparing the percentage of patients with clinical improvement at day 7, compared to historical controls based on the World Health Organization categorical scale of clinical improvement. Key secondary clinical endpoints include all-cause mortality at 28 and 60 days, need for mechanical ventilation or ICU care, and safety of bicalutamide in this population. We will also determine the impact of bicalutamide therapy on viral infectivity by studying the reduction in viral load, hormone modulation and engagement of the endocrine axis, and immune response modulation promoting pro-repair immune function in patients with COVID-19. Clinical trial registration number: NCT04374279.
Citation Format: Catherine H. Marshall, Srinivasan Yegnasubramanian, Hao Wang, Jennifer Durham, Ting Wang, Rachel Damico, Franco R. D'Alessio, Venkataramana K. Sidhaye, Andrew Pekosz, Joseph L. Mankowski, Sabra L. Klein, Sumati Murli, Elizabeth M. Jaffee, Samuel R. Denmeade. A phase II trial to promote recovery from COVID-19 with endocrine therapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr IA09.