A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data

Abstract

Background Men are more severely affected by COVID-19. Testosterone may influence SARS-CoV-2 infection and the immune response. Objective To clinically, epidemiologically, and experimentally evaluate the effect of antiandrogens on SARS-CoV-2 infection. Designs, settings, and participants A randomized phase 2 clinical trial (COVIDENZA) enrolled 42 hospitalized COVID-19 patients before safety evaluation. We also conducted a population-based retrospective study of 7894 SARS-CoV-2–positive prostate cancer patients and an experimental study using an air-liquid interface three-dimensional culture model of primary lung cells. Intervention In COVIDENZA, patients were randomized 2:1 to 5 d of enzalutamide or standard of care. Outcome measurements The primary outcomes in COVIDENZA were the time to mechanical ventilation or discharge from hospital. The population-based study investigated risk of hospitalization, intensive care, and death from COVID-19 after androgen inhibition. Results and limitations Enzalutamide-treated patients required longer hospitalization (hazard ratio [HR] for discharge from hospital 0.43, 95% confidence interval [CI] 0.20–0.93) and the trial was terminated early. In the epidemiological study, no preventive effects were observed. The frail population of patients treated with androgen deprivation therapy (ADT) in combination with abiraterone acetate or enzalutamide had a higher risk of dying from COVID-19 (HR 2.51, 95% CI 1.52–4.16). In vitro data showed no effect of 4 d of enzalutamide on virus replication ( p = 0.084). The epidemiological study has limitations that include residual confounders. Conclusions The results do not support a therapeutic effect of enzalutamide or preventive effects of bicalutamide or ADT in COVID-19. Thus, these antiandrogens should not be used for hospitalized COVID-19 patients or as prevention for COVID-19. Further research on these therapeutics in this setting are not warranted. Patient summary We studied whether inhibition of testosterone could diminish COVID-19 symptoms. We found no evidence of an effect in a clinical study or in epidemiological or experimental investigations. We conclude that androgen inhibition should not be used for prevention or treatment of COVID-19.

Impact of the COVID-19 outbreak on prostate cancer care in the Netherlands

“… [25] Although it has been suggested that ADT decreases the risk of COVID-19 infection in patients with prostate cancer, [26] this was not supported by a recent meta-analysis and phase 2 trial. [ 27 , 28 ]…”

The COVID-19 pandemic — what have urologists learned?

“…Low total testosterone levels in men have been associated with hyper-inflammatory syndrome and respiratory failure 116 , and total testosterone levels are inversely associated with increased risk of ICU admission or death 92 ; thus, the (most probably transitory) hypogonadism caused by SARS-CoV-2 infection was suggested to promote severe outcomes 92 . In the COVIDENZA trial, including men and women >50 years old, the effect of the inhibition of testosterone signalling through enzalutamide on the outcome of hospitalized patients with COVID-19 was evaluated 117 . Overall, 42 patients were enrolled and randomized 2:1 to receive 5 days of treatment with enzalutamide or standard of care 117 .…”

“…In the COVIDENZA trial, including men and women >50 years old, the effect of the inhibition of testosterone signalling through enzalutamide on the outcome of hospitalized patients with COVID-19 was evaluated 117 . Overall, 42 patients were enrolled and randomized 2:1 to receive 5 days of treatment with enzalutamide or standard of care 117 . Patients treated with enzalutamide required longer hospitalization (hazard ratio for discharge from hospital: 0.43, 95% CI 0.20–0.93) than patients treated with the standard of care 117 .…”

“…Overall, 42 patients were enrolled and randomized 2:1 to receive 5 days of treatment with enzalutamide or standard of care 117 . Patients treated with enzalutamide required longer hospitalization (hazard ratio for discharge from hospital: 0.43, 95% CI 0.20–0.93) than patients treated with the standard of care 117 . The trial was terminated early and the authors concluded that androgen inhibition should not be used for prevention or treatment of COVID-19 (ref.…”

“…The trial was terminated early and the authors concluded that androgen inhibition should not be used for prevention or treatment of COVID-19 (ref. 117 ).…”