A phase 2 clinical trial investigating the use of antiandrogen therapy in the treatment of hospitalized patients infected with SARS-CoV-2 will soon be launched, according to a presentation made at the American Association of Cancer Research (AACR) Virtual Meeting: COVID-19 and Cancer.1

In setting the stage for a description of the clinical trial, the presenting author, Catherine Marshall, MD, MPH, an assistant professor in the department of oncology at the Johns Hopkins University School of Medicine, provided a detailed overview of the research findings underlying its design.

Previous studies have shown that the morbidity and mortality of COVID-19 infection is higher in men compared with women. It is known that host cell-derived viral priming by the TMPRSS2 serine protease and subsequent viral binding to the ACE2 receptor on the host cell membrane are required for SARS-CoV-2 entry into the host cell. Furthermore, there is some evidence that these 2 pathways differ in men and women.

While the highest levels of TMPRSS2 expression are in the prostate, where its expression is induced by androgens, this protein is also expressed in many other organs including the stomach, pancreas, lung, and small intestine. Limited findings from preclinical studies are mixed with respect to whether TMPRSS2 expression in the lung differs by sex, and whether TMPRSS2 expression in the lung can be decreased with antiandrogen therapy.


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However, results from a recently conducted retrospective study of men with prostate cancer treated with androgen deprivation therapy versus not suggested that this type of treatment approach was associated with lower levels of infection with SARS-CoV-2, as well as fewer serious clinical sequelae in those infected with the virus.2

The ACE2 receptor is also found in multiple organs, including the lungs and pulmonary vasculature. Although it is not yet known whether the level of expression of this protein differs in men compared with women, the gene is located on the X chromosome and there is limited evidence that beta-estradiol can increased ACE2 receptor expression in bronchial epithelial cells. 

Based on these findings, a randomized clinical trial (RECOVER; ClinicalTrial.gov Identifier: NCT04374279) was designed to test the hypothesis that use of endocrine therapy is associated with improved clinical outcomes in patients with COVID-19, Dr Marshall explained.  

The study design involves enrollment of 60 adult men and women to be randomly assigned in a 1:1 ratio to receive once-daily bicalutamide, an oral, nonsteroidal antiandrogen, at a dose of 150 mg for 7 days in combination with standard-of-care therapy or standard-of-care therapy only. Patients will be stratified according to sex and type of standard-of-care therapy received, and followed for up to 60 days.

The primary study endpoint is clinical improvement at day 7 according to the World Health Organization (WHO) scale, with secondary study endpoints including all-cause mortality at 28 days, safety, changes in hormone levels, and other parameters assessing clinical status, as well viral status and inflammatory response.   

Rationales for selecting bicalutamide as the study drug included evidence that it downregulates TMPRSS2 expression in prostate cancer cells, as well as its association with increased levels of estradiol, low cost, and its manageable toxicity.

Patient inclusion criteria for this study include COVID-19 infection confirmed within 3 days of study enrollment, inpatient status, and minimal respiratory symptoms. Patients currently receiving any type of systemic hormonal therapy will be excluded from study enrollment.

Enrollment in the RECOVER trial is expected to begin in July 2020, although it had not yet been initiated at the time of this presentation.

References

  1. Marshall C; RECOVER trial team. Trial to promote recovery from COVID-19 using endocrine therapy.  Presented at: American Association for Cancer Research (AACR) Virtual Meeting: COVID-19 and Cancer. July 20-22, 2020.
  2. Montopoli M, Zumerle S, Vettor R, et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532) [published online May 6, 2020]. Ann Oncol. doi: 10.1016/j.annonc.2020.04.479