ABSTRACT
BACKGROUND: Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. METHODS: This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3-5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. DISCUSSION: In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04397718. Registered on May 21, 2020.
Subject(s)
COVID-19 , Veterans , Clinical Trials, Phase II as Topic , Hospitalization , Humans , Male , Multicenter Studies as Topic , Oligopeptides , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment OutcomeABSTRACT
BACKGROUND: The promise of precision oncology only can be realized when genetic alterations are identified that can be lever-aged to improve response and minimize toxicity. Identifying those alterations as efficiently as possible and then giving patients access to targeted therapy and clinical study requires a comprehensive strategy across health care systems. OBSERVATIONS: The US Department of Veterans Affairs (VA) and Prostate Cancer Foundation have established a network of VA centers to help develop best practices for precision oncology for the treatment of veterans with advanced prostate cancer. This article describes the genesis and structure of this network and its potential for contributing to care and research in the VA and the health care system as a whole. CONCLUSIONS: The Precision Oncology Program for Cancer of the Prostate network and its partnership with VA clinical and research efforts is anticipated to provide important insights into barriers and solutions to the implementation of precision oncology for prostate cancer across the VA.
ABSTRACT
OBJECTIVES: The advent of germline testing as a standard-of-care practice for certain tumor types and patients presents unique opportunities and challenges for the field of precision oncology. This article describes strategies to address workforce capacity, organizational structure, and genetics education needs within the US Department of Veterans Affairs (VA) with the expectation that these approaches may be applicable to other health care systems. OBSERVATIONS: Germline information can have health, reproductive, and psychosocial implications for veterans and their family members, which can pose challenges when delivering germline information in the setting of cancer care. Additional challenges include the complexity inherent in the interpretation of germline information, the national shortage of genetics professionals, limited awareness and knowledge about genetic principles among many clinicians, and organizational barriers, such as the inability to order genetic tests and receive results in the electronic health record. These challenges demand thoughtful implementation planning at the health care system level to develop sustainable strategies for the delivery of high-quality genetic services in precision oncology practice. CONCLUSIONS: The VA is uniquely positioned to address the integration of germline genetic testing into precision oncology practice due to its outsized role in treating veterans with cancer, training the health care workforce, and developing, testing, and implementing innovative models of clinical care.
