Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer

Zhou, Tie; Xu, Weidong; Zhang, Wei; Sun, Yongbing; Yan, Honghua; Gao, Xu; Wang, Fubo; Zhou, Qianxiang; Hou, Jingli; Ren, Shancheng; Yang, Qing; Yang, Bo; Xu, Chuanliang; Zhou, Qingqing; Wang, Meiyu; Chen, Chunyun; Sun, Yinghao

doi:10.1016/j.ejca.2020.04.013

Cited by 23 publications

(34 citation statements)

References 22 publications

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“…Proxalutamide has demonstrated to be an effective AR suppressor. In addition, Proxalutamide has been demonstrated to downregulate AR expression [10][11]. Finally, the suppression of membrane-attached ACE2 has been described as an additional pleiotropic mechanism of action of Proxalutamide for blocking SARS-CoV-2 cell entry.…”

Section: Discussionmentioning

confidence: 99%

“…Proxalutamide (GT0918) is a second-generation androgen receptor antagonist [10][11]. It has a dual mechanism of action in suppressing the AR.…”

Section: Introductionmentioning

confidence: 99%

“…It has a dual mechanism of action in suppressing the AR. In addition to direct AR antagonism, Proxalutamide has been shown to downregulate AR expression, a mechanism that is not present in bicalutamide or enzalutamide [11]. Because of the dual mechanism of action, it is expected to be a more effective and less toxic secondgeneration anti-androgen drug therapy.…”

Section: Introductionmentioning

confidence: 99%

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Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial

Cadegiani¹,

McCoy²,

Wambier³

et al. 2021

Cureus

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Background The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into type II pneumocytes is dependent on a modification of viral spike proteins by transmembrane protease serine 2 (TMPRSS2) expressed on the surface of human cells. TMPRSS2 is regulated by the androgen receptor, hence, SARS-CoV-2 infectivity is indirectly dependent on androgenic status and phenotype. Previously, we have reported that men affected by androgenetic alopecia (AGA) are overrepresented in severe coronavirus disease 2019 (COVID-19). Additionally, we have reported that men taking antiandrogenic drugs, e.g., 5-alpha-reductase inhibitors (5ARis), are less likely to have severe COVID-19. Here we aimed to test whether the androgen receptor antagonist, Proxalutamide, would be a beneficial treatment for subjects with SARS-CoV-2 infection. Methods Male and female subjects were recruited to a double-blinded, randomized, prospective, investigational study of Proxalutamide for the treatment of COVID-19. Mild to moderate, non-hospitalized subjects, who were confirmed positive for SARS-CoV-2, were treated with either Proxalutamide 200 mg/day or placebo. Endpoints for the study were remission time (days) and the percentage of subjects confirmed negative for SARS-CoV-2 on Day 7 after treatment. A negative SARS-CoV-2 test was defined by concentration-time (Ct)>40 determined by real-time reverse transcription-polymerase chain reaction (rtPCR). Results Two-hundred thirty-six (2360 subjects were included in the study (108 female, 128 male); 171 were randomized to the Proxalutamide arm and 65 were in the placebo group. On Day 7, SARS-CoV-2 became non-detectable with rtPCR (cT>40) in 82% of the subjects in the Proxalutamide group versus 31% in the placebo group (p < 0.001). The average clinical remission time for patients treated with Proxalutamide was 4.2 ±5.4 days versus 21.8 ±13.0 days in the placebo arm (p < 0.001). Conclusion Proxalutamide significantly accelerated viral clearance on Day 7 in mild to moderate COVID-19 patients versus placebo. Further, the time to clinical remission was significantly reduced in patients treated with Proxalutamide versus placebo.

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Section: Discussionmentioning

confidence: 99%

“…Proxalutamide (GT0918) is a second-generation androgen receptor antagonist [10][11]. It has a dual mechanism of action in suppressing the AR.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial

Cadegiani¹,

McCoy²,

Wambier³

et al. 2021

Cureus

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“…Proxalutamide has been evaluated for 28 days in Phase 1 safety studies for both men and women; furthermore, the pharmacokinetics clearance rate for proxalutamide is 22 hours. 20 As such, proxalutamide would be more suitable for application in men and women. We are currently completing a similar outpatient trial focused on female patients (NCT04853134).…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Proxalutamide (GT0918) Reduces the Rate of Hospitalization and Death in COVID-19 Male Patients: A Randomized Double-Blinded Placebo-Controlled Trial.

McCoy¹,

Goren²,

Cadegiani

et al. 2021

Preprint

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Background: Antiandrogens have demonstrated a protective effect for COVOD-19 patients in observational and interventional studies. The goal of this study was to determine if proxalutamide, an androgen receptor antagonist, could be an effective treatment for men with COVID-19 in an outpatient setting. Study design and methods: A randomized, double-blinded, placebo-controlled clinical trial was conducted at two outpatient centers (Brasilia, Brazil). Patients were recruited from October 21 to December 24, 2020 (ClinicalTrials.gov number, NCT04446429). Male patients with confirmed COVID-19 but not requiring hospitalization (COVID-19 8-point ordinal scale <3) were administered proxalutamide 200mg/day or placebo for up to 7 days. The primary endpoint was hospitalization rate at 30 days post-randomization.Results: A total of 268 men were randomized in a 1:1 ratio. 134 patients receiving proxalutamide and 134 receiving placebo were included in the intention-to-treat analysis. The 30-day hospitalization rate was 2.2% in men taking proxalutamide compared to 26% in placebo, P<0.001. The 30-day hospitalization risk ratio was 0.09; 95% confidence interval (CI) 0.03 to 0.27. Patients in the proxalutamide arm more frequently reported gastrointestinal adverse events, however, no patient discontinued treatment. In placebo group, 6 patients were lost to follow-up, and 2 patients died from acute respiratory distress syndrome.Conclusion: The hospitalization rate in proxalutamide treated men was reduced by 91% compared to usual care. Trial Registration: NCT04446429

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“…TRC-253 and GT0918 (proxalutamide) are nextgeneration ARSIs under development to overcome resistance mutations in the ligand-binding domain. 81 Galeterone (TOK-001) was found to competitively antagonize mutant and wild-type AR in addition to 17-alphahydroxylase inhibition and promotion of AR degradation. 82 Unfortunately, it failed to demonstrate efficacy in AR-V mCRPC during the ARMOR3-SV trial.…”

Section: Novel Pharmacologic Solutions To Enzalutamide Resistancementioning

confidence: 99%

A Clinical Evaluation of Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer: Guiding Principles for Treatment Selection and Perspectives on Research

Laccetti¹,

Morris²

2020

OTT

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Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer

Cited by 23 publications

References 22 publications

Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial

Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial

WITHDRAWN: Proxalutamide (GT0918) Reduces the Rate of Hospitalization and Death in COVID-19 Male Patients: A Randomized Double-Blinded Placebo-Controlled Trial.

A Clinical Evaluation of Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer: Guiding Principles for Treatment Selection and Perspectives on Research

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