Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer. (July 2020)

• Record Type: Journal Article
• Authors: Zhou, Tie; Xu, Weidong; Zhang, Wei; Sun, Ye; Yan, Honghua; Gao, Xu; Wang, Fubo; Zhou, Qianxiang; Hou, Jianguo; Ren, Shancheng; Yang, Qing; Yang, Bo; Xu, Chuanliang; Zhou, Qingqing; Wang, Meiyu; Chen, Chunyun; Sun, Yinghao
• Is Part Of: European journal of cancer. Volume 134(2020)
• Page Start: 29
• Page End: 40
• Publication Date: 2020-07
• Subjects: Castration-resistant prostate cancer -- Androgen receptor antagonist -- GT0918 -- Phase I; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.04.013
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Purpose: We conducted preclinical experiments and phase I clinical trial to investigate the safety, pharmacokinetics (PK) and antitumour effects of GT0918 in castration-resistant prostate cancer (CRPC). Experimental design: An androgen receptor (AR) competitive binding assay was performed, followed by evaluation of GT0918 on AR protein expression. The efficacy of GT0918 was investigated in a castration-resistant xenograft model. A phase I dose-escalation study of GT0918 in CRPC was also carried out to evaluate its safety, PK and antitumour efficacy. Results: GT0918 was demonstrated to inhibit the binding of androgen to AR more potently than MDV3100, and to effectively reduce the AR protein level. GT0918 inhibited the transcriptional activity of wild-type AR and AR with clinically relevant ligand-binding domain mutations. Furthermore, GT0918 significantly inhibited the growth of prostate cancer. A total of 16 patients was treated with GT0918 at five dose levels. Among these 16 patients, 10 and 2 patients, respectively, completed a three-cycle and six-cycle treatment, in which MTD was not reached. All the treatment-related adverse events were grade I, including hypercholesterolemia, hypertriglyceridemia, fatigue and anaemia. PK parameters showed that drug exposure increased with dose proportionally from 50 to 300 mg and a saturation was observed between 300 and 400 mg. PSA declines of ≥30% and ≥50% were, respectively, observed in six and two cases. All the 12 patients with metastatic soft tissue lesions confirmed stable disease. Conclusions: GT0918, a full AR antagonist without agonist effect, has high binding affinity to AR with AR protein down-regulation activity. GT0918 is demonstrated to be well tolerated with a favourable PK profile and exhibits promising antitumour activity in CRPC. Clinicaltrials: gov identifier CTR20150501. Highlights: GT0918 has high binding affinity to androgen receptor. GT0918 reduces the androgen receptor protein level effectively. GT0918 inhibits transcriptional activity of androgen receptor with mutations. GT0918 is well tolerated with a favourable pharmacokinetics profile. GT0918 has promising antitumour activity in castration-resistant prostate cancer.