PDF(Pubmed)
Abstract：
UNASSIGNED: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.
UNASSIGNED: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).
UNASSIGNED: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.
UNASSIGNED: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
UNASSIGNED: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).
UNASSIGNED: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.
UNASSIGNED: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
摘要：
背景：增加的GR信号传导是mCRPC中对AR抑制的抗性的补偿机制。ORIC-101是一种有效的和选择性的口服生物可利用的GR拮抗剂。
方法：安全，PK/PD,并研究了ORIC-101联合恩杂鲁胺在mCRPC进展的患者中的抗肿瘤活性。与恩杂鲁胺160mgQD组合测试80至240mgQD的ORIC-101剂量。在单剂量和稳态后评估PK/PD。在RP2D评估12周时的疾病控制率(DCR)。
结果：共纳入41例患者。没有剂量限制性毒性，RP2D选择为每天240mgORIC-101和160mg恩杂鲁胺。在RP2D，最常见的治疗相关AE是疲劳（38.7%），恶心（29.0%），食欲下降（19.4%），便秘（12.9%）。PK/PD数据证实ORIC‑101实现了GR目标参与所需的暴露。总的来说,在RP2D治疗的31名患者，基于DCR的临床获益不足(25.8%；80%CI：15.65%，38.52%)，未达到预定目标率，导致研究终止。基于基线GR表达的探索性亚组分析，存在AR抗性变体，和侵袭性变异PC的分子特征表明，在GR高表达且没有其他抗性标志物的患者中可能有益，虽然这需要确认。
结论：尽管ORIC-101和恩杂鲁胺的组合显示出可接受的耐受性，用ORIC-101抑制GR靶在患有对恩杂鲁胺耐药的转移性前列腺癌的男性中没有产生临床益处。
方法：安全，PK/PD,并研究了ORIC-101联合恩杂鲁胺在mCRPC进展的患者中的抗肿瘤活性。与恩杂鲁胺160mgQD组合测试80至240mgQD的ORIC-101剂量。在单剂量和稳态后评估PK/PD。在RP2D评估12周时的疾病控制率(DCR)。
结果：共纳入41例患者。没有剂量限制性毒性，RP2D选择为每天240mgORIC-101和160mg恩杂鲁胺。在RP2D，最常见的治疗相关AE是疲劳（38.7%），恶心（29.0%），食欲下降（19.4%），便秘（12.9%）。PK/PD数据证实ORIC‑101实现了GR目标参与所需的暴露。总的来说,在RP2D治疗的31名患者，基于DCR的临床获益不足(25.8%；80%CI：15.65%，38.52%)，未达到预定目标率，导致研究终止。基于基线GR表达的探索性亚组分析，存在AR抗性变体，和侵袭性变异PC的分子特征表明，在GR高表达且没有其他抗性标志物的患者中可能有益，虽然这需要确认。
结论：尽管ORIC-101和恩杂鲁胺的组合显示出可接受的耐受性，用ORIC-101抑制GR靶在患有对恩杂鲁胺耐药的转移性前列腺癌的男性中没有产生临床益处。
