Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2024 Mar 15;30(6):1111-1120. doi: 10.1158/1078-0432.CCR-23-3508.
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.
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).
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.
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.
糖皮质激素受体 (GR) 信号的增加被认为是转移性去势抵抗性前列腺癌 (mCRPC) 中对雄激素受体 (AR) 抑制产生耐药性的一种代偿机制。ORIC-101 是一种强效和选择性的口服生物可利用的 GR 拮抗剂。
在进展性 enzalutamide 治疗的 mCRPC 患者中，研究了 ORIC-101 与 enzalutamide 联合治疗的安全性、药代动力学/药效学和抗肿瘤活性。测试了 80 至 240 毫克每日一次的 ORIC-101 剂量与每日一次 160 毫克 enzalutamide 联合用药。单次剂量和稳态时评估药代动力学/药效学。在推荐的 2 期剂量 (RP2D) 时评估 12 周时的疾病控制率 (DCR)。
共纳入 41 例患者。没有剂量限制毒性，选择 RP2D 为 240 毫克 ORIC-101 和每日 160 毫克 enzalutamide。在 RP2D 时，最常见的治疗相关不良事件是疲劳 (38.7%)、恶心 (29.0%)、食欲下降 (19.4%)和便秘 (12.9%)。药代动力学/药效学数据证实 ORIC-101 达到了 GR 靶标结合所需的暴露量。总体而言，在 RP2D 治疗的 31 例患者中，根据 DCR 评估临床获益不足 (25.8%；95%置信区间：15.65-38.52)，未达到预设目标率，导致研究终止。基于基线 GR 表达、AR 耐药变异的存在以及侵袭性变异前列腺癌的分子特征的探索性亚组分析表明，高 GR 表达且无其他耐药标志物的患者可能受益，尽管这需要进一步证实。
尽管 ORIC-101 与 enzalutamide 联合治疗具有可接受的耐受性，但 ORIC-101 对 GR 靶标抑制并未在对 enzalutamide 耐药的转移性前列腺癌男性中产生临床获益。
