PDF(Pubmed)
Abstract：
UNASSIGNED: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC).
UNASSIGNED: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity.
UNASSIGNED: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response.
UNASSIGNED: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
UNASSIGNED: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity.
UNASSIGNED: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response.
UNASSIGNED: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
摘要：
■接受雄激素剥夺治疗和雄激素受体（AR）信号抑制剂（ARSI）的大多数转移性前列腺癌患者进展。糖皮质激素受体（GR）的激活与ARSI抵抗有关。这项单臂I期试验评估了联合AR拮抗剂（恩杂鲁胺）和选择性GR调节剂（relacorilant）在转移性去势抵抗性前列腺癌（mCRPC）患者中的安全性和药代动力学（PK）可行性。
■这是一项I期试验（NCT03674814），在难治性mCRPC患者中使用6+3设计进行治疗。在≥6名患者的队列中，根据安全性和PK措施，恩杂鲁胺的剂量保持在120mg/d不变，并逐步增加相关剂量。主要目标是安全性和建立药理活性剂量。次要目标与抗肿瘤活性有关。
■纳入35例mCRPC患者。在剂量递增阶段，三个剂量队列中累积了23个，12人在推荐的II期剂量入组。该组合通常耐受性良好，安全,并获得了理想的恩杂鲁胺PK。RP2D为120+150毫克/天，分别,已建立。研究的中位时间为2.2个月，其中4名患者的研究时间超过11个月。12名可评估患者中有4名具有前列腺特异性抗原（PSA）部分反应。
■这是第一个结合AR拮抗剂和非甾体选择性GR调节剂的前瞻性试验。该组合是安全的，并且在有限的患者亚组中观察到PSA反应和延长的疾病控制。进一步的前瞻性试验是合理的，以评估疗效和确定反应的预测生物标志物。
■这是一项I期试验（NCT03674814），在难治性mCRPC患者中使用6+3设计进行治疗。在≥6名患者的队列中，根据安全性和PK措施，恩杂鲁胺的剂量保持在120mg/d不变，并逐步增加相关剂量。主要目标是安全性和建立药理活性剂量。次要目标与抗肿瘤活性有关。
■纳入35例mCRPC患者。在剂量递增阶段，三个剂量队列中累积了23个，12人在推荐的II期剂量入组。该组合通常耐受性良好，安全,并获得了理想的恩杂鲁胺PK。RP2D为120+150毫克/天，分别,已建立。研究的中位时间为2.2个月，其中4名患者的研究时间超过11个月。12名可评估患者中有4名具有前列腺特异性抗原（PSA）部分反应。
■这是第一个结合AR拮抗剂和非甾体选择性GR调节剂的前瞻性试验。该组合是安全的，并且在有限的患者亚组中观察到PSA反应和延长的疾病控制。进一步的前瞻性试验是合理的，以评估疗效和确定反应的预测生物标志物。
