Lessons learned: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space.
Background: Selinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO-1), leading to nuclear accumulation of tumor suppressor proteins.
Methods: This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide.
Results: Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had ≥50% prostate-specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3-4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability.
Conclusion: Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents.
经验总结
在阿比特龙和/或恩杂鲁胺难治性转移性去势抵抗性前列腺癌（mCRPC）患者中, Selinexor使一个受试者子集中出现前列腺特异性抗原和/或影像学缓解, 表明在此适应症中具有临床活性。
尽管每周给药两次且进行了最大限度的症状管理, 但是在二代抗雄激素治疗难治性mCRPC患者中Selinexor仍导致明显的厌食、恶心和疲乏, 从而限制了在此患者人群中的进一步临床开发。
本研究强调了为阿比特龙治疗后和/或恩杂鲁胺治疗后mCRPC的II期研究选择主要终点这一挑战。
摘要
背景.Selinexor是一种首创的细胞核输出复合物选择性抑制剂, 对核输出蛋白（XPO‐1）具有特异性抑制作用, 导致肿瘤抑制蛋白在细胞核中累积。
方法.本项II期研究评价了Selinexor在阿比特龙和/或恩杂鲁胺难治性转移性前列腺癌（mCRPC）患者中的疗效和耐受性。
结果.入组了14例患者。最初Selinexor以65 mg/m2剂量每周两次给药（第1和3天）, 随后剂量减至60 mg固定剂量每周两次（第1和3天）, 3周给药, 1周停药, 以改善耐受性。中位治疗持续时间为13周。在中位数为4个月的随访中, 两例患者（14%）的前列腺特异性抗原（PSA）降幅≥50%, 七例患者（50%）发生了任何PSA降低。在基线时病灶可测量的八例患者中, 两例（25%）和四例患者（50%）的最佳影像学缓解分别为部分缓解和疾病稳定。五例患者（36%）出现严重不良事件（SAE；均与Selinexor无关）, 五例患者（36%）出现治疗相关性3–4级不良事件（AE）。最常见的任何严重程度的药物相关性AE为厌食、恶心、体重减轻、疲乏和血小板减少症。三例患者（21%）因不可接受的耐受性退出研究。
结论.在二线抗雄激素药物难治性mCRPC患者中, Selinexor显示出临床活性但耐受性不佳。
Trial registration: ClinicalTrials.gov NCT02215161.
©AlphaMed Press; the data published online to support this summary is the property of the authors.