A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone‐ and/or Enzalutamide‐Refractory Metastatic Castration‐Resistant Prostate Cancer

• Published in: The oncologist (Dayton, Ohio) Vol. 23; no. 6; pp. 656 - e64
• Main Authors: Wei, Xiao X., Siegel, Adam P., Aggarwal, Rahul, Lin, Amy M., Friedlander, Terence W., Fong, Lawrence, Kim, Won, Louttit, Mirela, Chang, Emily, Zhang, Li, Ryan, Charles J.
• Format: Journal Article
• Language: English
• Published: United States AlphaMed Press 01.06.2018
• Subjects: Aged; Androstenes - pharmacology; Androstenes - therapeutic use; Clinical Trial Results; Humans; Hydrazines - pharmacology; Hydrazines - therapeutic use; Male; Middle Aged; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Phenylthiohydantoin - therapeutic use; Prostatic Neoplasms, Castration-Resistant - drug therapy; Triazoles - pharmacology; Triazoles - therapeutic use
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2017-0624

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。