Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA
Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California, USA.
Oncologist. 2018 Jun;23(6):656-e64. doi: 10.1634/theoncologist.2017-0624. Epub 2018 Feb 27.
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.
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.
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.
Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m 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.
Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents.
在阿比特龙和/或恩扎卢胺难治的转移性去势抵抗性前列腺癌（mCRPC）患者中，塞来昔布在一部分患者中导致前列腺特异性抗原和/或影像学反应，表明该适应证中有临床活性。尽管每周两次给药和最大程度的症状管理，塞来昔布与第二代抗雄激素治疗难治的 mCRPC 患者的严重厌食、恶心和疲劳相关，限制了该患者人群中进一步的临床开发。这项研究强调了在阿比特龙和/或恩扎卢胺后 mCRPC 领域的 II 期研究中选择主要终点的挑战。
塞来昔布是一种首创的核输出化合物选择性抑制剂，可特异性抑制核输出蛋白 Exportin-1（XPO-1），导致肿瘤抑制蛋白在核内积累。
这项 II 期研究评估了塞来昔布在阿比特龙和/或恩扎卢胺难治的转移性去势抵抗性前列腺癌（mCRPC）患者中的疗效和耐受性。
共纳入 14 例患者。塞来昔布最初以 65mg/m2 每周两次（第 1 和 3 天）给药，随后减少至 60mg 平剂量每周两次（第 1 和 3 天），3 周给药，1 周停药，以提高耐受性。中位治疗持续时间为 13 周。在中位随访 4 个月时，两名患者（14%）的前列腺特异性抗原（PSA）下降≥50%，七名患者（50%）的 PSA 下降。在基线时有可测量疾病的 8 例患者中，两名患者（25%）有部分缓解，四名患者（50%）有最佳影像学反应的稳定疾病。五例患者（36%）发生严重不良事件（SAE；均与塞来昔布无关），五例患者（36%）发生治疗相关的 3-4 级 AE。任何严重程度的最常见药物相关不良事件（AE）为厌食、恶心、体重减轻、疲劳和血小板减少症。三名患者（21%）因无法耐受而退出研究。
塞来昔布在二线抗雄激素治疗难治的 mCRPC 患者中显示出临床活性和较差的耐受性。
