Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Weill Cornell Medicine, New York, New York.
JAMA Oncol. 2018 Oct 1;4(10):1344-1351. doi: 10.1001/jamaoncol.2018.2168.
Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)-targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring.
To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC).
DESIGN, SETTING, AND PARTICIPANTS: A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016.
Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred.
The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences).
Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]).
These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated.
ClinicalTrials.gov Identifier: NCT01812746.
重要性：通过前列腺特异性膜抗原（PSMA）靶向纳米粒将多西紫杉醇优先递送至肿瘤，在临床上是有效的，并且在治疗后 PSMA 阳性循环肿瘤细胞（CTC）的选择性减少对患者选择和疾病监测具有重要意义。
目的：评估靶向 PSMA 的多西紫杉醇载药纳米粒 BIND-014 对转移性去势抵抗性前列腺癌（mCRPC）患者的安全性和疗效。
设计、地点和参与者：这是一项多中心、开放标签、2 期临床试验，纳入了 42 例接受醋酸阿比特龙和/或恩扎鲁胺治疗后进展的 mCRPC 且无化疗史的患者，自 2013 年 6 月 24 日至 2016 年 6 月 10 日入组。
干预措施：患者在 21 天周期的第 1 天接受 60mg/m2 的 BIND-014 静脉滴注，联合泼尼松治疗，直至疾病进展或出现不可接受的毒性反应。
主要终点和次要终点：主要终点是根据前列腺癌工作组 2 建议和实体瘤反应评价标准 1.1 评估的影像学无进展生存期。次要终点包括前列腺特异性抗原（PSA）应答（自基线水平降低≥50%）和 CTC 数量变化（从≥5 个降至<5 个/7.5mL 血液）（CellSearch）。还评估了基于 CTC 上 PSMA 表达水平的 CTC 数量变化（Epic Sciences）。
结果：在 42 例患者（81%为白人）中，中位年龄为 66（范围，50-85）岁，中位接受剂量数为 6（范围，1-21）。40 例患者中有 12 例（30%；95%CI，18%-45%）出现 PSA 应答，19 例中有 6 例（32%[95%CI，15%-54%]）出现可测量疾病应答，26 例中有 13 例（50%；95%CI，32%-68%）出现 CTC 转换。中位影像学无进展生存期为 9.9（95%CI，7.1-12.6）个月。使用 Epic Sciences 非 EPCAM 基于 CTC 检测平台，在 18 例患者中的 16 例（89%）中检测到了 CTC；18 例患者中有 11 例（61%）在基线时具有 PSMA 表达水平高于分析阈值（PSMA 阳性）（范围，0.4-72.4CTC/mL）。治疗后，PSMA 阳性 CTC 被优先减少。与治疗相关的不良事件包括 1 级或 2 级疲劳（42 例患者中的 29 例[69%]）、恶心（23 例[55%]）、神经病变（14 例[33%]）和中性粒细胞减少性发热（1 例[2%]）。
结论和相关性：这些发现表明，在化疗初治的 mCRPC 患者中，BIND-014 治疗是有效的且耐受性良好的。抗肿瘤活性可能与 CTC 上的 PSMA 表达水平有关，这表明可以在治疗前确定可能从这种治疗中受益的患者。
试验注册：ClinicalTrials.gov 标识符：NCT01812746。
