Department of Urology, Yale University, New Haven, Connecticut.
Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.
Prostate. 2020 Jan;80(1):99-108. doi: 10.1002/pros.23922. Epub 2019 Nov 19.
Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.
A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.
PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.
PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.
前列腺特异性膜抗原（PSMA）在原发性和转移性前列腺癌中过度表达，是一种成熟的治疗和诊断靶点。PSMA 抗体药物偶联物（PSMA ADC）是一种完全人源化 IgG1 抗 PSMA 单克隆抗体，与单甲基奥瑞他汀 E 偶联，与 PSMA 阳性细胞结合并诱导细胞毒性。在一项 1 期研究中，PSMA ADC 具有良好的耐受性，并表现出活性，表现为血清前列腺特异性抗原（PSA）和循环肿瘤细胞（CTC）的降低。为了进一步评估 PSMA ADC，我们在转移性去势抵抗性前列腺癌（mCRPC）患者中进行了一项 2 期试验，这些患者在接受 abiraterone/enzalutamide（abi/enz）治疗后进展。
共有 119 名（84 名化疗经验丰富，35 名化疗初治）患者接受 PSMA ADC 2.5 或 2.3mg/kg 静脉注射，每 3 周一次，最多 8 个周期。评估抗肿瘤活性（PSA 和 CTC 自基线的最佳百分比下降，以及通过影像学评估的肿瘤反应）、探索性生物标志物和安全性（监测不良事件 [AE]、临床实验室检查和东部合作肿瘤学组表现状态）。
所有治疗患者（n=113）中有 14%和化疗初治患者（n=34）中有 21%出现 PSA 下降≥50%。所有治疗患者（n=77；基线时有≥5 CTCs 和治疗后结果的患者数量）中有 78%和化疗初治患者（n=19）中有 89%出现 CTC 下降≥50%；在研究过程中的某个时间点，所有治疗患者中有 47%和化疗初治患者中有 53%的患者从≥5 个 CTC 转为<5 CTC/7.5ml 血液。PSA 和 CTC 减少与 PSMA 表达（CTC 或肿瘤组织）高和神经内分泌血清标志物低有关。在化疗经验丰富的组中，PSMA ADC 治疗的最佳总体放射学反应是 51 名（60.7%）患者的疾病稳定；化疗初治组中有 5.7%的患者有部分缓解。最常见的≥常见不良事件术语标准（CTCAE）3 级治疗相关不良事件是中性粒细胞减少症、疲劳、电解质失衡、贫血和神经病。最常见的严重不良事件是脱水、低钠血症、发热性中性粒细胞减少症和便秘。两名接受 2.5mg/kg 治疗的患者因败血症死亡。
在接受 abi/enz 治疗的 mCRPC 患者中，PSMA ADC 在 PSA 下降、CTC 转换/减少和影像学评估方面显示出一定的活性。与治疗相关的临床显著不良事件包括中性粒细胞减少症和神经病。
