Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.
Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.
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DOI：
10.1016/s0140-6736(10)60172-9
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发表时间：
2010-04-24
期刊：
影响因子：
168.9
通讯作者：
Sawyers, Charles L.
中科院分区：
文献类型：
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作者：
Scher, Howard I.;Beer, Tomasz M.;Higano, Celestia S.;Anand, Aseem;Taplin, Mary-Ellen;Efstathiou, Eleni;Rathkopf, Dana;Shelkey, Julia;Yu, Evan Y.;Alumkal, Joshi;Hung, David;Hirmand, Mohammad;Seely, Lynn;Morris, Michael J.;Danila, Daniel C.;Humm, John;Larson, Steve;Fleisher, Martin;Sawyers, Charles L.
MDV 3100是一种设计合理的雄激素受体拮抗剂，与目前使用的雄激素受体拮抗剂相比，它能更有效地阻断雄激素受体（AR）结合、核转位和共激活因子募集。MDV 3100的独特之处还在于它可阻止DNA结合，诱导细胞凋亡，并且在AR过表达时无激动剂活性。由于去势抵抗性前列腺癌（CRPC）的生长似乎依赖于持续的雄激素受体信号传导，因此我们假设MDV 3100可能是CRPC男性患者的有效治疗。在1-2期试验中评估了抗肿瘤活性和安全性。符合条件的进行性转移性CRPC患者入组3-6例患者的队列。一旦确定了剂量的安全性，则将队列扩展至包括至少12例化疗初治患者和12例化疗后治疗患者。140例患者接受了每日30 - 600 mg剂量的治疗。用于评估雄激素受体阻滞的正电子发射断层扫描（PET）成像显示，在60 mg/天及以上剂量下，18-氟二氢睾酮结合率降低。在所有剂量下均观察到抗肿瘤作用，包括56%的患者血清PSA下降50%或以上、软组织缓解、稳定骨病以及循环肿瘤细胞计数从不利转为有利。放射学进展的中位进展时间为47周。持续治疗（>28天）的最大耐受剂量为240 mg，最常见的不良事件是剂量依赖性疲劳，通常在减少剂量后消退。在化疗初治和化疗后的CRPC患者中，观察到MDV 3100对所有评估结局的抗肿瘤活性令人鼓舞，从而确定CRPC患者并非一致为难治性。一项针对多西他赛治疗后疾病进展患者的III期试验正在进行中。
MDV3100 is a rationally-designed androgen receptor antagonist that blocks androgen receptor (AR) binding, nuclear translocation, and co-activator recruitment more effectively than the androgen receptor antagonists currently in use. MDV3100 is also unique in that it prevents DNA binding, induces apoptosis, and has no agonist activity when AR is overexpressed. Because growth of castration-resistant prostate cancer (CRPC) appears to depend upon continued androgen receptor signaling, we hypothesized that MDV3100 could be effective therapy for men with CRPC. Antitumor activity and safety were assessed in a phase 1-2 trial. Eligible patients with progressive metastatic CRPC were enrolled in cohorts of 3-6 patients. Once the safety of a dose was established, cohorts were expanded to include at least 12 chemotherapy-naïve and 12 post-chemotherapy treated patients. 140 patients were treated with doses ranging from 30 to 600 mg daily. Positron emission tomography (PET) imaging to assess androgen receptor blockade showed decreased 18-fluorodihydrotestosterone binding at dosages of 60 mg/day and above. Antitumor effects were observed at all dosages including declines in serum PSA of 50% or more in 56% of patients, responses in soft tissue, stabilized bone disease, and conversion from unfavourable to favourable circulating tumour cell counts. The median time to progression was 47 weeks for radiological progression. The maximal tolerated dose for sustained treatment (>28 days) was 240 mg and the most common adverse event was dose-dependent fatigue, which generally resolved following dose reduction. Encouraging antitumor activity on all outcomes assessed was observed for MDV3100 in both chemotherapy-naïve and post-chemotherapy patients with CRPC, establishing that patients with CRPC are not uniformly hormone-refractory. A phase 3 trial in patients with progressive disease after docetaxel treatment is underway.