Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, USA.
Department of Endocrinology and Medical Oncology, Genitourinary Cancer Section, University Federico II, Napoli, Italy.
Ann Oncol. 2014 Sep;25(9):1700-1709. doi: 10.1093/annonc/mdu038. Epub 2014 Mar 20.
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized by the arrival of multiple novel agents in the past 2 years. Immunotherapy in the form of sipuleucel-T, androgen axis inhibitors, including abiraterone acetate and enzalutamide, a chemotherapeutic agent, cabazitaxel, and a radiopharmaceutical, radium-223, have all yielded incremental extensions of survival and have been recently approved. A number of other agents appear promising in early studies, suggesting that the armamentarium against castrate-resistant prostate cancer is likely to continue to expand. Emerging androgen pathway inhibitors include androgen synthesis inhibitors (TAK700), androgen receptor inhibitors (ARN-509, ODM-201), AR DNA binding domain inhibitors (EPI-001), selective AR downregulators or SARDs (AZD-3514), and agents that inhibit both androgen synthesis and receptor binding (TOK-001/galeterone). Promising immunotherapeutic agents include poxvirus vaccines and CTLA-4 inhibitor (ipilimumab). Biologic agents targeting the molecular drivers of disease are also being investigated as single agents, including cabozantinib (Met and VEGFR2 inhibitor) and tasquinimod (angiogenesis and immune modulatory agent). Despite the disappointing results seen from studies evaluating docetaxel in combination with other agents, including GVAX, anti-angiogentic agents (bevacizumab, aflibercept, lenalinomide), a SRC kinase inhibitor (dasatinib), endothelin receptor antagonists (atrasentan, zibotentan), and high-dose calcitriol (DN-101), the results from the trial evaluating docetaxel in combination with the clusterin antagonist, custirsen, are eagerly awaited. New therapeutic hurdles consist of discovering new targets, understanding resistance mechanisms, the optimal sequencing and combinations of available agents, as well as biomarkers predictive for benefit. Novel agents targeting bone metastases are being developed following the success of zoledronic acid and denosumab. Finally, all of these modalities do not appear curative, suggesting that clinical trial enrollment and a better understanding of biology remain of paramount importance.
在过去的 2 年中，多种新型药物的出现彻底改变了转移性去势抵抗性前列腺癌（mCRPC）的治疗格局。免疫疗法形式的 sipuleucel-T、雄激素轴抑制剂，包括醋酸阿比特龙和恩扎鲁胺、化疗药物卡巴他赛以及放射性药物镭-223，均已延长了生存时间，并已最近获得批准。其他一些药物在早期研究中显示出良好的前景，这表明针对去势抵抗性前列腺癌的治疗手段可能会继续扩大。新兴的雄激素途径抑制剂包括雄激素合成抑制剂（TAK700）、雄激素受体抑制剂（ARN-509、ODM-201）、AR DNA 结合域抑制剂（EPI-001）、选择性 AR 下调剂或 SARDs（AZD-3514）以及同时抑制雄激素合成和受体结合的药物（TOK-001/galeterone）。有前途的免疫治疗药物包括痘病毒疫苗和 CTLA-4 抑制剂（ipilimumab）。针对疾病分子驱动因素的生物制剂也正在作为单一药物进行研究，包括卡博替尼（Met 和 VEGFR2 抑制剂）和 tasquinimod（血管生成和免疫调节剂）。尽管评估多西他赛与其他药物联合使用的研究结果令人失望，包括 GVAX、抗血管生成药物（贝伐单抗、阿柏西普、来那度胺）、Src 激酶抑制剂（达沙替尼）、内皮素受体拮抗剂（atrasentan、zibotentan）和大剂量钙三醇（DN-101），但评估多西他赛与簇集素拮抗剂 custirsen 联合使用的试验结果仍备受期待。新的治疗难题包括发现新的靶点、了解耐药机制、最佳排列和组合现有药物以及预测疗效的生物标志物。在唑来膦酸和地舒单抗成功的基础上，正在开发针对骨转移的新型药物。最后，所有这些方法似乎都不能治愈，这表明临床试验的参与和对生物学的更好理解仍然至关重要。
