Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer
Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer
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DOI：
10.1200/jco.2009.25.9259
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发表时间：
2010-03-20
影响因子：
45.3
通讯作者：
Scher, Howard I.
中科院分区：
文献类型：
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作者：
Danila, Daniel C.;Morris, Michael J.;Scher, Howard I.
目的配体介导的雄激素受体信号在去势耐受前列腺癌(CRPC)中持续存在。醋酸阿比特龙(AA)是一种有效的、选择性的CYP17抑制剂，它是睾丸、肾上腺和前列腺组织中雄激素生物合成所必需的。这项试验评估了AA联合泼尼松治疗继发性醛固酮增多症的有效性和安全性。患者与方法58例以多西他赛为主的化疗失败的进展性转移性CRPC患者接受AA(每日1000 mg)联合泼尼松(每日2次，每次5 mg)治疗。27名患者(47%)以前接受过酮康唑治疗。主要结果是前列腺特异性抗原(PSA)下降50%，根据实体肿瘤反应评估标准(RECIST)标准客观反应，以及东部合作肿瘤组(ECOG)表现状态(PS)和循环肿瘤细胞(CTC)数量的变化。结果22例(36%)患者PSA A&>=50%下降，其中31例未服用酮康唑的患者中有14例(45%)，27例接受酮康唑治疗的患者中有7例(26%)。在RECIST可评估的靶区病变的22例患者中，有4例(18%)出现部分反应。28%的患者的ECOG PS有改善。PSA进展的中位时间为169天(95%可信区间，82至200天)。29例患者中有10例(34%)的CTC在治疗后从>；=5转为<；5。AA相关不良反应多为1~2级，未见AA相关4级不良反应。结论AA联合泼尼松治疗CRPC患者耐受性良好，具有良好的抗肿瘤活性。加入小剂量强的松可降低盐皮质激素相关毒性(高血压或低钾血症)的发生率。对于III期研究，建议联合使用AA和泼尼松。
PurposePersistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.Patients and MethodsFifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was >= 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.ResultsA >= 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naive and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from >= 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.ConclusionAA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.