FDA批准前列腺癌药物Zytiga扩大适应证

圣路易斯(MD Consult)——2012年12月10日，杨森生物技术公司宣布美国食品药品管理局(FDA)已经批准了每日1次口服药物Zytiga(醋酸阿比特龙)的扩大适应证申请。此前，Zytiga仅被批准联合泼尼松用于曾接受含多烯紫杉醇化疗的转移性去势难治性前列腺癌(mCRPC)患者。基于这项新批准令，现在Zytiga联合泼尼松可更早用于mCRPC连续治疗，即在化疗之前使用。

根据说明书，Zytiga在体内转化为雄激素生物合成酶抑制剂阿比特龙，抑制17α-羟化酶/C17,20-裂解酶。该酶表达于睾丸、肾上腺和前列腺肿瘤组织，是雄激素生物合成所必需的酶。

这项新批准令是基于一项随机、双盲、安慰剂对照、国际多中心Ⅲ期临床研究的有效性和安全性结果。该研究评价了Zytiga+泼尼松与安慰剂+泼尼松用于1,088例未接受细胞毒性化疗、对雄激素剥夺治疗无应答的mCRPC男性患者。患者被随机分组，接受Zytiga(1,000mg，口服，1次/日)+泼尼松(5 mg，2次/日)或安慰剂+泼尼松(5 mg，2次/日)治疗。共同终点为无放射影像学进展生存期(rPFS)和总生存期(OS)。

遵照方案对rPFS的分析结果显示，与安慰剂+泼尼松组(对照组)相比，Zytiga+泼尼松组(Zytiga组) rPFS呈统计学显著改善。对照组中位rPFS为8.28个月，由于Zytiga组进展事件出现较慢尚未达到中位rPFS，结果具有统计学显著意义(P＜0.0001)。

此外，在另外一项预先设定的其中分析中，Zytiga组OS长于对照组，风险比(HR)为0.792：Zytiga组中位OS为35.3个月，而对照组为30.1个月[95%置信区间(CI)，0.655~0.956]，但未达到预先设定的统计学显著水平。

Zytiga最常见不良反应包括疲乏、关节肿胀或不适、水肿、潮热、腹泻、呕吐、咳嗽、高血压、呼吸困难、尿道感染和挫伤。最常见实验室异常包括贫血、血液碱性磷酸酶、天冬氨酸转氨酶和(或)丙氨酸转氨酶升高、高甘油三酯血症、高胆固醇血症、淋巴细胞减少症、高血糖症、低磷血症和低钾血症。

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ST LOUIS (MD Consult) - On December 10, 2012, Janssen Biotech announced that the US Food and Drug Administration (FDA) has approved a broader indication for the oral, once-daily medication Zytiga (abiraterone acetate). Previously, Zytiga in combination with prednisone had only been approved to treat men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel. With this new approval, Zytiga in combination with prednisone may now be used earlier in the treatment continuum for metastatic castration-resistant disease, before the use of chemotherapy.

According to the product label, Zytiga is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 �-hydroxylase/C17,20-lyase. This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

This new approval for Zytiga was granted on the basis of data that included efficacy and safety results of a phase 3, randomized, double-blind, placebo-controlled international clinical study, which evaluated the use of Zytiga plus prednisone compared with the use of placebo plus prednisone in 1088 men with mCRPC who had failed to respond to androgen deprivation therapy and had not received cytotoxic chemotherapy. Patients were randomly assigned to receive either Zytiga 1,000 milligrams (mg) administered orally once daily plus prednisone 5 mg administered twice daily or placebo plus prednisone 5 mg administered twice daily. The coprimary end points of the study were radiographic progression-free survival (rPFS) and overall survival (OS).

Results from a prespecified analysis examining rPFS demonstrated a statistically significant improvement in rPFS in the Zytiga plus prednisone arm (Zytiga arm) compared with patients in the placebo plus prednisone (control) arm. The median rPFS in the control arm was 8.28 months, but had not yet been reached in the Zytiga arm because progression events were occurring more slowly in the Zytiga arm compared with the control arm. These results reached statistical significance (P < .0001).

Additionally, in a separate prespecified interim analysis, OS was longer for patients in the Zytiga arm compared with the control arm with an hazard rate of 0.792: median overall survival was 35.3 months in the Zytiga arm versus 30.1 months in the control arm (95% confidence interval, 0.655 - 0.956). However, the prespecified value for statistical significance was unmet.

The most common adverse reactions of Zytiga include fatigue, joint swelling or discomfort, edema, hot flashes, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most commonly reported laboratory abnormalities include anemia, elevated blood levels of alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase, hypertriglyceridemia, hypercholesterolemia, lymphopenia, hyperglycemia, hypophosphatemia, and hypokalemia.