2011年4月28日，Centocor Ortho生物科技公司与美国食品药品管理局(FDA)宣布，Zytiga(醋酸阿比特龙)已获准与强的松联用治疗既往曾接受过含紫杉醇的化疗方案治疗且去势治疗无效的转移性前列腺癌患者。Zytiga是肝药酶CYP2D6的抑制剂，这种酶在睾酮的生成过程中起着重要作用。
Zytiga的疗效和安全性已在一项3期的随机、安慰剂对照、多中心研究中得到证实，受试者为1195例既往曾接受过紫杉醇化疗且去势治疗无效的晚期前列腺癌患者。在该试验中，患者接受Zytiga 1gm、每日1次联合强的松5 mg、每日2次治疗，或者安慰剂联合强的松5 mg、每日2次治疗。
研究结果显示，在预设的期中分析中，Zytiga联合强的松治疗组死亡风险相对减少35%[14.8个月 vs.
10.9个月；风险比(HR)，0.646；95%可信区间，0.534~0.768；P<0.0001]，中位生存期较安慰剂联合强的松治疗组延长3.9个月。最新的分析结果与期中分析一致，两个试验组的中位生存期相差4.6个月(15.8个月
vs.11.2个月，HR=0.74)。
临床研究中报告的最常见的不良反应(≥5%)为关节肿胀或不适、低钾血症、水肿、肌肉不适、潮热、腹泻、尿道感染、咳嗽、高血压、心律失常、尿频、夜尿、消化不良以及上消化道感染。
应避免将Zytiga与治疗指数较窄的CYP2D6底物联用。如果无替代治疗，则应慎用，并应考虑减少CYP2D6底物的剂量。此外，应尽量避免将CYP3A4强抑制剂与CYP3A4诱导剂联用，不得已联用时应谨慎行事。
Zytiga是一种口服药物，必须空腹服用。在服药前至少2 h或服用后1 h不得进食。若进餐时服用醋酸阿比特龙，则可导致阿比特龙的暴露量增至10倍。
通知：醋酸阿比特龙脂（Zytiga）有货
Horsham, Pa., April 28, 2011– Centocor Ortho Biotech Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved ZYTIGA™ (abiraterone acetate), an oral, once-daily medication for use in combination with prednisone for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.
Androgens are hormones that promote the development and maintenance of male sex characteristics. However, in prostate cancer, androgens can help fuel the tumor’s growth. Androgen production primarily occurs in the testes and adrenal glands; in men with prostate cancer, the tumor tissue is an additional source of androgens. ZYTIGA is an oral androgen biosynthesis inhibitor that works by inhibiting the CYP17 enzyme complex, which is required for the production of androgens at these three sources.
“This FDA approval represents a welcome new option in the treatment of metastatic prostate cancer,” said Howard Scher, MD, Chief of the Genitourinary Oncology Service, Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan-Kettering, and one of the co-lead investigators for the Phase 3 clinical study. “As a clinician, I believe the efficacy and safety profile of abiraterone acetate, as well as its oral, once-daily formulation, will help address the important need for additional therapeutic choices for men living with this serious disease.”
“In a Phase 3 study, treatment with ZYTIGA plus prednisone showed a significant increase in median survival compared with placebo plus prednisone,” said Professor Johann S. de Bono, MD, FRCP, MSc, PhD, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, and one of the co-lead investigators for the Phase 3 clinical study. “It’s an exciting time for men with prostate cancer, and I believe that ZYTIGA will play an essential role in clinical practice.”
Results of the pivotal Phase 3, randomized, placebo-controlled, multicenter study showed that at pre-specified interim analysis, treatment with ZYTIGA in combination with prednisone resulted in a 35 percent reduction in the risk of death (14.8 months vs. 10.9 months [hazard ratio (HR) = 0.646; 95 percent CI: 0.543, 0.768; p<0.0001]) and a 3.9 month difference in median survival compared to placebo plus prednisone. In an updated analysis, results were consistent with those from the interim analysis with a 4.6 month difference between the two arms in median survival (15.8 months vs. 11.2 months [HR = 0.74]).
At a predetermined number of events in the study, an interim analysis was conducted and it was determined that efficacy had been demonstrated. At that time, the study was unblinded at the recommendation of the Independent Data Monitoring Committee. Information regarding these results can be found at: http://www.centocororthobiotech.com/cobi/viewDocumentByTitleAlias.html?title=PR_101110.
The most common adverse reactions (greater than or equal to 5 percent) reported in the clinical study were: joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia and upper respiratory tract infection. Additional information is included in the Important Safety Information below.
“Prostate cancer is a significant public health threat in the United States,” said Wendy L. Poage, MHA, President, Prostate Conditions Education Council, a national organization committed to men’s health. “ZYTIGA is an important new option and a welcome addition to the armamentarium we have to fight this deadly disease.”
Pivotal Study Design
ZYTIGA, in combination with prednisone, was evaluated in a Phase 3, randomized, placebo-controlled, multicenter clinical study in patients who had received prior chemotherapy containing a taxane (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA 1 gram daily in combination with prednisone 5 milligrams (mg) twice daily or placebo in combination with prednisone 5 mg twice daily (control arm).
Indication
ZYTIGA™ (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.
Important Safety Information
Contraindications
ZYTIGA™ may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.
Warnings and Precautions
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess
Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention. Safety has not been established in patients with LVEF < 50% or NYHA Class III or IV heart failure. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.
Adrenocortical Insufficiency (AI) has been reported in clinical trials after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn or if the patient experiences unusual stress. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during and after stressful situations.
Hepatotoxicity - Increases in liver enzymes have led to drug interruption, dose modification and/or discontinuation. Monitor liver function and modify, withhold or discontinue ZYTIGA™ dosing as recommended (See Prescribing Information for more information).
Food Effect - ZYTIGA™ must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA™ is taken and for at least one hour after the dose of ZYTIGA™ is taken.
Adverse Reactions
The most common adverse reactions (≥5%) reported in clinical trials were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia and upper respiratory tract infection.
Drug Interactions
ZYTIGA™ is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.
About Metastatic Castration-Resistant Prostate Cancer
Metastatic castration-resistant prostate cancer or CRPC occurs when cancer has metastasized beyond the prostate and disease progresses despite serum testosterone below castrate levels.
The prostate is a gland located around the urethra (under the bladder) in men that produces part of the seminal fluid. In some cases, cancer of the prostate can grow slowly compared with other cancers. However, depending on factors including characteristics specific to the patient and the tumor, prostate cancer also can grow very quickly and spread widely.
Excluding skin cancer, prostate cancer is the most frequently diagnosed cancer in men in the United States. In 2010, more than 217,000 new cases of prostate cancer were estimated and more than 32,000 men died from the disease.
About ZYTIGA (abiraterone acetate)
ZYTIGA (abiraterone acetate) was developed by Ortho Biotech Oncology Research & Development, a Unit of Cougar Biotechnology, Inc., and will be marketed by Centocor Ortho Biotech Inc. Marketing applications for ZYTIGA have been filed with other regulatory authorities throughout the world.
ZYTIGA is the first oral, once-daily medication indicated for use in combination with prednisone for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. For more information about ZYTIGA, visit www.ZYTIGA.com.
About Centocor Ortho Biotech Inc.
Centocor Ortho Biotech Inc. redefines the standard of care in immunology, nephrology and oncology. Built upon a pioneering history, Centocor Ortho Biotech Inc. harnesses innovations in large-molecule and small-molecule research to create important new therapeutic options. Beyond its innovative medicines, Centocor Ortho Biotech is at the forefront of developing education and public policy initiatives to ensure patients and their families, caregivers, advocates and health care professionals have access to the latest treatment information, support services and quality care. In addition to metastatic castration-restistant prostate cancer, Centocor Ortho Biotech markets oncology treatments for diseases such as recurrent ovarian cancer, relapsed or refractory multiple myeloma, hairy cell leukemia and anemia due to the effect of concomitantly administered chemotherapy. For more information about Centocor Ortho Biotech, visit www.centocororthobiotech.com.
Centocor Ortho Biotech Inc. is a member of the Johnson & Johnson Family of Companies.
About the Ortho Biotech Oncology Research & Development, unit of Cougar Biotechnology, Inc.
Ortho Biotech Oncology Research & Development, Unit of Cougar Biotechnology, Inc., partners with affiliated units and companies in the Janssen Pharmaceutical Companies, such as Centocor Ortho Biotech Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., in the research and development of oncology and supportive care treatments.
* NOTE: Centocor Ortho Biotech Inc. provides support to Prostate Conditions Education Council for initiatives benefitting prostate cancer patients.
新药延长前列腺癌患者生存时间
强生公司的Zytiga（醋酸阿比特龙，abiraterone acetate），属于新类型列腺癌治疗药，于今年4月29日获得美国FDA批准。这类药物能以崭新的作用方式阻断促使肿瘤生长的那些雄性激素。Medivation公司和武田制药公司正在开发类似药物，他们的研究成果将在6月首个周末在芝加哥召开的美国临床肿瘤学会议报告。
Dennis Prestholdt是一名退休工程师，今年67岁。这名前列腺癌患者将其最近这三年时间能够得以继续生存归功于Zytiga。他于2008年参加一项临床试验，开始使用Zytiga。据高盛集团公司分析师估计，在未来5年Zytiga可能每年创造21亿美元销售额。
强生公司的Zytiga只是一个先驱者。从Medivation公司和武田制药公司的同类产品等如果能够获得批准，与Zytiga一起，将使前列腺癌治疗药市场价值从目前不足10亿美元至2015年增加至50亿。
自从多西紫杉醇（docetaxel）/泼尼松（prednisone）显示出总体生存益处，被FDA批准用于去势抵抗的转移性前列腺癌已经整整7年过去了。在过去5~6年中前列腺癌治疗新药开发少有成绩，现今这个领域药物创新有了不少进展，虽然这些药物尚不能治愈疾病，但医师已经有了多种选择帮助患者延长生命。
生存时间延长三倍
将时间退回至1985年，对进行激素治疗的晚期前列腺癌患者而言通常生命预期约12个月，如果采用近年来获准的治疗药物，生存时间可能增加三倍。
位于美国旧金山的Medivation公司和日本Astellas制药公司合作开发的MDV3100 预期在2013年获得美国批准，至2017年使年销售额达到17亿美元。
日本武田在大阪的千禧（Millennium）公司对TAK700开展了研究，后期试验将在2013或2014年完成。
根据美国癌症协会统计，每年约有21.8万美国男性子被诊断出患有前列腺癌，3.2万死于此症。六分之一男性会在人生中被诊断出前列腺癌，在救治后其中一小部分免不了恶化。如果肿瘤局限于前列腺——这个位于膀胱和尿道间核桃大小腺体，这类患者可作手术切除或以放疗消除。老龄患者因为前列腺肿瘤生长缓慢，即使不采取措施也不会改变他们的寿命预期。
癌症扩散
前列腺癌患者约有15%会扩散。这类患者没有治愈希望，治疗的目标是针对生产雄激素的睾丸，因为这些雄激素促使前列腺癌细胞生长，从而前列腺癌治疗一种方法是手术摘除睾丸，另外一种方法是化学去势，即所谓的雄激素剥夺，如使用雅培公司的Lupron（Leuprolide Acetate，醋酸亮丙瑞林）或阿斯利康公司的Casodex（bicalutamide，比卡鲁胺）。
这些药物开始总能奏效，但随着时间的推移，通常在两年或稍长时间后治疗最终失败。当肾上腺或肿瘤细胞开始生产少量雄激素，从而刺激癌肿重新生长，阻断睾酮的治疗方法就不再有效。
新的理论
强生公司的Zytiga作用于被称作为“CYP17”的酶这个促使睾丸外生成雄激素的靶位——阻断CYP17就能切断肿瘤的雄激素“燃料供应”。这改变了先前的治疗思维。
传统的激素治疗使本文起首提及的Prestholdt先生的PSA（前列腺特异性抗原——与前列腺癌相关的一种蛋白）水平检查在10年后方才开始攀升，也就是说病情开始“重上征途”，重新发展。于是他在互联网上搜寻，得知了有关Zytiga的临床试验，进一步得知这种药为醋酸阿比特龙。他向主持临床的美国加利福尼亚大学临床药学副教授Charles J. Ryan博士发送电子邮件并亲临访问，2008年初得以参与试验开始服用该药。
一项研究发现，对标准激素治疗和化疗不再应答的晚期前列腺癌患者给予Zytiga可延长生存时间11至15个月。
在一项较小规模的试验中Prestholdt先生和其他患者在化疗前接受Zytiga，许多人从中获益。Ryan博士报告说：开始治疗后两个月内，Prestholdt的PSA水平降至零，40个月后依然保持这一状态。
Zytiga的安全性和疗效建立在一项1195名晚期去势抵抗，先前作过多西紫杉醇化疗的晚期前列腺癌患者的临床研究基础上。患者接受Zytiga每天一次（250 mg），联用泼尼松每日两次或安慰剂（糖丸）。
这项研究旨在确定整体存活率，从开始治疗至死亡的时间长度。接受Zytiga并联用泼尼松的患者中位存活时间14.8个月，安慰剂组10.9个月。
在接受Zytiga的患者最常见的副作用包括关节肿胀或不适，血钾水平低下，体液滞留（通常是腿和足），肌肉不适，潮热，腹泻，尿路感染，咳嗽，高血压，心搏异常，尿频，夜间排尿增加，肠胃不适或消化不良和上呼吸道感染。
Zytiga由伦敦肿瘤研究院发现，BTG公司开发，之后授权给Cougar生物技术公司，后者于2009年6月被强生公司收购。强生公司预期至2015年使Zytiga销售额达到8亿美元。治疗费用每月5千美元，治疗周期4个月。