SAN ANTONIO (EGMN) – The addition of the PARP inhibitor BSI-201 to chemotherapy with gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer resulted in a dramatic 50% reduction in the risk of death, compared with chemotherapy alone, in an updated analysis of a high-profile phase II study.

These impressive phase II results with the poly (ADP [adenosine diphosphate]-ribose) polymerase (PARP) inhibitor have led to an ongoing, definitive, phase III registration study involving a planned 420 patients at more than 90 U.S. centers. Accrual for the trial is proceeding extremely rapidly, Dr. Joyce O’Shaughnessy said at the San Antonio Breast Cancer Symposium.

“The PARP inhibitors certainly look promising. The phase III study will be finished in the first quarter of 2010. If the phase III holds up and confirms the phase II, hopefully BSI-201 will be available toward the end of 2010,” added Dr. O’Shaughnessy, codirector of the breast cancer research program at Baylor University Medical Center at Dallas.

The phase II study involves 123 patients with estrogen receptor–, progesterone receptor–, and HER2-negative measurable metastatic breast cancer who had received not more than two prior cytotoxic regimens. They were randomized to gemcitabine and carboplatin alone or in combination with BSI-201.

Initial results were reported in a plenary session at the American Society of Clinical Oncology annual meeting in 2009. In the update,median overall survival was 12.2 months in the BSI-201 group, compared with 7.7 months with chemotherapy alone (hazard ratio, 0.50; P = .005). Roughly 20 patients in each study arm remain unaccounted for; final overall survival results will be available in the spring.

The therapeutic rationale for using a PARP inhibitor in the setting of metastatic triple-negative disease lies in the drug’s ability to enhance chemotherapy-induced DNA damage. The PARP1 protein is the most abundant protein in the tumor cell nucleus. It plays a critical role in the repair of breaks in single-strand DNA.

Inhibiting PARP1 results in single-strand breaks going unrepaired. They degenerate into double-strand breaks, which the tumor cells find particularly difficult to repair. So the cells die, Dr. O’Shaughnessy explained.

BSI-201 didn’t potentiate the familiar toxicities of gemcitabine and carboplatin. The frequency and nature of adverse events in the two study arms were similar.

The PARP inhibitor was given intravenously at 5.6 mg/kg on days 1,4,8, and 11 of every 21-day treatment cycle. Gemcitabine and carboplatin were administered in standard fashion on days 1 and 8.

BSI-201 is being developed by BiPar Sciences Inc. Dr. O’Shaughnessy is on the speakers bureau for Sanofi-Aventis, which has acquired the company.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

圣安东尼奥(EGMN)——一项备受瞩目的II期研究的最新分析显示，与单纯吉西他滨/卡铂化疗相比，在化疗基础上加用PARP抑制剂BSI-201可使转移性三阴性乳腺癌患者的死亡风险显著降低50%。

 

Joyce O’Shaughnessy博士在圣安东尼奥乳腺癌会议上表示，由于多聚腺苷二磷酸核糖聚合酶(PARP)抑制剂II期研究的这些结果令人满意，因此目前正在进行决定性的III期注册研究。III期研究计划在美国90多个研究中心招募420例患者。目前，招募工作进行得非常迅速。

 

达拉斯市贝勒大学医学中心乳腺癌研究计划的联合主管O’Shaughnessy博士补充说：“无疑PARP抑制剂的应用前景令人乐观。III期研究将在2010年第一季度完成。如果III期研究支持并证实II期研究结果，那么BSI-201将有望于2010年年底上市。”

 

II期研究共纳入123例雌激素受体、孕酮受体和HER2均阴性的可测转移性乳腺癌患者。这些患者此前接受的细胞毒性治疗方案不超过2种。患者被随机分入吉西他滨/卡铂单纯化疗组和吉西他滨/卡铂+BSI-201联合治疗组。

 

初步结果已在2009年举行的美国临床肿瘤学会年会的全体大会上予以报告。最新结果显示，BSI-201组中位总体生存时间为12.2个月，单纯化疗组为7.7个月（危险比：0.50；P = 0.005）。 每组中约有20例患者的数据尚未得以阐释；最终总体生存率结果将可在春季知晓。

 

应用PARP抑制剂治疗转移性三阴性疾病的治疗依据在于该药能够增强化疗诱导的DNA损伤。PARP1蛋白是肿瘤细胞核中含量最丰富的蛋白。该蛋白在修复断裂单链DNA中发挥着重要作用。

 

O’Shaughnessy博士解释说，抑制PARP1蛋白可使断裂单链一直处于未修复状态，并进一步造成令肿瘤细胞特别难以修复的双链断裂，从而导致肿瘤细胞死亡。

 

BSI-201不会增强吉西他滨和卡铂的常见毒性。两个研究组中不良事件的发生率和种类相似。

 

在每21天一个治疗周期的第1、4、8和11天，经静脉给予5.6 mg/kg PARP抑制剂。在第1和8天，按标准给药方式给予吉西他滨和卡铂。

 

BSI-201由BiPar Sciences公司研发。O’Shaughnessy博士是收购上述公司的赛诺菲-安万特的演讲团成员。

 

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