Olaparib, an oral PARP inhibitor that shows antitumor activity against cancers associated with BRCA mutations, had an acceptable side effect profile and did not produce the usual toxic effects of chemotherapy in a small phase 1 study published online June 24 in the New England Journal of Medicine.

The drug caused regression or stabilization of refractory breast, ovarian, and prostate cancers arising from BRCA1 or BRCA2 mutations in 23 patients, and had no activity against cancers unrelated to these genetic mutations in 37 patients.

“Readers may be surprised by the editors’ decision to publish a small, early-stage trial, but this trial not only reports important results – it also points to a new direction in the development of anticancer drugs,” Dr. J. Dirk Iglehar and Dr. Daniel P. Silver wrote in an editorial accompanying this report.

That new direction is “synthetic lethality” via the inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerases, or PARPs. PARPs play a key role in the repair of DNA breaks. In the case of olaparib, the drug specifically induces a DNA lesion restricted only to tumor cells and a genetic loss of function for the DNA repair pathway required to repair those cells.

This approach also showed promise in treating breast cancers in two phase II studies reported in May at the annual meeting of the American Society of Clinical Oncology. In a randomized study conducted among 116 women with metastatic triple-negative breast cancer, the PARP inhibitor BSI-201 prolonged median survival and increased response rates. The second study comprised 54 patients with advanced BRCA-deficient breast cancer who underwent treatment with olaparib. Of the 27 patients who received a high dose of the drug, 11 had a complete response and 10 had a partial response. Dr. Andrew Tutt, a co-investigator in the phase I study published online in the New England Journal of Medicine, presented the data at the ASCO meeting.

The phase I trial was sponsored by KuDOS Pharmaceuticals, a subsidiary of AstraZeneca, and will be published in the July 9 print issue of the journal. It involved 60 patients with advanced solid tumors refractory to standard therapies, reported Dr. Peter C. Fong of the Institute of Cancer Research, Royal Marsden National Health Service Foundation Trust, Surrey (United Kingdom) and his associates.

Oral olaparib showed antitumor activity only in carriers of the BRCA1 or BRCA2 mutations. Eight women with ovarian cancer showed a partial response on CT or MRI, including 6 whose tumors regressed by more than 50%. Of three women who had BRCA2-related breast cancer, one who had pulmonary and lymph-node metastases experienced a complete remission lasting more than 60 weeks; the other two showed disease stabilization for 7 months.

Similarly, a man whose BRCA2-related prostate cancer had metastasized despite castration experienced remission of more than 2 years duration after taking olaparib. This was accompanied by resolution of bone metastases and a 50% reduction in PSA level, reported Dr. Fong and his colleagues (doi:10.1056/NEJMoa0900212).

Overall, adverse effects were mild and were no more frequent in carriers of the BRCA mutations than in noncarriers. Adverse effects considered possibly related to olaparib included nausea (31% of patients), fatigue (30%), vomiting (20%), taste alteration (13%), and anorexia (12%). There was a low incidence of myelosuppression, with three patients developing anemia and two developing thrombocytopenia.

In their editorial comment, Dr. Iglehart of Brigham and Women’s Hospital and Dr. Silver of the Dana-Farber Cancer Institute, both in Boston, Massachusetts, wrote that perhaps as important as these clinical results is the finding that BRCA-associated cancers are susceptible to the synthetic lethal approach. The strategy of targeting DNA-repair deficiencies in tumor cells should also prove useful in a variety of other malignancies, they noted (doi:10.1056/NEJMe0903044).

No relevant financial conflicts of interest were reported for Dr. Fong, Dr. Iglehart, and Dr. Silver. Several of Dr. Fong’s colleagues in the trial reported holding patents relevant to this study or are employees of KuDOS Pharmaceuticals or AstraZeneca.

 

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

《新英格兰医学杂志》6月24日在线发表的一项小型1期研究中显示，一种具有抗BRCA突变相关肿瘤活性的口服PARP抑制剂——Olaparib的不良反应在可接受范围之内，未发生化疗中常见的毒性反应。

在23例表现BRCA1或BRCA2突变的难治性乳腺癌、卵巢癌及前列腺癌患者中，该药物治疗可使病变消退或稳定，而在37例与此基因突变无关的肿瘤患者中未显示任何抗肿瘤活性。

“读者可能对编辑决定发表这样一项小型的早期阶段试验表示惊奇，其实这项试验的意义不仅在于报告了重要的结果，更重要的是指示了抗肿瘤药物研发的新方向。”J. Dirk Iglehar和Daniel P. Silver医生在与该研究报告同时发表的述评中写道。

这个新方向就是通过抑制多聚（腺苷酸二磷酸[ADP]核糖）聚合酶或PARP 的“合成致死性”。 PARP在DNA突变修复中扮演关键角色。在olaparib的作用机制中，该药物特异性诱导仅限于肿瘤细胞的DNA病变及修复这些细胞所需DNA修复途径的基因功能缺失。
 

在5月份的美国临床肿瘤学会年会上报告的两项II期乳腺癌治疗研究中也显示了这种方法颇具前景。在一项对116例女性转移性三阴性乳腺癌患者的随机研究中，PARP抑制剂BSI-201延长了患者的中位生存时间并提高了药物反应率。第二项研究中包括54例接受olaparib治疗的晚期BRCA缺陷乳腺癌患者，在接受该药物高剂量治疗的27例患者中，11例达到完全反应，10例达到部分反应。这项在线发表于新英格兰医学杂志的I期研究的协同研究者Andrew Tutt医生在ASCO年会上展示了上述数据。

这项I期试验的发起者是KuDOS制药公司，这是阿斯利康的一个子公司，该试验将发表于7月9日发行的新英格兰医学杂志印刷版。研究中纳入60例对标准治疗抵抗的晚期实体肿瘤患者，英国萨里郡皇家Marsden国家医保基金会肿瘤研究所的Peter C. Fong医生及其合作者说。

口服olaparib仅在BRCA1 或BRCA2突变携带者中显示抗肿瘤活性。8例卵巢癌患者CT或MRI显示部分反应，其中6例肿瘤缩小超过50%。在3例BRCA2相关的女性乳腺癌患者中，1例肺和淋巴结转移者达到持续60周以上的完全缓解；其他2例已维持疾病稳定达7个月。

相似的，1例去势后仍发生转移的BRCA2相关的前列腺癌患者接受olaparib治疗后维持疾病缓解达2年以上，并伴有骨转移消退及PSA 水平降低50%，Fong医生及其同事报告(doi:10.1056/NEJMoa0900212)。

总体看，不良反应均为轻度，且BRCA突变携带者的不良反应发生率并不高于非BRCA突变携带者。考虑可能与olaparib有关的不良反应包括恶心（患者发生率31%）、疲倦（30%）、呕吐（20%）、味觉改变（13%）及食欲不振（12%）。骨髓抑制的发生率很低，3例患者发生贫血，2例患者发生血小板减少。

同是来自麻萨诸塞州波士顿市的Brigham妇女医院的Iglehart医生和Dana-Farber肿瘤研究所的Silver医生在述评中写道，“可能与临床结果同等重要的是发现BRCA相关肿瘤对合成致死方法敏感。这种目标为肿瘤细胞DNA修复缺陷的治疗策略在各种各样其他恶性肿瘤中也将被证实有效”，他们指出(doi:10.1056/NEJMe0903044)。

Fong、Iglehart和Silver医生报告无任何相关经济利益冲突。Fong医生在该试验中的一些同事报告拥有这项研究相关的专利权，还有一些合作者为KuDOS制药公司或阿斯利康公司的雇员。