ESMO2019 | 卵巢癌研究进展

ESMO2019会议，西班牙当地时间9月28日下午，巴塞罗那厅容纳上千人的主会场座无虚席，等待Presidential Symposium上公布三项PARP抑制剂在卵巢癌一线维持治疗中的III期临床研究结果，其中两项研究同时在线发表在《新英格兰医学》杂志上，盛况空前。次日，ESMO会议的《Daily Reporter》更是头版头条报道了这些研究结果，并且加了编者按，称卵巢癌治疗进入了新纪元。

研究一：PRIMA/ENGOT-OV26/GOG-3012：尼拉帕利用于新诊断晚期卵巢癌的维持治疗

研究二：PAOLA-1/ENGOT-OV25：奥拉帕利联合贝伐珠单抗用于新诊断卵巢癌患者接受含铂化疗联合贝伐珠单抗治疗后的维持治疗

研究三：VELIA/GOG-3005:维利帕利（Veliparib）加入一线化疗中及其维持治疗用于高级别浆液性卵巢癌、输卵管癌或原发性腹膜癌

研究一、三同时在线发表于《新英格兰医学》

Editorial

应对卵巢癌的新方案

Dr. Branislav Bystrický

卵巢癌在欧洲乃至世界范围内的发病率均居女性肿瘤的前列。直至不久前，这一恶性疾病的治疗仍进步缓慢。腹腔化疗兴而复衰，血管抑制剂疗效甚微，更多的临床试验以失败告终。

目前，卵巢癌的一线治疗方案仍是沿用多年的卡铂与紫杉醇联合化疗，加用贝伐单抗的疗效甚微。而二线治疗时，多依据先前的铂类药物敏感性制订化疗方案。近期，我们见证了PARP抑制剂在卵巢癌后线治疗中的显著疗效，其中BRCA基因突变的患者获益尤甚。而PARP抑制剂单药及联合其他靶向药物在一线治疗中的效果也在积极的探索中。

昨日下午（2019/9/28），几项PARP抑制剂（包括尼拉帕利、奥拉帕利和维利帕利）的大型III期临床试验结果在大会上报告，并作为头条新闻刊载于今天的《Daily Reporter》（2019/9/29）。PRIMA研究结果表明，标准一线治疗达完全缓解或部分缓解后，使用尼拉帕利维持治疗可显著改善无进展生存（PFS），而对有同源重组修复缺陷（HRD+）的患者，尼拉帕利可使其PFS增加一倍以上。研究中的主要不良反应为血液毒性。奥拉帕利也有一项相似的临床研究（PAOLA-1），在此研究中，两组患者均使用贝伐单抗维持治疗，其中一组加用奥拉帕利。结果发现，标准一线治疗后使用贝伐单抗联合奥拉帕利的维持治疗，可改善全组患者PFS，其中HRD+患者的PFS可延长一倍以上。有趣的是，两药联用组的高血压风险低于单药组。因此，尼拉帕利或奥拉帕利应被纳入卵巢癌患者完成一线治疗后的的常规治疗，尤其是HRD+患者。

另一种PARP抑制剂维利帕利被用于更早的治疗中，即与一线化疗联用。一线化疗联合维利帕利治疗后使用维利帕利维持治疗可改善全部患者的PFS，且HRD+患者获益更为显著。值得注意的是本研究中未使用贝伐单抗。因此，我们现在有三种PARP抑制剂在一线或维持治疗中表现优异。但许多问题仍悬而未决：PARP抑制剂是否应与化疗联用，它们是否仅在维持治疗中表现出较低的毒性？是否还有使用贝伐单抗的必要性？应用何种方法、在何种时机检测HRD？……尽管存在一些争议，但就卵巢癌、输卵管癌、原发性腹膜癌的治疗而言，我们已经迈入了PARP抑制剂的新纪元。

（曹俊雅 译   刘继红 审校）

原文

A new scenario for ovarian cancer

By Dr Branislav Bystrický

Worldwide, Ovarian cancer is the seventh most common cancer in women and its incidence in Europe tops the list of female cancers. Until recently, there was slow progress in the treatment of this deadly disease. We have witnessed the rise and the fall of intraperitoneal chemotherapy, a marginal benefit of angiogenesis inhibitors and plenty of negative trials.

First-line treatment remains age-old chemotherapy with carboplatin and paclitaxel. Addition of the angiogenesis inhibitor, bevacizumab, confers a modest benefit. Second-line treatment was, up to now, chemotherapy with agents based on previous platinum effectiveness. Recently, we have seen major advances with the incorporation of PARP inhibitors in later lines of treatment, especially in patients harbouring BRCA-mutant tumours. The effectiveness of PARP inhibitors and their combination with other targeted agents is being exploited in earlier lines of treatment. Yesterday afternoon, we saw presentations of the results from large phase III trials of three PARP inhibitors-niraparib, olaparib and veliparib—which are reported in the top story in this editon of the Daily Reporter. Niraparib significantly improve progression-free survival (PFS) as maintenance treatment after complete or partial response with standard first-line treatment. PFS was more than doubled in the population with homologous recombination deficiency (HRD+). Toxicity was mainly haematological in nature (Abstract LBA1). A similar trial of maintenance treatment after standard first-line treatment was conducted with another PARP inhibitor- olaparib. In this trial, the addition of olaparib to maintenance bevacizumab significantly improved PFS in all patients, doubling the duration of PFS in HRD+ patients. Interestingly, the incidence of hypertension was lower in the combined arm (Abstract LBA _PR). Niraparib or olaparib should now be incorporated into out treatment schedules, especially for HRD+ patients completing first-lines treatment for ovarian cancer.

A third PARP inhibitor, veliparib, was tested in the earlier disease setting, together with first-line chemotherapy. Again, the addition of veliparib to front-line chemotherapy, followed by maintenance veliparib improved PFS in the whole population, with a more pronounced effect in HRD+ patients. Bevacizumab was not used in this study (Abstract LBA3). Thus, we now have three very active PARP inhibitors for first-line or maintenance treatment (following first-line chemotherapy). However, some questions remain. Should we use these agents with chemotherapy? Are they less toxic for patients as maintenance treatment only? Do we need bevacizumab at all? What test should we be using for HRD and when should we be used? Nevertheless, we have now definitely entered the era of PARP inhibitors for ovarian, fallopian tube and primary peritoneal cancers.

ESMO会议《Daily Reporter》的头版头条报道

刘继红教授和PAOLA-1研究的PI，法国医生Isabelle Ray-Coquard交流后合影

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