Currently, 3 PARP inhibitors, olaparib, rucaparib, and niraparib, are approved by the FDA for treating patients with ovarian cancer in various settings. At the ASCO 2019 Annual Meeting, data from several important studies of PARP inhibitors in recurrent ovarian cancer were presented. In this commentary, I briefly review the data and share my thoughts on these studies.
The first study I am going to discuss is the phase III ARIEL3 trial, which was designed to measure the impact of rucaparib as maintenance therapy in recurrent ovarian cancer after response to platinum chemotherapy. In the original analysis we published, rucaparib maintenance therapy significantly improved the primary endpoint of PFS compared with placebo. In the current analysis, we wanted to measure the impact rucaparib maintenance therapy might have on subsequent lines of therapy. The key question here is how long the benefit from maintenance therapy with rucaparib can persist into the next line of therapy. Of more importance, if a patient receives a PARP inhibitor and then has disease progression, is her disease still sensitive to the next line of therapy?
我将要讨论的第一项研究是 ARIEL3 III期试验，这是一项被设计用于检测卢卡帕尼作为经过铂类化疗后复发性卵巢癌维持治疗的疗效。在我们公布的最初分析数据中，卢卡帕尼相对于安慰剂显著延长了PFS的主要终点。在目前的分析数据中，我们想检测卢卡帕尼的维持治疗对于后续治疗的影响。主要的问题在于，卢卡帕尼的维持治疗能够延续多久直至下一轮治疗。最重要的是，如果病人接受了PARP抑制剂并且之后疾病进展，那么她是否对于之后的治疗仍旧敏感呢？
The exploratory endpoints evaluating subsequent lines of therapy included PFS2 (defined as the time from initial randomization to disease progression on the next line of therapy or death), time to first subsequent therapy, and time to second subsequent therapy. Not surprisingly, what we saw was that each of these exploratory endpoints evaluating postprogression treatment outcomes was significantly prolonged by rucaparib maintenance therapy relative to patients on placebo. These findings are important because they demonstrate no detrimental effect on subsequent lines of therapy from using a PARP inhibitor as maintenance therapy.
We also had the opportunity to update the safety data in this analysis. We found, with extended follow-up, that the safety profile of rucaparib maintenance therapy was consistent with our previous report. Overall, the current analysis of ARIEL3 showed that the benefits from rucaparib maintenance therapy persisted into subsequent lines of therapy with a consistent toxicity profile.
The next study I would like to address is the randomized phase II AVANOVA2 trial, which examined the impact of adding bevacizumab to niraparib for treating patients with platinum-sensitive recurrent ovarian cancer. The concept of this trial was to look at the opportunity to improve outcomes by combining an anti-angiogenic agent with a PARP inhibitor, both of which have proved to be active in treating recurrent ovarian cancer. The first phase of this study identified a recommended phase II dose, and the second phase aimed to assess PFS, the primary endpoint of the trial. Overall, AVANOVA2 was a relatively small study with just under 100 patients enrolled but with important outcomes. The patient population in this trial was slightly enriched for the presence of BRCA mutations. Typically, BRCA mutations are present in 15% to 20% of patients with ovarian cancer, and in AVANOVA2, about a third of the patients were BRCA positive, with most of the mutations being somatic. Predominantly, patients had received 1 or 2 lines of prior therapy.
下一个研究项目我想陈述的是随机II期AVANOVA2试验, 此项研究用于测试贝伐单抗联合尼拉帕尼用于治疗铂类敏感的复发性卵巢癌患者的疗效。这一试验的设想是观察PARP抑制剂结合抗血管生成剂是否有改善结果的机会。这两类药都被证明对于复发性卵巢癌的治疗中具有活性。此项研究的I期试验确定了用于II期试验的药物推荐剂量，并且II期试验旨在评估PFS，即此项试验的重要终点。总得来说，AVANOVA2 是一个相对较小的试验，只有不到100人入组但却有了重要的结果。此项研究适当增加了BRCA突变人群的入组人数。通常来说，BRCA突变在卵巢癌患者中的比例为15% 到20%，在AVANOVA2试验中，大约有1/3的病人是BRCA基因阳性，大多数体细胞突变。大部分病人前期接受过一线或者二线治疗。
The outcomes from this trial are interesting and consistent with a previous report comparing cediranib plus olaparib vs olaparib in the same setting. In AVANOVA2, a substantial improvement in investigator-assessed PFS was observed with the addition of bevacizumab to niraparib. Looking at subgroup analysis based on BRCA status, the PFS benefit was more prominent in the wild-type BRCA patient cohort vs those with tumors harboring mutated BRCA. One plausible reason for this finding could be that BRCA-mutated platinum-sensitive recurrent disease responds well to PARP inhibitors and adding bevacizumab might not yield much additional benefit. When looking at subgroup analysis based on homologous recombination deficiency (HRD) status, the PFS benefit was similar in patients who were positive or negative for HRD. The investigators also looked at subgroups based on chemotherapy-free interval. In patients with short (6-12 months) or long (> 12 months) intervals, a significant PFS benefit was observed with the combination regimen, although it was greater in those with a short chemotherapy-free interval. These results probably reflect the impact of bevacizumab, which has activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer.
此项试验的结果非常有意思并且与前期的报告设定一致，西地尼布联合奥拉帕尼 v.s. 奥拉帕尼单药。 在AVANOVA2，研究者评估的PFS在尼拉帕尼加用贝伐珠单抗后有了显著的改善。看一下亚组的分析数据是基于BRCA的状态，BRCA 野生型组群相较于BRCA突变携带者显著获益。这一发现的一个可能的原因是BRCA突变的铂类敏感性复发性疾病对于PARP抑制剂具有良好的应答，添加贝伐珠单抗可能不会产生太多额外的好处。再看一下基于同源重组缺陷状态的亚组，无论HRD是否阳性，PFS获益没有显著差异。研究者们还观察了基于无化疗间隙的亚组。 在短时间间隔(6-12个月)或长时间间隔(> 12个月)的患者中，联合治疗方案可显著改善PFS，但在长时间间隔的患者中效果更好。这些结果可能反映了贝伐珠单抗的影响，它在铂类敏感性和铂类抗性复发性卵巢癌中都有活性。
In my opinion, AVANOVA2 is an important trial, and it begs the question whether there could be a chemotherapy-free option for patients with platinum-sensitive recurrent ovarian cancer. Indeed, several studies are in progress or being planned to test this hypothesis, one of which is the ongoing phase III NRG-GY004 trial looking at single-agent olaparib vs cediranib plus olaparib vs platinum-based chemotherapy in women with platinum-sensitive recurrent ovarian cancer. Another study is the planned phase III AVATAR trial that will compare niraparib plus bevacizumab with standard of care in the same setting. It is exciting to have new potential combination modalities involving PARP inhibitors in platinum-sensitive recurrent ovarian cancer.
在我看来，AVANOVA2是一项重要的试验，并且提出了一个问题，对于铂敏感性复发性卵巢癌患者，是否可能有一种不需要化疗的选择。事实上，多项研究正在进行或者是正在计划验证这一假定，其中一项正在进行的NRG-GY004 III期试验观察了奥拉帕尼单药v.s.西地尼布加上奥拉帕尼v.s.铂类为基础的化疗方案在女性铂类敏感的复发性卵巢癌中的疗效对照。另一项研究是AVATAR III期试验计划尼拉帕尼联合贝伐单抗与在相同环境下的标准治疗进行疗效对照。令人兴奋的是，在铂敏感性复发性卵巢癌中，有新的潜在的PARP抑制剂联合治疗模式。
The last study I am going to review is SOLO3, a phase III trial of olaparib vs nonplatinum single-agent chemotherapy in women with platinum-sensitive recurrent ovarian cancer harboring germline BRCA mutations. SOLO3 is a highly anticipated trial because it asks the question whether a PARP inhibitor is better than chemotherapy in recurrent disease. This is a very interesting concept because we know that PARP inhibitors have substantial activity in recurrent ovarian cancer. The question is: How do they compare with chemotherapy?
最后一项试验我将要回顾的是SOLO3，一项关于奥拉帕尼对照非铂类单药化疗的III期试验，旨对比两种治疗方案在BRCA突变的铂类敏感的复发性卵巢癌患者中的疗效。SOLO3 是一项备受期待的试验，因为它提出了一个问题：PARP抑制剂在复发性卵巢癌中的疗效是否优于化疗。这是一个非常有趣的概念，因为PARP抑制剂在复发性卵巢癌中具有很大的活性。问题是，他们如何将之于化疗比较呢 ？
We saw in SOLO3 that the ORR (assessed by blinded independent central radiographic review) for olaparib was pretty remarkable at 72% compared with 51% for chemotherapy, with most of the responses being partial response. The increased response rates were seen in patients with 2 prior lines of chemotherapy as well as those with 3 or more prior lines of chemotherapy. Although nonplatinum chemotherapy has better response rates in patients with platinum-sensitive disease than those with platinum-resistant disease, it still begs the question whether platinum-based chemotherapy should have been used instead as the control arm in this trial. Olaparib was also better than nonplatinum chemotherapy in terms of secondary endpoints, including PFS and time to subsequent lines of therapy. Importantly, there was no difference in quality of life between the 2 arms, and the toxicity profile of olaparib was very consistent with previous findings.
Overall, SOLO3 is an important study showing that a PARP inhibitor is better than nonplatinum chemotherapy in patients with platinum-sensitive recurrent disease with germline BRCA mutations. Clinical trials are ongoing or planned to specifically address how PARP inhibitors will fit into the treatment paradigm for ovarian cancer. Our hope is that PARP inhibitors, either as single agents or in combination regimens, might actually replace chemotherapy in a situation where chemotherapy is the current standard of care. More new data on PARP inhibitors in ovarian cancer are eagerly awaited.
What are your thoughts on using PARP inhibitors in patients with platinum-sensitive recurrent ovarian cancer? I encourage you to answer the polling question and post your thoughts in the comments box below.