Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer
Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer
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DOI：
10.1093/annonc/mdz018
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发表时间：
2019-04-01
影响因子：
50.5
通讯作者：
Matulonis, U. A.
中科院分区：
文献类型：
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作者：
Liu, J. F.;Barry, W. T.;Matulonis, U. A.
背景：奥拉帕尼是一种聚（ADP-核糖）聚合酶抑制剂，西地尼布是一种口服抗血管生成药物。在这项II期研究的主要分析中，与奥拉帕尼单药治疗相比，西地尼布/奥拉帕尼联合治疗复发性铂敏感性卵巢癌可改善无进展生存期（PFS）。进行此更新的分析，以表征总生存期（OS）和更新PFS outcome.Patients和方法：90例患者参加了2011年10月至2013年6月在美国的9个学术中心的随机，开放标签，II期研究。数据截止日期为2016年12月21日，中位随访时间为46个月。参与者患有复发性铂敏感性卵巢癌，高级别浆液性或类浆液性组织学或具有有害的生殖系BRCA 1/2突变（gBRCAm）。受试者随机接受奥拉帕尼胶囊400毫克，每天两次或西地尼布30毫克，奥拉帕尼胶囊200毫克，每天两次，直到疾病progression.Results：在这个更新的分析，中位PFS与西地尼布/奥拉帕尼保持显着较长的奥拉帕尼单药相比（16.5与8.2个月，风险比0.50; P = 0.007）。按BRCA状态定义的分层内的子集分析显示PFS改善具有统计学意义（23.7 vs 5.7个月，P = 0.002）和OS（37.8 vs 23.0个月，P = 0.047），尽管总体研究人群的OS无统计学差异（44.2 vs 33.3个月，风险比0.64; P = 0.11）。两组gBRCAm患者的PFS和OS相似。西地尼布/奥拉帕尼最常见的CTCAE 3/4级不良事件仍然是疲劳、腹泻和高血压。结论：与奥拉帕尼单药治疗复发性铂敏感性卵巢癌相比，西地尼布/奥拉帕尼联合治疗可显著延长PFS。亚组分析表明，这种获益幅度是由无gBRCAm患者的PFS延长驱动的。西地尼布/奥拉帕尼联合治疗也显著增加了该患者亚组的OS。对该组合的其他研究正在进行中，并应纳入基于BRCA状态的分析。
Background: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes.Patients and methods: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression.Results: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension.Conclusions: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status.