《柳葉刀》2017年9月12日在線先發

http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)32440-6/fulltext

Rucaparib維持治療鉑類化療緩解后複發性卵巢腺癌（ARIEL3試驗）：一項隨機、雙盲、安慰劑對照的3期臨床試驗

背景

Rucaparib是一種聚腺苷二磷酸核糖聚合酶抑製劑，在BRCA突變的或高比例全基因組染色體雜合性缺失的複發性卵巢腺癌中具有抗腫瘤活性。在這項臨床試驗中，我們在高級別、複發性、鉑類藥物敏感的卵巢腺癌患者中，，評價了二線治療或後期含鉑方案化療緩解后使用Rucaparib對比安慰劑的效果。

方法

在這項隨機、雙盲、安慰劑對照的3期臨床試驗中，我們在11個國家的87家醫院和癌症中心招募患者，符合條件的患者為：

年齡≥18歲

鉑類藥物敏感的高級別漿液性或子宮內膜樣卵巢腺癌、原發性腹膜或輸卵管腺癌

既往接受過至少2種含鉑化療方案

最後一次含鉑化療方案獲得完全或部分緩解

CA125濃度小於正常值的上限

體能評分0-1分

器官功能良好。

有癥狀的或未治療的中樞神經系統轉移的患者、開始研究前接受抗癌治療≤14天的患者、或者既往接受過聚腺苷二磷酸核糖聚合酶抑製劑治療的患者為不符合入組條件。我們採用計算機生成的序列號（6名患者為一區組，通過同源重組修復基因突變狀態、倒數第二個含鉑方案治療后無進展間隔期、對最後一個含鉑方案治療的最佳緩解情況進行分層分組），按照2：1的比例將患者分組，一組每日兩次口服Rucaparib600mg、一組口服安慰劑，28天一周期。患者、研究人員、現場人員、評價人員以及資助方均對分組情況不知曉。主要終點為研究人員評價的無進展生存期，對3個巢式隊列採用一種序列降階梯法評價無進展生存期，這3個巢式隊列為：BRCA突變患者（生殖細胞或體細胞BRCA突變引起的腺癌）、同源性重組缺陷患者（BRCA突變或BRCA野生型、高雜合性缺失）以及意向性治療患者，在篩選患者時評價，以後每12周評價一次。這項試驗已在ClinicalTrials.gov網站註冊，註冊號NCT01968213，入組已完成。

結果

2014年4月7日至2016年7月19日，我們將564名患者隨機分組：Rucaparib組375名（66%）、安慰劑組189名（34%）。Rucaparib組中BRCA突變腺癌患者的中位無進展生存期為16.6個月（95%CI，13.4–22.9，130名[35%]患者），而安慰劑組BRCA突變腺癌患者的中位無進展生存期為5.4個月（3.4–6.7，66名[35%]患者）（風險比，0.23[95%CI，0.16-0.34]，p<0.0001）；在同源性重組缺陷腺癌患者中，則是13.6個月（10.9–16.2）對比5.4個月（5.1–5.6，0.32[0.24–0.42]；p<0.0001）；在意向性治療患者中，則為10.8個月（8.3–11.4）對比5.4個月（5.3–5.5，0.36[0.30–0.45]；p<0.0001）。安全性患者（Rucaparib組372名[99%]對比安慰劑組189名[100%]）中≥3級的治療突發性不良事件，Rucaparib組報告有209名（56%）、安慰劑組28名（15%），最常見者為貧血或血紅蛋白濃度下降（70名[19%]對比1名[1%]）、丙氨酸或天冬氨酸轉氨酶升高（39名[10%]對比0）。

解釋

縱觀所有主要分析組，在含鉑方案化療獲得緩解的、鉑類藥物敏感的卵巢癌患者中，Rucaparib明顯延長了無進展生存期。對於二線或後期含鉑化療完全或部分緩解后鉑類藥物敏感的卵巢癌女性，在維持治療對比安慰劑的情況下，作為一種新的標準治療，可以考慮使用聚腺苷二磷酸核糖聚合酶抑製劑進行維持治療，ARIEL3試驗為此提供了進一步的證據。

《壹篇》南南和北北

Rucaparib maintenance treatment for recurrent ovariancarcinoma after response to platinum therapy (ARIEL3): arandomised, double-blind, placebo-controlled, phase 3trial

Background

Rucaparib, a poly(ADP-ribose) polymerase inhibitor, hasanticancer activity in recurrent ovarian carcinoma harbouring aBRCA mutation or high percentage of genome-wide loss ofheterozygosity. In this trial we assessed rucaparib versus placeboafter response to second-line or later platinum-based chemotherapyin patients with high-grade, recurrent, platinum-sensitive ovariancarcinoma.

Methods

In this randomised, double-blind, placebo-controlled, phase 3trial, we recruited patients from 87 hospitals and cancer centresacross 11 countries. Eligible patients were aged 18 years or older,had a platinum-sensitive, high-grade serous or endometrioidovarian, primary peritoneal, or fallopian tube carcinoma, hadreceived at least two previous platinum-based chemotherapyregimens, had achieved complete or partial response to their lastplatinum-based regimen, had a cancer antigen 125 concentration ofless than the upper limit of normal, had a performance status of0–1, and had adequate organ function. Patients were ineligible ifthey had symptomatic or untreated central nervous systemmetastases, had received anticancer therapy 14 days or fewer beforestarting the study, or had received previous treatment with apoly(ADP-ribose) polymerase inhibitor. We randomly allocatedpatients 2:1 to receive oral rucaparib 600 mg twice daily orplacebo in 28 day cycles using a computer-generated sequence (blocksize of six, stratified by homologous recombination repair genemutation status, progression-free interval after the penultimateplatinum-based regimen, and best response to the most recentplatinum-based regimen). Patients, investigators, site staff,assessors, and the funder were masked to assignments. The primaryoutcome was investigator-assessed progression-free survivalevaluated with use of an ordered step-down procedure for threenested cohorts: patients with BRCA mutations (carcinoma associatedwith deleterious germline or somatic BRCA mutations), patients withhomologous recombination deficiencies (BRCA mutant or BRCAwild-type and high loss of heterozygosity), and theintention-to-treat population, assessed at screening and every 12weeks thereafter. This trial is registered with ClinicalTrials.gov,number NCT01968213; enrolment is complete.

Findings

Between April 7, 2014, and July 19, 2016, we randomly allocated564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo.Median progression-free survival in patients with a BRCA-mutantcarcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) inthe rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients)in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34];p<0·0001). In patients with a homologous recombination deficientcarcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2)versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In theintention-to-treat population, it was 10·8 months (8·3–11·4) versus5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001).Treatment-emergent adverse events of grade 3 or higher in thesafety population (372 [99%] patients in the rucaparib group vs 189[100%] in the placebo group) were reported in 209 (56%) patients inthe rucaparib group versus 28 (15%) in the placebo group, the mostcommon of which were anaemia or decreased haemoglobin concentration(70 [19%] vs one [1%]) and increased alanine or aspartateaminotransferase concentration (39 [10%] vs none).

Interpretation

Across all primary analysis groups, rucaparib significantlyimproved progression-free survival in patients withplatinum-sensitive ovarian cancer who had achieved a response toplatinum-based chemotherapy. ARIEL3 provides further evidence thatuse of a poly(ADP-ribose) polymerase inhibitor in the maintenancetreatment setting versus placebo could be considered a new standardof care for women with platinum-sensitive ovarian cancer followinga complete or partial response to second-line or laterplatinum-based chemotherapy.

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