Targeting homologous recombination deficiency with intensified chemotherapy versus standard chemotherapy followed by olaparib in stage III breast cancer (SUBITO): an open-label, randomised, controlled, phase 3 trial.

Methods

This open-label, randomised, controlled, phase 3 trial included patients from eight hospitals and one cancer centre in the Netherlands and one cancer centre in France.

这项开放标签、随机、对照的III期试验包括来自荷兰八家医院和一家癌症中心以及法国一家癌症中心的患者。

Newly diagnosed patients aged between 18-66 years with stage IIIA-C, HER2-negative, HRD breast cancer without distant metastases who had a pathogenic germline BRCA1/2 mutation or evidence of a HRD tumour on testing were randomly assigned (1:1) to receive IACT or conventional chemotherapy using interactive response technology.

年龄在18-66岁之间，新诊断为III A-C期、HER2阴性、HRD乳腺癌且无远处转移的患者，如果存在致病性遗传性BRCA1/2突变或通过检测显示肿瘤HRD阳性，则使用交互式响应技术随机分配（1:1）接受IACT或常规化疗。

IACT comprised dose-dense alkylating chemotherapy (ddAC; four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks intravenously), supported by 6 mg prophylactic pegfilgrastim subcutaneously every 2 weeks. 2 weeks after stem cell mobilisation, patients received two IACT cycles 3 weeks apart (3000 mg/m2 cyclophosphamide on day 1, 250 mg/m2 thiotepa on day 2, and 400 mg/m2 carboplatin intravenously on days 1 and 2), followed by autologous stem cell transplantation.

IACT包括密集剂量的烷化化疗（ddAC；每2周静脉注射多柔比星60 mg/m2和环磷酰胺600 mg/m2，共四周期），并每2周皮下注射6 mg预防性pegfilgrastim。干细胞动员2周后，患者接受两个IACT周期，间隔3周（第1天静脉注射环磷酰胺3000 mg/m2，第2天静脉注射噻替派250 mg/m2，第1和第2天静脉注射卡铂400 mg/m2），随后进行自体干细胞移植。

Conventional chemotherapy comprised four ddAC cycles, followed by four cycles of intravenous carboplatin area under the curve 6 every 3 weeks, and 80 mg/m2 paclitaxel every week for 12 weeks (carboplatin-paclitaxel intravenously), followed by 1 year of oral olaparib (300 mg twice daily).

常规化疗包括四个周期的ddAC，随后是四个周期的静脉注射卡铂曲线下面积（AUC）6，每3周一次，以及每周80 mg/m2的紫杉醇，持续12周（卡铂-紫杉醇静脉注射），之后是为期一年的口服奥拉帕利（每日两次，每次300 mg）。

All patients proceeded to surgery and radiotherapy according to local practice.

所有患者均按照当地实践进行了手术和放疗。

Stratification factors were treatment centre, age, stage, and oestrogen receptor status.

分层因素包括治疗中心、年龄、分期和雌激素受体状态。

The primary endpoint was overall survivalin the intention-to-treatpopulation (all randomly allocated patients).

主要终点是在意向治疗人群中观察的总生存（所有随机分配的患者）。

The trial was registered at ClinicalTrials.gov, NCT02810743, and is ongoing, but is closed for inclusion.

该试验已在ClinicalTrials.gov注册，编号为NCT02810743，并且正在进行中，但已停止纳入新患者。

Results

From Jan 25, 2017, through to Oct 5, 2023, 356 patients were screened for eligibility, and 174 patients were randomly assigned to receive IACT (n=87) or olaparib (n=87).

从2017年1月25日至2023年10月5日，共有356名患者接受了资格筛查，其中174名患者被随机分配接受IACT治疗（n=87）或奥拉帕利治疗（n=87）。

All patients were female, and median age was 42 years (IQR 37-50).

所有患者均为女性，中位年龄为42岁（四分位数间距37-50岁）。

We did not ask explicit informed consent for collecting data on ethnicity of patients, because we focused on a very rare patient subgroup and therefore used pragmatic eligibility criteria following standard General Data Protection Regulation. 28 (32%) in the IACT group and 22 (25%) patients in the olaparib group had germline BRCA1/2 mutations.

我们没有明确要求获取患者种族数据的知情同意，因为我们关注的是一个非常罕见的患者亚组，因此采用了实用的资格标准，遵循标准的通用数据保护条例。IACT组中有28名（32%）患者和奥拉帕利组中有22名（25%）患者具有胚系BRCA1/2突变。

With a median follow-up of 41 months (IQR 27-59), the 4-year overall survivalwas 77·0% (95% CI 67·7-87·7 in the IACT group and 76·4% (66·9-87·4) in the olaparib group (hazard ratiofor death 1·11 [95% CI 0·57-2·17]; p=0·37).The most common grade 3-4 adverse events were platelet count decreased (80 [99%] in the IACT group vs 18 [19%] in the olaparib group), neutrophil count decreased (77 [95%] in the IACT group vs 56 [61%] in the olaparib group), and anaemia (50 [62%] in the IACT group vs 37 [41%] in the olaparib group).

中位随访时间为41个月（四分位数间距27-59），IACT组的4年总生存率为77·0%（95%置信区间67·7-87·7），而奥拉帕利组为76·4%（95%置信区间66·9-87·4）（死亡风险比为1·11 [95%置信区间0·57-2·17]；p=0·37）。最常见的3-4级不良事件为血小板计数减少（IACT组80例[99%]，奥拉帕利组18例[19%]），中性粒细胞计数减少（IACT组77例[95%]，奥拉帕利组56例[61%]）和贫血（IACT组50例[62%]，奥拉帕利组37例[41%]）。

Treatment-emergent serious adverse events occurred in 38 (47%) of 81 patients in the IACT group versus 24 (26%) of 91 patients in the olaparib group.

在IACT组的81名患者中，有38名（47%）出现了治疗后严重的不良事件，而在奥拉帕利组的91名患者中，有24名（26%）出现了治疗后严重的不良事件。

Febrile neutropenia was the most common serious adverse eventin both groups (36 [44%] in the IACT group; 11 [12%] in the olaparib group).

发热性中性粒细胞减少症是两组中最常见的严重不良事件（IACT组36例[44%]；奥拉帕利组11例[12%]）。

No treatment-related deaths were reported.

未报告与治疗相关的死亡事件。

interpretation

These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib.

这些数据表明，在III期、HER2阴性、HRD乳腺癌中，针对HRD可获得有希望的结果，而使用自体干细胞救援的强化化疗并未显示出比当前最佳化疗联合奥拉帕利有任何优势。

funding

Dutch Cancer Society, the Dutch Ministry of Health, the Netherlands Organization for Health Research and Development, A Sister's Hope, [Z]aan de Wandel, AstraZeneca, MSD, and Eurocept Pharmaceuticals.

荷兰癌症协会、荷兰卫生部、荷兰健康研究与发展组织、姐妹希望、[Z]aan de Wandel、阿斯利康、默沙东和欧洲制药公司。