Fuzuloparib with or without apatinib in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations (FABULOUS): interim analysis of a multicentre, three-arm, open-label, randomised, phase 3 trial.

The FABULOUS study assessed fuzuloparib (an oral PARP inhibitor) with or without apatinib (an oral angiogenesis inhibitor) for breast cancer.

FABULOUS研究评估了口服PARP抑制剂fuzuloparib与或不与口服血管生成抑制剂apatinib联合用于乳腺癌。

Methods

FABULOUS was an open-label, randomised, phase 3 trial done at 40 sites in China.

FABULOUS 是在中国 40 个地点进行的一项开放标签、随机、III 期试验。

Eligible patients were women aged 18-75 years, with HER2-negative metastatic breast cancer with deleterious or suspected deleterious germline BRCA1 or BRCA2 (BRCA1/2) mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1.

符合条件的患者为 18-75 岁的女性，患有 HER2 阴性的转移性乳腺癌，具有有害或疑似有害的遗传性 BRCA1 或 BRCA2 (BRCA1/2) 突变，并且东部肿瘤协作组表现状态为 0 或 1。

Patients were randomly assigned (1:1:1) to receive oral fuzuloparib 100 mg twice daily plus oral apatinib 500 mg once daily, oral fuzuloparib 150 mg twice daily, or chemotherapy of the physician's choice (either oral capecitabine 1000-1250 mg/m2 twice daily on days 1-14 of each 21-day cycle or intravenous vinorelbine 25-30 mg/m2 on days 1 and 8 of each 21-day cycle).

患者按1:1:1的比例随机分配，接受口服富祖洛帕利100 mg每日两次加口服阿帕替尼500 mg每日一次，口服富祖洛帕利150 mg每日两次，或者选择医生的化疗方案（口服卡培他滨1000-1250 mg/m2每日两次，连续14天，每21天为一个周期，或静脉注射长春瑞滨25-30 mg/m2，在每个21天周期的第1天和第8天）。

Randomisation was done via a centralised interactive web-response system using block randomisation (block size of six), stratified by the number of previous chemotherapy regimens for metastatic disease, hormone receptor status, and previous use of platinum-based therapy.

随机分组通过中央互动网络响应系统进行，采用分块随机化（分块大小为六），根据转移性疾病的既往化疗方案数量、激素受体状态和既往使用铂类药物的情况进行分层。

The primary endpoint was progression-free survivalper blinded independent central review (BICR).

主要终点是根据盲法独立中心评审（BICR）的无进展生存期。

Herein, we reported the findings of prespecified interim analysis.

在此，我们报告了预先设定的中期分析结果。

Efficacy was assessed in the intention-to-treatpopulation.

疗效评估在意向治疗人群中进行。

Safety was analysed in patients who received at least one dose of study medication.

安全性分析针对至少接受过一次研究药物治疗的患者进行。

This study is registered with ClinicalTrials.gov (NCT04296370).

本研究已在ClinicalTrials.gov注册（NCT04296370）。

Recruitment and follow-up are ongoing to achieve the target sample size and obtain long-term efficacy and safety data.

招募和随访正在进行中，以达到目标样本量并获取长期疗效和安全性数据。

Results

Between Oct 12, 2020, and Dec 13, 2023, 203 eligible patients were enrolled and assigned to receive fuzuloparib-apatinib (n=70), fuzuloparib (n=67), or chemotherapy (n=66). 191 (94%) patients were Han Chinese, and 12 (6%) were other ethnicity Chinese.

在2020年10月12日至2023年12月13日期间，共有203名符合条件的患者参与研究并被分配接受fuzuloparib-apatinib(n=70)，fuzuloparib(n=67)或化疗(n=66)治疗。其中191名（94%）患者为汉族，另外12名（6%）患者为其他民族的中国人。

At the present interim analysis, median time from randomisation to cutoff date was 24·2 months (IQR 13·2-31·8).

在当前的中期分析中，从随机分组到截止日期的中位时间为24.2个月（四分位数间距13.2-31.8）。

Median progression-free survivalper BICR was 11·0 months (95% CI 8·4-13·1) with fuzuloparib-apatinib, 6·7 months (4·2-7·6) with fuzuloparib, and 3·0 months (1·6-5·3) with chemotherapy.

根据BICR评估，fuzuloparib-apatinib组的中位无进展生存期为11.0个月（95%置信区间8.4-13.1），fuzuloparib组为6.7个月（4.2-7.6），化疗组为3.0个月（1.6-5.3）。

Compared with chemotherapy, fuzuloparib-apatinib (HR 0·27 [95% CI 0·17-0·43]; one-sided p<0·0001) or fuzuloparib alone (0·49 [0·32-0·75]; p=0·0004]) groups had significantly longer progression-free survival. Additionally, the fuzuloparib-apatinib group had significantly longer progression-free survivalthan fuzuloparib (0·60 [0·40-0·91]; p=0·0079).

与化疗相比，fuzuloparib-apatinib组（HR 0.27 [95% CI 0.17-0.43]；单侧p<0.0001）和fuzuloparib单独组（0.49 [0.32-0.75]；p=0.0004）的无进展生存期显著更长。此外，fuzuloparib-apatinib组的无进展生存期也显著长于fuzuloparib单独组（0.60 [0.40-0.91]；p=0.0079）。

The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [13%]) and hypertension (nine [13%]) in the fuzuloparib-apatinib group; anaemia (25 [37%]) and decreased neutrophil count (14 [21%]) in the fuzuloparib group; and decreased neutrophil count (14 [24%]) and decreased white blood cell count (11 [19%]) in the chemotherapy group.

在fuzuloparib-apatinib组中，最常见的3-4级治疗相关不良事件是中性粒细胞减少（九例[13%]）和高血压（九例[13%]）；在fuzuloparib组中，最常见的为贫血（25例[37%]）和中性粒细胞减少（14例[21%]）；在化疗组中，最常见的为中性粒细胞减少（14例[24%]）和白细胞减少（11例[19%]）。

Serious treatment-related adverse events occurred in nine (13%), 12 (18%), and eight (14%) patients in the fuzuloparib-apatinib, fuzuloparib, and chemotherapy groups, respectively.

在fuzuloparib-apatinib组、fuzuloparib组和化疗组中，分别有九例（13%）、12例（18%）和八例（14%）患者出现了严重的治疗相关不良事件。

There were no treatment-related deaths in the fuzuloparib-apatinib and chemotherapy groups, and one (1%) patient in the fuzuloparib group died due to a treatment-related adverse event(septic shock).

在fuzuloparib-apatinib组和化疗组中，均未出现与治疗相关的死亡事件，而在fuzuloparib组中，有一名（1%）患者因治疗相关的不良事件（败血性休克）死亡。

interpretation

Fuzuloparib, either as monotherapy or in combination with apatinib, provided statistically significant improvements in progression-free survivalcompared with chemotherapy in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations, presenting as new treatment options.

无论是单药使用还是与阿帕替尼联合使用，fuzuloparib在与化疗相比时，为HER2阴性的转移性乳腺癌患者（携带种系BRCA1/2突变）提供了统计学上显著的无进展生存期改善，为新的治疗选择。

funding

Jiangsu Hengrui Pharmaceuticals, Natural Science Foundation of China, National Key Research and Development Program of China, Guangdong Science and Technology Department, Science and Technology Program of Guangzhou, Bureau of Science and Technology of Guangzhou, and Program for Guangdong Introducing Innovative and Entrepreneurial Teams.

江苏恒瑞医药、中国自然科学基金、中国国家重点研发计划、广东省科技厅、广州市科技计划、广州市科学技术局以及广东省引进创新与创业团队计划。