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.
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BACKGROUND: Addition of anti-angiogenic inhibitors has the potential to enhance the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors; however, clinical evidence for their use in breast cancer is scarce. The FABULOUS study assessed fuzuloparib (an oral PARP inhibitor) with or without apatinib (an oral angiogenesis inhibitor) for breast cancer. METHODS: FABULOUS was an open-label, randomised, phase 3 trial done at 40 sites in China. 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. 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). 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. The primary endpoint was progression-free survival per blinded independent central review (BICR). Herein, we reported the findings of prespecified interim analysis. Efficacy was assessed in the intention-to-treat population. Safety was analysed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov (NCT04296370). Recruitment and follow-up are ongoing to achieve the target sample size and obtain long-term efficacy and safety data. FINDINGS: 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. At the present interim analysis, median time from randomisation to cutoff date was 24·2 months (IQR 13·2-31·8). Median progression-free survival per 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. 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 survival than fuzuloparib (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. Serious treatment-related adverse events occurred in nine (13%), 12 (18%), and eight (14%) patients in the fuzuloparib-apatinib, fuzuloparib, and chemotherapy groups, respectively. 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). INTERPRETATION: Fuzuloparib, either as monotherapy or in combination with apatinib, provided statistically significant improvements in progression-free survival compared with chemotherapy in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations, presenting as new treatment options. 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.