Fuzuloparib Plus Apatanib Prolongs Progression-Free Survival in HER2-Negative Metastatic Breast Cancer With Germline BRCA Mutations
Key Clinical Takeaways
- Design/Population: FABULOUS was an open-label, randomized, phase 3 study conducted across 40 sites enrolling 203 patients with HER2-negative metastatic breast cancer and germline BRCA1/2 mutations. Patients were randomized 1:1:1 to receive fuzuloparib plus apatinib, fuzuloparib alone, or physician’s-choice chemotherapy (capecitabine or vinorelbine).
- Key Outcomes: Median PFS was 11 months with fuzuloparib plus apatinib, 6.7 months with fuzuloparib, and 3 months with chemotherapy. Both fuzuloparib regimens significantly improved PFS versus chemotherapy, with additional benefit observed from the combination regimen compared with monotherapy.
- Safety: Grade 3/4 treatment-related adverse events occurred in 13% of patients in the fuzuloparib plus apatinib arm, 18% in the fuzuloparib arm, and 14% in the chemotherapy arm. The most common toxicities were neutropenia, hypertension, and anemia, and 1 treatment-related death (septic shock) occurred with fuzuloparib monotherapy.
- Clinical Relevance: The combination of fuzuloparib and apatinib achieved the longest PFS and acceptable safety profile, suggesting synergistic activity between PARP and angiogenesis inhibition. These results position fuzuloparib-based regimens as promising new targeted therapies for patients with HER2-negative metastatic breast cancer and germline BRCA mutations.
Results from the phase 3 FABULOUS trial demonstrated that the addition of apatinib, an oral antiangiogenic inhibitor, to fuzuloparib significantly improved progression-free survival (PFS) compared with fuzuloparib monotherapy or standard chemotherapy among patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer harboring germline BRCA1/2 mutations.
According to Huiping Li, MD, Peking University Cancer Hospital and Institute, Beijing, China, and coauthors, the “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.”
In this open-label study, 203 patients were randomized 1:1:1 to receive either 100 mg of twice daily fuzuloparib plus 500 mg of once daily apatinib (n = 70), 150 mg of twice daily fuzuloparib (n = 67), or physician’s choice of capecitabine or vinorelbine (n = 66). Patients were stratified according to the number of prior chemotherapy regimens, hormone receptor status, and prior platinum-based therapy. The primary end point was PFS, assessed by blinded independent central review. A key secondary end point was safety.
At analysis, the median PFS was 11 months in the fuzuloparib plus apatinib arm, 6.7 months in the fuzuloparib monotherapy arm, and 3 months in the chemotherapy arm. Both fuzuloparib plus apatinib (hazard ratio [HR], 0.27; 95% CI, 0.17 to 0.43; P < .0001) and fuzuloparib monotherapy (HR, 0.49; 95% CI, 0.32 to 0.75; P = .0004) significantly prolonged PFS compared with chemotherapy. Fuzuloparib plus apatinib also improved PFS compared with fuzuloparib monotherapy (HR, 0.60; 95% CI, 0.40 to 0.91; P = .0079).
The most common grade 3/4 treatment-related adverse events included decreased neutrophil count (13%) and hypertension (13%) in the fuzuloparib plus apatinib arm; anemia (37%) and decreased neutrophil count (21%) in the fuzuloparib monotherapy arm; and decreased neutrophil count (24%) and decreased white blood cell count (19%) in the chemotherapy arm. Serious treatment-related adverse events occurred in 13%, 18%, and 14% of patients, respectively. No treatment-related deaths occurred in the fuzuloparib plus apatinib arm or the chemotherapy arm. One treatment-related death occurred in the fuzuloparib monotherapy arm due to septic shock.
As Dr Li et al concluded, “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.”
Source:
Li H, Liu J, Ouyang Q, et al. 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. Lancet Oncol. Published online: December 2025. doi: 10.1016/S1470-2045(25)00523-6
