FZOCUS-1 Trial Shows Fuzuloparib Maintenance Therapy Improves Survival in Advanced Ovarian Cancer
核心洞察
The phase 3 FZOCUS-1 trial demonstrated that fuzuloparib monotherapy significantly improved progression-free survival compared to placebo in patients with newly diagnosed advanced ovarian cancer (搜索).
Adding apatinib to fuzuloparib did not provide additional benefit over fuzuloparib alone, marking the first study to show that combining an antiangiogenic agent with a PARP (搜索) inhibitor does not improve outcomes in BRCA-mutated or HRD-positive ovarian cancer (搜索).
Fuzuloparib monotherapy achieved a median PFS of 29.9 months versus 11.1 months with placebo, representing a 42% reduction in disease progression risk.
The phase 3 FZOCUS-1 trial has demonstrated that fuzuloparib monotherapy significantly improves progression-free survival in patients with newly diagnosed advanced ovarian cancer (搜索), while revealing that adding an antiangiogenic agent does not provide additional clinical benefit. The multicenter, randomized, double-blind, placebo-controlled study represents the first to show that combining a PARP (搜索) inhibitor with an antiangiogenic agent fails to improve outcomes in BRCA-mutated or homologous recombination deficiency-positive ovarian cancer.
Primary Efficacy Results
At a median follow-up of 40 months, fuzuloparib monotherapy achieved a median progression-free survival of 29.9 months (95% CI, 22.1-36.1) compared with 11.1 months (95% CI, 8.3-16.6) for placebo (HR, 0.58; 95% CI, 0.44-0.75; 1-sided P < .0001). This represents a 42% reduction in the risk of disease progression or death.
The combination of fuzuloparib plus apatinib produced a median PFS of 26.9 months (95% CI, 20.3-36.6), with a hazard ratio of 0.57 (95% CI, 0.44-0.75; 1-sided P < .0001) compared with placebo. However, this did not represent a significant improvement over fuzuloparib monotherapy.
"To our knowledge, this study is the first to indicate that the addition of an antiangiogenic agent [in this case, apatinib] to a PARP (搜索) inhibitor [in this case, fuzuloparib] does not improve PFS among patients who have BRCA-mutated or homologous recombination deficiency-positive ovarian cancer (搜索)," wrote study co-authors led by Lingying Wu, MD, of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China.
Study Design and Patient Population
FZOCUS-1 enrolled patients aged 18 to 75 years with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer (搜索). Eligible patients had stage III or IV disease, had undergone primary debulking surgery or neoadjuvant therapy with interval debulking surgery, received 6 to 9 cycles of platinum-based chemotherapy with complete or partial response, and had an ECOG performance status of 0 or 1.
Patients were randomly assigned in a 2:2:1 ratio to receive oral fuzuloparib at 100 mg twice daily plus oral apatinib at 375 mg daily, oral fuzuloparib at 150 mg twice daily, or matching placebo. Treatment was initiated no later than 12 weeks following completion of platinum-based chemotherapy.
The study population had a median age of 54 years (range, 29-75). Most patients had HRD disease (72.1%), had undergone primary debulking surgery (57.1%), and achieved R0 resection following cytoreduction (55.6%). BRCA1 (搜索)/2 mutations were present in 31.5% of patients.
Overall Survival and Safety Profile
The median overall survival was not reached in any of the three treatment arms. The 36-month OS rates were 77.0% (95% CI, 71.3%-81.7%) for fuzuloparib monotherapy, 78.9% (95% CI, 73.3%-83.4%) for the combination arm, and 76.6% (95% CI, 68.2%-83.0%) for placebo.
Treatment-related adverse events occurred in 98.9% of patients receiving fuzuloparib monotherapy, 97.8% receiving the combination, and 94.1% receiving placebo. Grade 3 or higher treatment-related adverse events occurred at rates of 45.7%, 48.7%, and 7.4%, respectively.
"The AE profile of fuzuloparib monotherapy was in line with the safety data reported in previous fuzuloparib trials," the study authors noted. "TRAEs of grade 3 or higher were mainly hematological toxicities. Anemia, neutropenia, and thrombocytopenia were common AEs associated with PARP (搜索) inhibitors."
The incidence of hypertension and proteinuria was higher in the fuzuloparib plus apatinib group compared to the fuzuloparib monotherapy group, which the authors attributed to the addition of apatinib.
Clinical Implications
Fuzuloparib received approval in China in December 2020 for treating patients with platinum-sensitive recurrent ovarian cancer (搜索), fallopian tube cancer (搜索), or primary peritoneal cancer (搜索) harboring a BRCA mutation following second-line or later chemotherapy. The agent was subsequently approved in China for frontline maintenance treatment of patients with advanced ovarian cancer based on prior interim analysis data from FZOCUS-1.
The trial's findings provide important insights into combination strategies for ovarian cancer (搜索) maintenance therapy, suggesting that the addition of antiangiogenic agents to PARP (搜索) inhibitors may not enhance clinical outcomes in this patient population.