Senaparib maintenance significantly delays disease progression in patients with advanced ovarian cancer
In recent years, poly-ADP ribose polymerase (PARP) inhibitors have revolutionised the the maintenance treatment for patient with ovarian cancer (OC). In the phase 3 FLAMES trial, senaparib maintenance monotherapy led to an unprecedented reduction in the risk of progression or death in patients with newly diagnosed OC, irrespective of the BRCA mutation status. As such, these data support senaparib as a maintenance treatment for patients with advanced OC after response to first-line chemotherapy.
The emergence of poly-ADP ribose polymerase (PARP) inhibitors has revolutionised the paradigm of maintenance therapy for ovarian cancer (OC), effectively prolonging remission and arresting disease progression in advanced cases. Senaparib is a novel, highly potent PARP inhibitor characterised by a distinctive molecular structure, which ensures exceptional target selectivity and a wide safety window. Early-phase trials demonstrated the efficacy of senaparib with promising antitumour activity in OC. In these studies, the recommended phase 2 dose of 100 mg daily achieved more than a 40-fold coverage above the minimal effective exposure, suggesting the potential for outstanding clinical efficacy. The phase 3 study FLAMES aimed to investigate the efficacy and safety of senaparib in Chinese patients with newly diagnosed advanced OC as a first-line maintenance therapy.
Methods
The phase III FLAMES trial enrolled patients with newly diagnosed, FIGO stage III-IV, high-grade serous or endometrioid OC, who completed first-line platinum-based chemotherapy with a complete (CR) or partial response (PR). In total, 404 patients were randomly assigned (2:1) to receive senaparib (n=262) or placebo (n=131). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) according to RECIST v1.1. Secondary endpoints included PFS by investigator assessment, safety, time to discontinuation or death, time to first subsequent therapy or death and chemotherapy-free interval.
Results
After a median follow-up of 22.4 and 22.2 months in the senaparib and placebo groups, respectively, a significant PFS benefit was observed for senaparib over placebo (HR[95%CI]: 0.43[0.32-0.58]; p < 0.0001), with the median PFS that was not reached for senaparib as compared to 13.6 months with placebo. As such, the median PFS assessment by the investigator also resulted in an HR of 0.43. At 24 months, PFS rates were 63.0% vs. 31.3% in the senaparib and placebo groups, respectively. This PFS benefit was observed across all subgroups and was seen irrespective of BRCA mutation status (HR: 0.43 for both BRCA-mutated and wild-type groups). In addition, all the secondary efficacy endpoints favoured senaparib over placebo. The median time to study treatment discontinuation or death was 23.4 vs. 11.4 months in the senaparib and placebo arms, respectively (HR:0.68). In addition, the chemotherapy-free interval and median time to first subsequent therapy or death were not reached in the senaparib arm, while they were reported at 16.7 and 14.4 months, respectively, in the placebo arm. Incidence rates of grade ≥3 treatment-emergent adverse events (TEAEs) were 66.3 % vs 20.3% in patients receiving senaparib and placebo, respectively, with AEs leading to dose reduction in 63.3 % vs 6.0% of patients and discontinuation in 4.4 % vs. 0% of patients. There were no AEs leading to death. Importantly, patients who needed a senaparib dose reductions did not experience a worsening in PFS compared to those who maintained their dose.
Conclusion
In the FLAMES study, senaparib maintenance monotherapy led to an unprecedented reduction in the risk of progression or death in patients with newly diagnosed OC, irrespective of the BRCA mutation status. Additionally, senaparib was well tolerated and no new safety signals were identified. These results support senaparib as a maintenance treatment for patients with advanced OC after response to first-line chemotherapy.
Reference
Wu X, et al. Efficacy and safety of senaparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer (FLAMES study): A randomized, double-blind, placebo-controlled, phase III trial. Presented at ESMO 2023; LBA36.
