Discussion
cancers, toxicity, platinum-sensitive disease, cross-sensitivity, hypertension, platinum-resistant recurrent OC, platinum-sensitive recurrent OC
CANCERS, HYPERTENSION, DRUG-DRUG INTERACTION
In this phase 1 trial, the chemo-free combination of fuzuloparib and apatinib demonstrated good tolerability and therapeutic efficacy in biomarker-unselected patients with recurrent gynecological cancers. No MTD was established, and no saturation of plasma drug exposure was observed up to fuzuloparib 100 mg bid plus apatinib 500 mg qd.This highest tested dose combination was determined to be the RP2D. The safety profile of the fuzuloparib-apatinib combination was consistent with the individual agents, with no new safety signals identified. The most frequently reported grade 3 or worse TRAEs were hypertension (the most common TRAE associated with apatinib monotherapy [In this study, obvious anti-tumor activity was seen for fuzuloparib plus apatinib, with a confirmed ORR of 36.5% and DCR of 65.4% across all dose levels. Specifically, the ORR was 80% for patients with platinum-sensitive recurrent OC, which was much higher than the 35.3% for patients with platinum-resistant recurrent OC. The cross-sensitivity between platinum-based chemotherapy and fuzuloparib-apatinib combination could be partly explained by the overlap between resistance mechanisms of platinum and PARP inhibitor, which involves the reactivation of the HR repair pathway [A handful of clinical trials have assessed the combination of an anti-angiogenic agent and a PARP inhibitor as treatment for recurrent OC, and the ORR ranged from 60%-79.6% in platinum-sensitive disease [Although the PARP inhibitors olaparib and talazoparib have shown robust efficacy in gWhen used as combination therapy, the PK profile of fuzuloparib (40–100 mg bid) was similar to that of fuzuloparib monotherapy; however, the exposure of apatinib (250–500 mg qd) at steady state was reduced by 47.7%-65.0% across dose levels when compared to apatinib used as monotherapy. This observation indicates the presence of drug-drug interaction. As the PK profiles of two drugs in multiple doses for combination therapy have been investigated, the data imply that higher dose level of apatinib may be tolerable when combined with fuzuloparib. Besides, the decreased exposure of apatinib suggests potential lower related toxicity of apatinib when used in combination with fuzuloparib. Based on the PK data, it’s recommended that the dose of apatinib be adjusted first in the combination, in the management of intolerable AEs that were potentially related to either agent.