Mansoor Raza Mirza, MD
The combination of bevacizumab (Avastin) plus niraparib (Zejula) demonstrated clinical activity in women with relapsed, platinum-sensitive epithelial ovarian cancer and had a manageable toxicity profile, according to phase I findings presented during the 2017 ESMO Congress in Madrid.
Results of the trial showed that the combination treatment demonstrated an objective response rate (ORR) of 45%. Of 12 patients receiving a fixed-dose of bevacizumab and various doses of niraparib, 1 (8%) patient achieved complete response, 5 (42%) patients achieved partial responses, and stable disease, respectively, providing a disease control rate of 91%; progressive disease was reported for 1 (8%) patient.
Additionally, the median progression-free survival (PFS) was 49 weeks. Three patients remain on bevacizumab/niraparib treatment.
Mansoor Raza Mirza MD, chief oncologist at Copenhagen University Hospital explained that data from a prior randomized phase II study indicated that the combination of a PARP inhibitor plus an anti-angiogenic drug, was superior to PARP inhibition alone, prompting this study of niraparib paired with bevacizumab.
The phase I ENGOT-OV24/AVANOVA1 study investigated the safety and tolerability of combined bevacizumab and niraparib and determined the recommended phase II dose (RP2D) of niraparib in women with platinum-sensitive epithelial ovarian cancer. The primary objective was safety and tolerability of the combination therapy, to spare patients with recurrent ovarian cancer from cytotoxic chemotherapy.
Secondary objectives included the determination of the RP2D of bevacizumab/niraparib pharmacokinetics, (PK) and pharmacodynamics (PD), and to describe the antitumor response. The RP2D was defined as the maximum-tolerated dose (MTD), or dose level minus one of the dose levels, at which at least 1 of 3 or 2 of 6 patients experience dose-limiting toxicities.
Bevacizumab at 15 mg/kg intravenously every 21 days was administered in combination with escalating doses of oral 100, 200, or 300 mg niraparib daily in a classic 3 + 3 escalation design to 3, 3, and 6 patients with high-grade serous/endometrioid carcinoma and measurable disease by RECIST or GCIG criteria.
Three patients had germline BRCA2 mutation, while the remaining had non-germline BRCA mutations. Four patients had homologous recombination deficiency. Eleven patients had an ECOG performance score of 0 and 1 patient had a performance score of 1. The median age was 64 and 1 patient each was FIGO stages IC, IIB, and IIIA at diagnosis, 5 were IIIC, and 4 were stage IV.
During the first 21-day cycle, grade 3 adverse events (AEs) occurred, including hypertension (n = 5), anemia (n = 3) and thrombocytopenia (n = 1). During this cycle grade 2 fatigue, constipation, and nausea were reported in 1 patient each. One dose-limiting toxicity of grade 3 thrombocytopenia lasting for more than 5 days was observed at the highest dose level.
Dose reductions of niraparib were made in 4 patients—1 patient at 200 mg and 3 patients at 300 mg doses. Bevacizumab was discontinued in 2 patients. Nine patients discontinued treatment, 8 due to progressive disease and 1 patient withdrew consent.
“Overlapping exposure bands were observed across dosing groups, which is consistent with previous studies,” Mirza said, adding that niraparib PK and PD were also consistent with historical data. “Fixed-dose bevacizumab plus 300 mg niraparib can be safely administered for extended periods.”
Bevacizumab at 15 mg/kg on day 1 plus 300 mg oral niraparib once daily was taken forward as the RP2D in the ongoing phase II ENGOT-OV24-NSGO/AVANOVA (NCT02354131) trial, which is being conducted in 94 women with platinum-sensitive ovarian cancer and compares single-agent niraparib with the combination.
“Toxicity of the combination is manageable and patients are spared of the effects of cytotoxic chemotherapy for a considerable period,” Mizra summarized.
Mirza MR, Wang J, Mau-Sorensen M, et al. A phase 1 study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the recommended phase 2 dose (RP2D) in women with platinum-sensitive epithelial ovarian cancer (ENGOT-OV24/AVANOVA1). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 953P.