Platinum-based chemotherapy followed by poly(ADP-ribose) polymerase (PARP) inhibitor maintenance is the established standard of care for platinum-sensitive recurrent ovarian cancer. However, use of platinum-based chemotherapy is limited due to risk of cumulative toxicity. The PARP inhibitor niraparib has demonstrated efficacy both as maintenance therapy following platinum chemotherapy (NOVA trial) and as a monotherapy in pretreated recurrent platinum-sensitive ovarian cancer (QUADRA trial). Preclinical and early phase I/II data (AVANOVA1) evaluating the combination of niraparib with the angiogenesis inhibitor bevacizumab showed enhanced efficacy, indicating synergistic mechanisms of action for this chemotherapy-free combination. At the 2019 American Society for Clinical Oncology (ASCO) Annual Meeting, Mansoor Mirza, MD (Copenhagen University Hospital, Copenhagen, Denmark), presented results from the randomized phase II AVANOVA2 trial (Abstract 5505), which compared single-agent niraparib (300 mg daily) to the combination of niraparib (300 mg daily) and bevacizumab (15 mg/kg every 3 weeks) in 97 patients with platinum-sensitive recurrent high-grade serous/endometroid ovarian cancer. Patients who previously received bevacizumab were also eligible for this trial (approximately 25%).
The combination of niraparib and bevacizumab significantly improved median progression-free survival (PFS) compared to niraparib monotherapy (11.9 months vs 5.5 months; HR 0.35, P<.0001). The greatest PFS benefit was seen in patients with a chemotherapy-free interval of 6 to 12 months (11.3 months vs 2.2 months; HR 0.29, P = .0006), but those with a chemotherapy-free interval of more than 12 months also benefit from the combination (13.1 months vs 6.1 months; HR 0.42, P = .0062). Presence or absence of homologous recombination deficiencies (HRD) did not impact the PFS benefit. The overall response rate (ORR) was superior in patients receiving combination therapy (60% vs 27%; P = .001), as was the disease control rate (79% vs 53%; P = .008).
The combination of niraparib and bevacizumab was tolerable and managed with dose reductions, which were required in half of the patients. Among adverse events associated with bevacizumab were increased rates of hypertension, enhanced neutropenia, a few cases of deep vein thrombosis, and proteinuria. Importantly, quality of life was similar between the two arms. Dr Mirza concluded that the combination of niraprib and bevacizumab is safe and tolerable treatment option for platinum-sensitive recurrent ovarian cancer. The randomized, phase III NSGO-AVATAR trial will further evaluate this combination in platinum-sensitive recurrent ovarian cancer. The discussant of this study, Don Dizon, MD (Lifespan Cancer Institute, Providence, Rhode Island, United States), indicated that chemotherapy-free regimens may provide an important treatment option for patients with platinum-sensitive recurrent disease, but highlighted that many patients will receive PARP inhibitors in the first-line setting and, moving forward, studies are needed to determine the efficacy of continued PARP inhibition in patients progressing on first-line PARP inhibitors.
For an interesting expert discussion on chemotherapy-free regimens in recurrent platinum- sensitive ovarian cancer, see this conference data review from the 2019 ASCO Annual Meeting.