Poly (ADP-ribose) polymerase (PARP) inhibitors are relatively new, yet important, targeted therapies being used in the treatment of BRCA-mutation cancer cell lines. At the European Society for Medical Oncology Congress 2019 in Barcelona, Spain, results from 3 independent clinical trials showed the value of PARP inhibitors as first-line or maintenance therapies in patients with advanced ovarian cancer. These findings expand the utility of PARP inhibitors beyond the treatment of recurrent ovarian cancer and demonstrate the potential benefit of these agents in patients with homologous recombination deficiency (HRD)-positive tumors.
Olaparib (Lynparza; AstraZeneca) is FDA approved for use as maintenance therapy in patients with advanced ovarian cancer with BRCA1 or BRCA2 germline mutations who are in complete or partial response to first-line platinum-based chemotherapy. The phase 3 PAOLA-1/ENGOT-ov25 trial investigated olaparib plus bevacizumab (Avastin; Genentech) as maintenance therapy in 806 patients with newly diagnosed advanced ovarian cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy plus bevacizumab. Patients were randomized to a maintenance regimen with olaparib plus bevacizumab or placebo plus bevacizumab.
Compared with placebo plus bevacizumab, maintenance therapy with olaparib plus bevacizumab improved median progression-free survival (PFS) from 16.6 months to 22.1 months (P <.0001) in the overall population, irrespective of BRCA status. Patients with HRD-positive ovarian cancer also had a PFS benefit from olaparib plus bevacizumab (regardless of BRCA status), with a median PFS of 37.2 months versus 17.7 months for placebo plus bevacizumab.
Niraparib (Zejula; GlaxoSmithKline) was recently approved by the FDA for use in patients with advanced ovarian cancer associated with HRD-positive status who have received ≥3 lines of chemotherapy. In the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial, 733 patients with newly diagnosed advanced ovarian cancer who responded to platinum-based chemotherapy were randomized to niraparib or placebo as maintenance therapy.
Median PFS was approximately 6 months longer in the niraparib arm than in the placebo arm (13.8 months vs 8.2 months, respectively; P <.001). In patients with HRD-positive disease, the difference in median PFS was even more striking at 21.9 months in the niraparib arm versus 10.4 months in the placebo arm (P <.001). In patients with HRD-negative disease, median PFS was 8.1 months versus 5.4 months in the niraparib and placebo arms, respectively.
In the phase 3 VELIA/GOG-3005 trial, which enrolled 1140 patients with newly diagnosed advanced ovarian cancer, researchers evaluated veliparib (ABT-888; AbbVie) as maintenance therapy after first-line treatment with a combination of veliparib plus carboplatin and paclitaxel. Patients were randomized to either chemotherapy plus placebo followed by placebo maintenance (ie, control arm); chemotherapy plus veliparib followed by placebo maintenance; or chemotherapy plus veliparib followed by veliparib maintenance (ie, veliparib throughout).
PFS was significantly longer in the veliparib-throughout group, and the magnitude of the PFS benefit was greater in patients with HRD-positive disease. Median PFS was 23.5 months with veliparib as part of first-line therapy and maintenance therapy versus 17.3 months with placebo (P <.001). In patients with HRD-positive disease, median PFS was extended by 11 months in the veliparib-throughout group (31.9 vs 20.5 months). In those with BRCA mutations, median PFS was 34.7 months in the veliparib-throughout group and 22 months in the control group (P <.001).
Studies are needed to clarify the benefit of PARP inhibitors as first-line and maintenance therapies in patients with and without BRCA mutations. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival and hopefully we will improve long-term outcome,” said Ana Oaknin, MD, PhD, Vall d’Hebron Institute of Oncology, Barcelona, Spain, in a statement released by the National Cancer Institute.