Copenhagen, Denmark—Substantial gains in progression-free survival (PFS) can be achieved when patients with platinum-sensitive recurrent ovarian cancer are placed on maintenance therapy with niraparib, according to results of a multinational Phase III trial.
The overall population—with or without BRCA mutations, positive or negative for homologous recombination deficiency (HRD)—“achieved a clinically significant improvement in PFS,” reported Mansoor R. Mirza, MD, the chief oncologist at Rigshospitalet of Copenhagen University, Denmark. According to Dr. Mirza, these are “landmark results” that make niraparib (Tesaro) maintenance appropriate for all patients with recurrent ovarian cancer.
The ESMO-invited discussant for the study, Sandro Pignata, MD, PhD, echoed this assessment. Dr. Pignata, the head of the Uro-Gynaecological Department of the IRCCS National Cancer Institute, in Naples, Italy, characterized the findings as an “extraordinary result that will modify our treatment of recurrent ovarian cancer.”
The results of the study, called ENGOT-OV16/NOVA, were presented at the European Society for Medical Oncology (ESMO) 2016 Congress (abstract LBA3_PR) and simultaneously published in The New England Journal of Medicine (2016 Oct 7. [Epub ahead of print], PMID: 27717299).
The trial randomly assigned 553 patients with recurrent ovarian cancer in a 2:1 ratio to 300 mg of the poly(ADP-ribose) polymerase (PARP) enzyme inhibitor niraparib or placebo once daily. For entry, patients were required to have had a complete or partial response to their last round of platinum-based chemotherapy. Two independent cohorts defined by BRCA mutation were enrolled (203 with mutations and 350 without). The patients started the therapies no later than eight weeks after they completed their last cycle of platinum-based chemotherapy and continued to take them until disease progression.
For PFS, the primary end point, the median time to an event in the BRCA mutation cohort was 21 months in the niraparib group versus 5.5 months in the placebo group, producing a hazard ratio (HR) of 0.27 (P<0.001) (Table). In the group without BRCA mutations, the median PFS was 9.3 months in those treated with niraparib versus 3.9 months in those treated with placebo (HR, 0.45; P<0.001). In the patients without BRCA mutations who were HRD-positive, the median PFS was 12.9 months among those who received niraparib and 3.8 months among those who received placebo (HR, 0.38; P<0.001). An evaluation of the efficacy of niraparib in those without BRCA mutations who were HRD-negative was not prespecified in the trial design but was included in an exploratory analysis. It also suggested clinically meaningful benefit (HR, 0.58).
Secondary efficacy end points supported the primary results. For example, the time to subsequent treatment was substantially longer for patients treated with niraparib, whether or not BRCA mutations were present (HR, 0.31; P<0.0001 and HR, 0.55; P<0.001, respectively). An analysis of the chemotherapy-free interval showed a similar advantage for niraparib. The overall survival data were not yet mature because less than 20% of patients died in each cohort, although no detrimental effect on survival has been seen (HR, 0.73; P=0.1545).
These improvements in the niraparib group were achieved without any detrimental effect on quality of life, according to data collected with the Functional Assessment of Cancer Therapy–Ovarian Symptom Index and European Quality of Life-5 Dimensions questionnaires. This is likely related to a low risk for high-grade symptomatic adverse events (AEs). The only grade 3 or higher AEs that occurred in more than 10% of patients were hematologic. These were all more common among those treated with niraparib and included thrombocytopenia (33.8% vs. 0.6%), neutropenia (19.6% vs. 1.7%) and anemia (25.3% vs. 0%). These were largely asymptomatic and treated with dose adjustments.
Compared with the placebo group, niraparib-treated patients had higher rates of many gastrointestinal AEs, such as nausea (73.6% vs. 35.2%), vomiting (34.3% vs. 16.2%) and constipation (39.8% vs. 20.1%), as well as fatigue (59.4% vs. 41.3%), insomnia (24.3% vs. 9.5%), headache (25.9% vs. 9.5%), dizziness (16.6% vs. 7.3%) and cough (15.0% vs. 4.5%). A few AEs, such as abdominal pain (29.6% vs. 22.6%), were numerically higher among patients who received placebo.
In the United States, the PARP inhibitor olaparib (Lynparza, AstraZeneca) is indicated for patients with BRCA-mutated ovarian cancer treated with three or more prior lines of chemotherapy. In Europe, it is indicated as a maintenance therapy in BRCA-mutated platinum-sensitive recurrent ovarian cancer. Based on this new Phase III trial, niraparib may receive a broader indication. Other PARP inhibitors, such as rucaparib (Clovis Oncology) and veliparib (AbbVie) also have reached late stages of clinical testing.
Noting that the niraparib Phase III study is the first to use HRD status to evaluate response, Andres Poveda, MD, the head of the Gynecological Cancer Clinic in Valencia, Spain, also suggested that the findings are likely to alter practice. Relative to previous studies with olaparib, “this study more than doubles the population of [ovarian cancer] patients shown to benefit from a PARP inhibitor.”
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