BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.
Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.
Thewere published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).
In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.
“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.
Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.
The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.
“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”
For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.
Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.
All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.
Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.
The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.
For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.
As a result, surveillance after chemotherapy is the approach used for many patients, he added.
Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the it showed benefit in patients who received at least three prior therapies.
The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.
“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”
Invited discussant, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.
“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.
Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?
“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.
The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.
SOURCE: González-Martin A et al. ESMO 2019: .