1. Goodwin, Peter M.

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COPENHAGEN, Denmark-Marked prolongation of progression-free survival (PFS) in all groups of patients with platinum-sensitive recurrent ovarian cancer was reported at the European Society for Medical Oncology 2016 Congress in findings from the double-blind phase III European Network of Gynaecological Oncology Trial groups (ENGOT-OV16/NOVA) trial of the oral poly adenosine diphosphate-ribose polymerase (PARP) 1/2 inhibitor, niraparib, compared with placebo in patients with platinum-sensitive recurrent ovarian cancer (N Engl J Med 2016; DOI: 10.1056/NEJMoa1611310).

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Niraparib maintenance therapy was effectively converting ovarian cancer to a chronic disease, noted Mansoor Raza Mirza, MD, Chief Oncologist at Copenhagen University Hospital and Medical Director of the Nordic Society of Gynaecologic Oncology. The drug prolonged PFS in all categories of patients with platinum-sensitive recurrent ovarian cancer, irrespective of the status of biomarkers such as the presence or absence of the germline breast cancer susceptibility gene (gBRCA) and homologous recombination deficiency (HRD).


"We have seen tremendous clinical benefit both in [the] germline BRCA mutated and non-germline BRCA mutated population," Mirza told Oncology Times. Ovarian cancer was being converted from a recurrent to a chronic disease, he said.


Patients with the gBRCA mutation had "a 73 percent reduction of the risk of progression," he noted, and that was "tremendous clinically" (hazard ratio 0.27). And in patients without the gBRCA mutation, there was still a big benefit (hazard ratio 0.45).


Sandro Pignata, MD, Director or the Uro-Gynecological Department at the National Cancer Institute "G. Pascale" Foundation in Naples, Italy, who discussed Mirza's report at ESMO 2016, described the findings as "extraordinary results that modified the clinical history or these patients." And he said the gain of 6 months additional PFS for patients without the gBRCA mutation was a "significant" effect of PARP inhibition. "The results of this study are extraordinary [and] will modify the therapy of ovarian cancer," he said.


Mirza said there were limited treatment options in recurrent ovarian cancer because of factors such as cumulative toxicity and a lack of additional benefit from platinum-based chemotherapy. Other current options for maintenance therapy also had limitations, he noted. "Bevacizumab can only be given once and improves progression-free survival by just a few months, and the PARP inhibitor olaparib has only been approved in patients with a germline BRCA mutation."


The ENGOT-OV16/NOVA trial randomized 553 patients to receive niraparib 300 mg or placebo once daily. They were divided into two cohorts-203 patients who had the gBRCA mutation and 350 who did not. Within the non-gBRCA group a third population was defined-patients whose tumors tested positive for HRD.


Niraparib significantly improved the primary endpoint of PFS compared to placebo in both cohorts and all subgroups. Patients with the gBRCA mutation had a median PFS with niraparib of 21.0 months compared 5.5 months of placebo (hazard ratio 0.27). In the non-gBRCA mutation group the drug extended survival to 9.3 months from 3.9 months in the placebo group (hazard ratio 0.45). And in the subgroup of the non-gBRCA cohort who had tested positive for HRD median PFS was prolonged from 3.9 months to 9.3 months (HR 0.38).


Mirza said the results show the drug had a meaningful effect in irrespective of HRD status. "This is extremely clinically meaningful, and especially if you look at the durability of the response-the curves are separated all the way with one-fifth of the patients at 18 months on niraparib without progression," he said. "That means we cannot use HRD to determine if these patients should receive treatment or not. So we have to take the whole population until we have a better test."


Overall Survival

Mirza noted that data on overall survival were still immature because of insufficient events. "One more important thing we can see is [that] about 40-43 percent of long-term responders at this time are still on niraparib and have not progressed. Which is extremely impressive."


Patient-reported outcomes were similar for niraparib and placebo. And there were no deaths during study treatment. And significant improvements were also observed in all secondary endpoints. Compared to placebo, niraparib significantly prolonged the second progression-free survival, time to first subsequent treatment, and chemotherapy-free interval in all groups-mutation and mutation-free and in the HRD subgroup.


Commenting on the results, Andres Poveda, MD, Head of the Gynaecological Cancer Clinic at the Oncology Foundation Institute in Valencia, Spain, said: "This study more than doubles the population of patients who benefit from a PARP inhibitor." He welcomed the detailed findings about the effects of gBRCA and HRD status. "Personalized medicine has arrived in high-grade serous ovarian cancer."


Mirza said this was a breakthrough for patients with ovarian cancer. "We have never seen such large benefits in progression-free survival in recurrent ovarian cancer. Niraparib significantly improved all endpoints across a broad patient population representing 70 percent of all patients with ovarian cancer. So this is really going to change the way we treat our patients [and] the way we talk to our patients about the prognosis."


Peter M. Goodwin is a contributing writer.