By Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
Tesaro’s PARP inhibitor, niraparib, has generated a lot of excitement in recent weeks. On September 12, Tesaro announced that it had received an FDA fast track designation for the treatment of patients with recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer. In addition to the initiation of a rolling submission of a New Drug Application (NDA) for niraparib to the FDA that Tesaro intends to complete during the fourth quarter, the company also announced plans to submit the Marketing Authorization Application (MAA) for niraparib to the European Medicines Agency (EMA) in the fourth quarter. These plans were driven by the promise of the NOVA data that were presented today at the 2016 European Society of Medical Oncology (ESMO) meeting in Copenhagen1 and published in the New England Journal of Medicine.2 NOVA (ENGOT-OV16) was a randomized, placebo-controlled, Phase III trial conducted by the European Network for Gynecological Oncological Trial groups and investigators in the United States, Canada and Hungary. This trial compared single-agent niraparib versus placebo as maintenance therapy following second-line induction therapy in platinum-sensitive ovarian cancer patients who have either germline mutation in breast cancer susceptibility gene 1 or breast cancer susceptibility gene 2 (gBRCA) or a tumor with high-grade serous histology. One thing that sets the NOVA trial apart is the large number of patients included who do not have a gBRCA mutation (350 of the 553 total enrolled patients). The non-gBRCA mutation patients were further stratified according to tumors with homologous recombination deficiency (HRD), defined by the myChoice HRD test (Myriad Genetics).
The primary endpoint was progression free survival (PFS), which was significantly greater for niraparib compared with placebo in each of the three subpopulations (p<0.001). In the gBRCA mutant cohort, median PFS was 21.0 months in the niraparib arm (n=138) and 5.5 months in the placebo arm (n=65) (HR 0.27; 95% confidence interval [CI], 0.17 to 0.41). The same pattern was seen in the overall non-gBRCA cohort: 9.3 months with niraparib (n=234) versus 3.9 months with placebo (n=116) (HR 0.45; 95% CI, 0.34 to 0.61). Further, this effect was more pronounced in the HRD-positive subgroup of the non-gBRCA cohort: 12.9 months with niraparib (n=106) compared with 3.8 months with placebo (n=56) (HR 0.38; 95% CI, 0.24 to 0.59).
These data were received extremely positively by the crowd in attendance. During the discussion, the strong data in this “BRCA-like” group were considered particularly exciting and could change the landscape of treatment in ovarian cancer. Given the large number of non-gBRCA patients included in the trial as well as the positive results, Tesaro can seek a broad label without the BRCA mutation restriction. Indeed, during the discussion, emphasis was placed not on BRCA, or being “BRCA-like,” but rather on the platinum sensitivity of this patient population. In Europe, niraparib will be seeking a label very similar to Lynparza™ (olaparib, AstraZeneca); in the United States, however, niraparib will have a broad label, distinct from Lynparza, whose FDA-approved indication limits its use to fourth-line in patients with gBRCA mutations.
In platinum-sensitive ovarian cancer patients with gBRCA mutations, PARP inhibitors are ascendant. As noted above, Lynparza is currently approved in the United States and Europe, albeit with divergent indications. Clovis Oncology’s rucaparib adds another dimension to this space. In a combined analysis of two Phase II studies (Study 10 and ARIEL2, n=106) and using an assay developed by Foundation Medicine, the BRCA (germ line and somatic) mutant subgroup demonstrated a 53.8% objective response rate and 10-month median PFS in patients previously treated with a median of three prior chemotherapies and predominantly platinum-sensitive.4 Previous analysis of just the ARIEL2 study indicated improved efficacy in patients with BRCA (germ line and somatic) mutation and in patients with BRCA-like HRD-positive ovarian cancer, in comparison with non-BRCA-like patients.5
The PARP inhibitors are racing to establish and gain share in this space. Clovis has completed their accelerated approval application with the U.S. FDA for use in BRCA (germ line and somatic) mutant patients who have been treated with two or more prior chemotherapies. This application received a priority review, which could put it on the market by February 2017; they plan to file an MAA in Europe by the end of 2016. Tesaro is further behind, but the robust Phase III NOVA data will likely put it at an advantage once it launches; U.S. and European filings should be complete in the fourth quarter of 2016. While Lynparza is already EMA-approved in patients with gBRCA mutations, niraparib’s Phase III data in “BRCA-like” patients may help eclipse Lynparza’s standing; in the United States, the launch of niraparib may have a more pronounced effect on Lynparza, as it is expected to be approved and utilized in an earlier treatment setting. With so many novel agents demonstrating strong efficacy, the stars are beginning to shine brightly on the ovarian cancer space.
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