Niraparib is promising as maintenance therapy in ovarian cancer
Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
Approximately 85% of women with ovarian cancer will develop recurrent disease. Women with ovarian cancer are commonly treated with a range of antineoplastic agents over the course of their lifetime. As such, there is a great need for additional active therapeutic agents in this setting. Recently, substantial effort has been directed toward "precision" or "personalized medicine" in oncology.
Precision medicine, targeted therapies in oncology
Precision medicine refers to the customization of medical therapy based on the genetic characterization of the individual patient or the molecular profile of the patient's tumor. As a result of large-scale molecular profiling from projects such as the International Cancer Genome Consortium and The Cancer Genome Atlas, an abundance of molecular data has been generated through the characterization of multiple tumor types. This has led to the discovery of key cancer drivers, alterations, and specific molecular profiles that have distinct prognostic and treatment implications. These data, in combination with the commercial availability of molecular profiling tests, has made precision medicine a reality for women with ovarian cancer.
This wealth of new information has led to development of targeted therapeutics that block the growth and spread of cancer by acting on specific molecules or molecular pathways. Targeted therapies approved for cancer treatment include hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, and immunotherapies.14
How PARP inhibitors work
PARP inhibitors are a class of agents that are emerging as important therapies for ovarian cancer. These agents block the nuclear protein PARP, which functions to detect and repair single-strand DNA breaks with the resulting accumulation of double-stranded DNA breaks.15 In the setting of DNA damage, the homologous recombination repair pathway is activated for repair. However, homologous recombination deficiencies (HRD) can arise as a result of BRCA1 or BRCA2 mutations or BRCA-independent pathways, which effectively disable this DNA repair pathway. As a result, when PARP inhibitors are used in patients with HRD, the cell cannot repair double-stranded DNA breaks and this leads to "synthetic lethality."16
Understanding this molecular mechanism of PARP inhibitors as well as the frequent abnormalities in the BRCA genes and HRD pathways in ovarian cancer has provided an important potential therapeutic target in ovarian cancer. A number of PARP inhibitors are now commercially available and are undergoing testing in ovarian cancer.
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Niraparib for ovarian cancer
In a randomized, double-blind, phase 3 trial by Mizra and colleagues, 553 women with platinum-sensitive recurrent ovarian cancer who responded to therapy were divided according to the presence or absence of a germline BRCA (gBRCA) mutation and randomly assigned to niraparib 300 mg or placebo once daily. Women in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group. This was most pronounced in women in the gBRCA cohort (21.0 vs 5.5 months). Importantly, niraparib was associated with improved progression-free survival in HRD-positive patients without gBRCA mutations (12.9 vs 3.8 months) as well as in the HRD-negative subgroup (6.9 vs 3.8 months).17
Overall, niraparib was well tolerated. About 15% of women discontinued the drug due to toxicity. Significant (grade 3 or 4) adverse events were seen in three-quarters of women treated with niraparib, and they most commonly consisted of hematologic toxicities. Patient-reported outcomes were similar for both groups, indicating no significant effect from niraparib on quality of life.17
WHAT THIS EVIDENCE MEANS FOR PRACTICE
This study's results suggest that niraparib has clinical activity against ovarian cancer. Importantly, niraparib was active in women with gBRCA mutations, in those with HRD without a gBRCA mutation, and potentially in women without HRD. If approved by the US Food and Drug Administration, niraparib will join olaparib and rucaparib as a newly approved therapeutic agent for ovarian cancer. This study provides important evidence that suggests niraparib maintenance therapy may be an efficacious and important addition to the treatment armamentarium for platinum-sensitive ovarian cancer.
This study's results suggest that niraparib has clinical activity against ovarian cancer. Importantly, niraparib was active in women with gBRCA mutations, in those with HRD without a gBRCA mutation, and potentially in women without HRD. If approved by the US Food and Drug Administration, niraparib will join olaparib and rucaparib as a newly approved therapeutic agent for ovarian cancer. This study provides important evidence that suggests niraparib maintenance therapy may be an efficacious and important addition to the treatment armamentarium for platinum-sensitive ovarian cancer.
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