The first phase III trial of an inhibitor of poly (ADP-ribose) polymerase (PARP) yielded unprecedented results in treating ovarian cancer. The trial was presented at the European Society for Medical Oncology (ESMO) in Copenhagen, Denmark, and electronically reported concurrently in The New England Journal of Medicine in October 2016 by Mirza and colleagues.1 The trial is reviewed in this issue of The ASCO Post. This ambitious phase III placebo-controlled double-blind randomized trial called NOVA enrolled 553 patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, and peritoneal cancers. The trial represented 107 sites from the United States, Europe, and Canada. Remarkably, the time from the first patient enrolled to data maturation was just over 3 years.
The study enrolled 2 cohorts: cohort 1 included 203 patients with germline BRCA (gBRCA) mutations, 138 of whom were randomized to receive niraparib and 65, placebo; cohort 2 included 350 patients with non-gBRCA disease, 234 of whom were randomized to receive niraparib and 116, placebo. The primary endpoint was progression-free survival in the intent-to-treat populations.
Both cohorts achieved statistically and clinically relevant results. In the gBRCA cohort, median progression-free survival was 21.0 vs 5.5 months (hazard ratio [HR] = 0.27, P < .001). In the non-gBRCA cohort, median progression-free survival was 9.3 vs 3.9 months (HR = 0.45, P < .001). Although relatively well tolerated, 74.1% of those treated with niraparib experienced grade 3 or 4 adverse events.
Homologous Recombination Deficiency
PARP is one of the cellular mechanisms of repairing single-strand DNA breaks. When single-strand breaks are unrepaired, they persist and increase the frequency of double-stranded DNA damage. BRCA is one of the body’s mechanisms of repairing these double-stranded breaks, and when a cell is lacking BRCA, PARP inhibition leads to cell death through a process called “synthetic lethality.” This process of fixing double-stranded DNA damage has been termed “homologous recombination.” In fact, other enzymes besides BRCA have been identified in cells deficient in homologous recombination.”
Homologous recombination deficiency testing, which includes but is not limited to, somatic BRCA mutations helps to predict PARP inhibitor sensitivity. Cancers with homologous recombination deficiency are typically of high-grade serous histology and, since they are highly responsive to platinum compounds, have a better prognosis than those with proficient homologous recombination.
In the NOVA trial, an homologous recombination deficiency assay was used to enrich the activity of niraparib in the non-gBRCA cohort. Indeed, treatment with niraparib in the homologous recombination deficiency–positive group showed clinical activity (median progression-free survival of 12.9 vs 3.8 months; HR = 0.38, P < .001), intermediate between gBRCA (HR = 0.27) and non-gBRCA cohorts (HR = 0.45). Interestingly, there was still a statistically significant treatment effect in the non–homologous recombination deficiency, non-gBRCA patients (median progression-free survival of 6.9 months vs 3.8 months, HR = 0.58, P = 0.02), suggesting that the homologous recombination deficiency assay is not entirely predictive. The clinical significance of this 3.1-month difference in progression-free survival is debatable.
New Challenges, Active Research
Two other PARP inhibitors are currently approved by the U.S. Food and Drug Administration (FDA) in “treating” ovarian cancer. Olaparib (Lynparza) is labeled after three lines of therapy and is indicated for those with gBRCA mutations, whereas rucaparib (Rubraca) is labeled after two lines of therapy. In addition to those with gBRCA mutations, rucaparib is also indicated for patients with somatic BRCA mutations.
Like homologous recombination deficiency, somatic BRCA testing requires the procurement of tumor tissue, creating new challenges. Current evidence suggests that the original tumor specimen from the primary debulking surgery can be tested and that little chronologic drift occurs in the molecular signature of the cancer. However, this is an area of active research, and repeat tumor biopsies may be needed for accurate homologous recombination deficiency or somatic BRCA testing.
It is important to remember that essentially all women with gBRCA mutations are homologous recombination deficiency–positive, but somatic BRCA is only a component of homologous recombination deficiency. Other non-BRCA somatic genes can be predictive of PARP inhibitor activity. In addition to testing tissue, the real challenge will be to educate providers to test for BRCA again—this time in the tumor—if the germline result is negative.
Impending FDA Approval
Based on the NOVA data outlined here, the FDA has established a target action date under the Prescription Drug User Fee Act of June 30, 2017, and is not currently planning to hold an advisory committee meeting to discuss the niraparib application. The NOVA study was labeled “maintenance” after response to retreatment to platinum-based chemotherapy. This is in contrast to the current approval for “treatment” in the setting of measurable disease for olaparib and rucaparib.
In reality, close to half of those enrolled on NOVA had only “partial responses” to their penultimate chemotherapy regimen, meaning that effective therapy was discontinued when they were randomized to receive niraparib or placebo. This essentially blurs the boundaries between “treatment” and “maintenance” in this setting. Finally, the December 2016 FDA approval of adding bevacizumab (Avastin) to chemotherapy in the setting of platinum-sensitive relapsed ovarian cancer, followed by “maintenance” bevacizumab, further complicates treatment decisions.
Niraparib is clearly an active and tolerable PARP inhibitor in treating ovarian cancer based on the NOVA data. The impending FDA approval as well as the precise FDA-labeled indication are eagerly anticipated. Sequencing of agents, comparative effectiveness of PARP inhibitors, novel combinations, mechanisms of resistance, and ways to improve survivorship—and ultimately overall survival—remain active areas of research. ■
Disclosure: Dr. Monk has served as an advisor or consultant for Advaxis, Amgen, AstraZeneca, Clovis, Genentech, Gradalis, Insys, Mateon (formally OxiGENE), Merck, Roche, Pfizer, PPD, Precision Oncology, and Tesaro. He has served as a speaker for AstraZeneca, Genentech, Janssen/Johnson & Johnson, and Roche, and his institution has received grants for clinical research from Amgen, Array BioPharma, Genentech, Janssen/Johnson & Johnson, Lilly, Morphotek, and Tesaro.
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In a phase III trial (ENGOT-OV16/NOVA) reported at the 2016 ESMO (European Society for Medical Oncology) Congress and in The New England Journal of Medicine by Mansoor R. Mirza, MD, of the...