Niraparib Maintenance Therapy in Platinum Sensitive, Recurrent Ovarian Cancer

Ling Jun Chen, Mercer University College of Pharmacy

According to the American Cancer Society, epithelial ovarian cancer has the highest mortality of any gynecological tumor. [1] Platinum- and taxane-based chemotherapy regimens have been suggested as first-line treatments for ovarian cancer. It has been shown that the effectiveness of these treatments diminish over time due to accumulating dose-related toxicity. [2]

Niraparib is a poly ADP-ribose polymerase (PARP) inhibitor, which inhibits both DNA repair and programmed cell death.  It is an oral, once-daily medication that is currently being evaluated in four ongoing trials. Niraparib is an investigational agent and the U.S. Food and Drug Administration has not approved it. [3]

Niraparib Maintenance Therapy in Platinum Sensitive, Recurrent Ovarian Cancer [4]
Design Randomized, placebo-controlled, phase 3 trial; N= 553
Objective To evaluate the efficacy and safety of niraparib versus placebo as maintenance treatment
Study Groups Germline BRCA (n= 203): Niraparib (n=138), placebo (n= 65); non-gBRCA cohort (n= 350): Niraparib (n= 234); placebo (n= 116)
Methods Patients were categorized according to the presence or absence of a germline BRCA (gBRCA) mutation. A BRCA mutation is a mutation in either of BRCA1 and BRCA2 genes, which are tumor suppressor genes.   All patients were platinum-sensitive and had recurrent ovarian cancer.  They were randomly assigned in a 2:1 ratio to receive niraparib 300 mg or placebo once daily.
Duration August 2013 to June 2016
Primary Outcome Measure Duration of progression-free survival
Baseline Characteristics Germline BRCA mutation No germline BRCA Mutation
Niraparib Placebo Niraparib Placebo
Median age, years (range) 57 (36-83) 58 (38-73) 63 (33-84) 61 (34-82)
Cancer stage, n (%)
I or II 23 (16.7) 10 (15.4) 22 (9.4) 5 (4.3)
III 95 (68.8) 46 (70.8) 173 (73.9) 86 (74.1)
IV 20 (14.5) 9 (13.8) 38 (16.2) 24 (20.7)
Time to progression after penultimate platinum therapy, n (%)
6 to <12 months 54 (39.1) 26 (40.0) 90 (38.5) 44 (37.9)
≥12 months 84 (60.9) 39 (60.0) 144 (61.5) 72 (62.1)
Complete response to recent platinum therapy 71 (51.4) 33 (50.8) 117 (50.0) 60 (51.7)
Previous lines of chemotherapy, n (%)
1 1 (0.7) 0 0 0
2 70 (50.7) 30 (46.2) 155 (66.2) 77 (66.4)
≥3 67 (48.6) 35 (53.8) 79 (33.8) 38 (32.8)
Results Duration of progression-free survival
Niraparib, month Placebo, month Hazard Ratio 95% CI p-value
gBRAC mutation 21.0 5.5 0.27 0.17 – 0.41 <0.001
Non-gBRAC mutation with homologous recombination deficiency positivity 12.9 3.8 0.38 0.24 -0.59 <0.001
Non-gBRAC mutation 9.3

 

3.9 0.45 0.34 – 0.61 <0.001
Adverse Events Common Adverse Events: nausea (73.6%), fatigue (59.4%), anemia (50.1%), constipation (39.8%), vomiting (34.3%), headache (25.9%), hypertension (19.3%)
Serious Adverse Events: thrombocytopenia (61.3%), neutropenia (30.2%), myalgia (8.2%)
Percentage that Discontinued due to Adverse Events: 9.3% (due to hematologic abnormalities)
Study Author Conclusions The duration of progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer was significantly longer in the niraparib group than in the placebo group, regardless of the presence or absence of gBRCA mutations or homologous recombination deficiency status. The treatment-associated myelotoxicity required dose modifications or delays but was not associated with a long-term increase in mortality or morbidity.

 

 

Niraparib maintenance therapy is a breakthrough for patients with recurrent ovarian cancer because it provides significant clinical benefit regardless of BRCA status. It cumulates less toxicity and adverse effects compared to platinum-based chemotherapy. Study does not address niraparib dose individualization and more research is needed on this front to avoid treatment-associated myelotoxicity. A limitation specific to the medication could be the adverse event profile, which showcased a particularly high rate of hematologic abnormalities.

 

References

 

  1. Siegel R, Naishadham D,  Jemal A. Cancer statistics, 2012. CA Cancer J Clin2012;62(1):10-29.
  2. Hanker LC, Loibl S, Burchardi N, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol 2012;23:2605-12.
  3. Davis J. Tesaro receives FDA fast track designation for niraparib and initiates rolling NDA submission. TesaroTM. Available at: http://ir.tesarobio.com/releasedetail.cfm?ReleaseID=988681. Accessed November 1, 2016.
  4. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016.
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