Niraparib Approved by FDA for Ovarian Cancer

The PARP inhibitor niraparib (Zejula) has been approved by the FDA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

The approval is based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 74% compared with placebo for patients with germlineBRCA-positive platinum-sensitive, recurrent ovarian cancer.^1,2

The median progression-free survival (PFS) with maintenance niraparib was 21 months compared with 5.5 months for placebo in patients with germlineBRCAmutations (HR, 0.26; 95% CI, 0.17-0.41;&nbsp;P<.0001). These findings remained consistent across subgroups of patients, including those withoutBRCAmutations.

&ldquo;Despite high response rates to platinum-based treatment in recurrent ovarian cancer patients, the effectiveness of such chemotherapy diminishes over time. Unfortunately, progression-free survival generally gets shorter after each subsequent treatment with a platinum-based chemotherapy regimen. Therefore, a treatment like Zejula that can increase progression-free survival after platinum therapy is very meaningful to patients and their families,&rdquo; Ursula Matulonis, MD, director, gynecologic oncology at Dana-Farber Cancer Institute and professor of medicine, Harvard Medical School, said in a statement.

&ldquo;Until recently, there have been few treatment advances for women with recurrent ovarian cancer and even fewer options available for women who do not harborBRCAmutations. We are excited to have the opportunity to offer appropriate patients an oral, once-daily maintenance treatment that reduces the risk of cancer progression and extends the time between courses of chemotherapy for patients who have few treatment options,&rdquo; added Matulonis.

The phase III NOVA study randomized patients in a 2:1 ratio across 2 independent cohorts. In the first cohort, 201 patients with germlineBRCAmutations received niraparib at 300 mg daily (n = 138) or placebo (n = 65). In the second cohort, 345 patients with non-germlineBRCA-mutant tumors received the PARP Inhibitor (n = 231) or placebo (n = 114). Patients in this group were tested for homologous recombination deficiency (HRD), and could be either positive (n = 162) or negative (n = 134). Of those who tested positive, 47 had somaticBRCAmutations and 115 were wild-type.

Patient demographics were well balanced between the arms for each cohort. In the germlineBRCAgroup, the median age was 57 years and 65.9% had an ECOG performance status (PS) of 0. In the placebo group, the median age was 58 years and 73.8% of patients had an ECOG PS of 0. Overall, 48.6% and 53.8% of patients had received &ge;3 prior therapies, in the niraparib and placebo arms, respectively.

Across both cohorts, the majority of patients had stage III cancer (68.8% to 74.1%). Approximately half of patients had achieved a complete response to prior platinum-based therapy and a quarter had received prior bevacizumab. In the non-BRCA-mutant arm, 33.8% and 32.8% of patients had received &ge;3 prior therapies.

The median time to progression or death during the first subsequent therapy following the study (PFS2) was 25.8 months for those who received maintenance niraparib versus 19.5 months for placebo (HR, 0.48; 95% CI, 0.28-0.82;P= .006).

Findings for overall survival were not yet mature (fewer than 20% of events). At the time of the analysis, niraparib had reduced the risk of death by 27% versus placebo, although this finding was not statistically significant (HR, 0.73; 95% CI, 0.480-1.125;P= .1545).

In patients with HRD-positive,BRCAwild-type tumors, median PFS was 9.3 versus 3.7 months for niraparib and placebo, respectively (HR, 0.38; 95% CI, 0.23-0.63;&nbsp;P<.001). In those with HRD-positive, somatic BRCA-mutated tumors, the median PFS was 20.9 months with niraparib versus 11.0 months for placebo (HR, 0.27; 95% CI, 0.08-0.90;&nbsp;P= .02). In patients with HRD-negative, non-germline BRCA-mutated tumors, median PFS was 6.9 versus 3.8 months for niraparib and placebo, respectively (HR, 0.58; 95% CI, 0.36-0.92;&nbsp;P= .02).

In those with non-germlineBRCAmutations regardless of HRD status, the median chemotherapy-free interval was 12.7 versus 8.6 months for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.37-0.67;&nbsp;P<.001). The median time to subsequent therapy was 11.8 versus 7.2 months (HR, 0.55; 95% CI, 0.41-0.72;&nbsp;P<.001) and the median PFS2 was 18.6 and 15.6 months for the niraparib and placebo arms, respectively (HR, 0.69; 95% CI, 0.49-0.96;&nbsp;P= .03).

Across cohorts, 14.7% of 367 niraparib-treated patients discontinued therapy due to an adverse event (AE) compared with 2.2% of the 179 patients in the placebo arm. There were no treatment-related deaths in the study. In the follow-up period, 1 patient in the niraparib arm and 2 in the placebo group died of myelodysplastic syndrome or acute myeloid leukemia. One of these deaths in each arm was deemed to be treatment related.

&ldquo;The approval of Zejula, the first maintenance therapy approved in the United States for recurrent ovarian cancer, is extremely encouraging for the ovarian cancer community,&rdquo; Mansoor Raza Mirza, MD, ENGOT-OV16/NOVA study chair and medical director of the Nordic Society of Gynaecological Oncology (NSGO), said in a statement. &ldquo;The unique design of the NOVA study, which included women both with and without germlineBRCAmutations, allowed us to determine that Zejula provides significant progression-free survival improvement in a very broad patient population. Having the option of prescribing Zejula without the need for a diagnostic test could fundamentally change the way we treat this disease from &lsquo;watch and wait&rsquo; after a response to chemotherapy, to active treatment. With the significant increase in PFS observed in NOVA, I believe that we are changing the course of disease for patients with ovarian cancer, regardless of platinum sensitivity and independent ofBRCAmutation or biomarker status.&rdquo;

The most common all-grade AEs for niraparib versus placebo, respectively, were nausea (73.6% vs 35.2%, respectively), thrombocytopenia (61.3% vs 5.6%), fatigue (59.4% vs 41.3%), anemia (50.1% vs 6.7%), constipation (39.8% vs 20.1%), vomiting (34.3% vs 16.2%), and neutropenia (30.2% vs 6.1%).

The most common grade 3/4 AEs in the niraparib arm were hematologic, and included thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%). The most common non-hematologic AEs were hypertension (8.2%), fatigue (8.2%), and nausea (3%). A majority of hematologic AEs were experienced in the first 3 cycles.

Tesaro, the manufacturer of niraparib, initiated a rolling submission of data from the NOVA trial for a new drug application in September 2016, after receiving a fast track designation from the FDA. In its statement today, the company reported that it anticipates that niraparib will be officially launched in the United States in late April.

&ldquo;We are so gratified to bring this unique new medicine to women with ovarian cancer, and would like to thank the patients who gave selflessly to participate in this trial with the assistance of their caregivers and physicians. We consider clinical trial participants to be the most important contributors to the success of the Zejula clinical development program,&rdquo; Mary Lynne Hedley, PhD, president and chief operating officer of Tesaro, said in a statement. &ldquo;We would also like to express our appreciation to the FDA for its rapid and thorough assessment of the Zejula application in less than 3 months after it was accepted for review, as well as our partners at ENGOT for their diligence and care in executing the NOVA clinical trial. Tesaro is committed to supporting women bravely facing ovarian cancer and we are planning to work with patients, healthcare providers and payers to ensure access to this paradigm-changing medicine.&rdquo;

References

1. Mirza MR, Monk BJ, Oza A, et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA3_PR.
2. Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer [published online October 8, 2016].N Engl J Med. DOI: 10.1056/NEJMoa1611310.

In the germlineBRCAmutation group, the chemotherapy-free interval was 22.8 months with niraparib compared with 9.4 months for placebo (HR, 0.26; 95% CI, 0.17-0.41;&nbsp;P<.001). The median time to subsequent therapy was 21 months with niraparib versus 8.4 months with placebo (HR, 0.31; 95% CI, 0.21-0.48).