The U.S. Food and Drug Administration (FDA) has approved Zejula (niraparib) as a first-line maintenance therapy for women with advanced ovarian cancer who responded to platinum-based chemotherapy, regardless of their BRCA mutation status.
This indication also includes patients with advanced fallopian tube or primary peritoneal cancer.
The decision comes two months after FDA’s acceptance of a supplemental New Drug Application (sNDA), which was reviewed under the Real-Time Oncology Review (RTOR) pilot program, designed to speed the review process. According to the FDA, the application was approved two months before the agency’s goal date for a decision.
Zejula is now approved in the U.S. in three treatment regimens for women with advanced ovarian cancer, regardless of BRCA mutations. The previous two are as a maintenance therapy for recurrent ovarian cancer that responded to platinum-based chemotherapy, and as a late-line therapy for tumors positive for homologous recombination deficiency (HRD). That is, tumors with mutations in certain genes involved in DNA repair, including BRCA genes, or with genomic instability — a high frequency of mutations within the genome.
Because such tumors are more dependent on other DNA repair mechanisms involving the PARP enzyme — a DNA damage sensor — they are more likely to respond to treatments blocking PARP activity (PARP inhibitors), such as Zejula.
Zejula is marketed by Tesaro, a subsidiary of GlaxoSmithKline (GSK), in the U.S. and in Europe. The therapy is also being reviewed for the same indication in China.
“Women with advanced ovarian cancer have a five-year survival rate of less than 50%. This expanded indication means that many more women with this devastating disease can receive earlier treatment with Zejula, which can extend the time it takes for their cancer to progress,” Hal Barron, MD, GSK’s chief scientific officer and president of research & development, said in a press release.
The FDA’s decision was based on the positive data from the PRIMA Phase 3 trial (PRIMA/ENGOTOV26/GOG-3012; NCT02655016). Results showed that Zejula was superior to placebo in halting cancer progression in women with newly diagnosed advanced cancer of the ovary, peritoneum, or fallopian tube, regardless of BRCA mutations.
PRIMA, conducted in 20 countries, included 733 women who responded at least partly to first-line platinum-based chemotherapy and were at high risk for relapse.
About half of the women (51%) had HRD-positive tumors. This was assessed with Myriad‘s myChoice test, which is under FDA review as the test of choice to identify chemo-responsive patients likely to benefit from Zejula as maintenance therapy.
Participants were randomly assigned, within 12 weeks of completing the last chemotherapy cycle, to either 300 mg of Zejula (487 women) or a placebo (246 women) once daily for 36 months (three years) or until disease progression.
The starting dose of Zejula was later individualized, so that women weighing less than 77 kg (about 170 lbs) or had a platelet count below 150K/microL would be treated at 200 mg, instead of 300 mg.
Data showed that Zejula-treated patients, regardless of HRD status, had a 38% lower risk of disease progression or death, compared with those on a placebo. Notably, this survival benefit was even greater in women with HRD-positive tumors (including those with BRCA mutations), who showed a 57% reduction in the risk of disease progression or death.
The 24-month overall survival of women with HRD-positive tumors also favored Zejula (91% of women) over placebo (85%), representing a nearly 40% reduction in the risk of death at two years.
Zejula’s safety profile was consistent with that seen in previous clinical trials, and no treatment-related deaths were reported.
Women treated with the individualized starting dose showed lower rates of treatment-related side effects graded as severe or worse than did the overall patient population. These included low platelet counts (21% compared to 39%), low red blood cell counts (23% compared to 31%), and low levels of neutrophils — a type of white blood cell (15% compared to 21%).
“PRIMA was designed for patients with ovarian cancer who have a high unmet need … This approval is an important step forward in the treatment of ovarian cancer. In my opinion, maintenance treatment with niraparib [Zejula] should be considered an option for appropriate patients who responded to first-line platinum-based chemotherapy versus active surveillance,” said Bradley Monk, MD, a PRIMA investigator at St. Joseph’s Hospital, in Phoenix, Arizona.
Added Audra Moran, president and CEO of the Ovarian Cancer Research Alliance: “PARP inhibitors represent a major advancement in the fight against ovarian cancer, and having a new first-line maintenance option for platinum-responsive advanced ovarian cancer patients — regardless of BRCA mutation status — is especially exciting.”
“We are determined to keep funding research and partnering with scientists who are on the frontline of finding new treatments like this one to help those impacted by this disease,” she said.
Zejula’s prescribing information in the U.S. now includes the individualized starting daily dose of 200 mg or 300 mg for first-line maintenance therapy. The starting dose for recurrent ovarian cancer and late-line treatment indications is 300 mg once-daily.