FDA Grants Priority Review to GSK’s Zejula for Late Stage Ovarian Cancer

The U.S. Food and Drug Administration (FDA) has accepted the application of Tesaro, a GSK company, seeking to extend approval for Zejula (niraparib) to women with late stage ovarian cancer who have received three or more prior chemotherapy treatments. 

The potentially new indication will cover advanced ovarian, fallopian tube, or primary peritoneal cancer patients. It would treat women whose cancer either has a BRCA mutation, or a mutation in other DNA repair genes (causing homologous recombination deficiency, HRD), and whose disease has progressed more than six months after the last platinum-based chemotherapy.

The supplemental New Drug Application (sNDA) — given priority review, with a decision expected by Oct. 24 — was supported by results of the QUADRA  Phase 2 trial (NCT02354586). Zejula demonstrated relevant activity not only in patients with BRCA mutations, but also in women with heavily pretreated ovarian cancer without such mutations.

“The results of the QUADRA study demonstrate that Zejula is active as a late-line treatment for patients beyond those with BRCA mutations. With this study, we continue to advance our mission to provide more patients with ovarian cancer an opportunity to benefit from treatment with Zejula,” Mary Lynne Hedley, PhD, president and CEO of Tesaro, said in a press release.

Zejula is currently approved in the U.S. and Europe as a maintenance therapy in women who have had a recurrence of high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer, but who have completely or partially responded to platinum-based chemotherapy.

The medicine, which is taken as a once-daily pill, can be used in women with or without germline, or inherited, mutations in BRCA1 or BRCA2 genes.

Zejula belongs to the class of poly(ADP-ribose) polymerase (PARP) inhibitors, which means it works by blocking the activity of PARP proteins — enzymes involved in the repair of damaged DNA inside cells.

The medicine acts as a targeted therapy that disrupts tumor cells’ ability to fix DNA damage, triggering their death, particularly in cells that already have a faulty DNA-repair mechanism.

BRCA mutations are the most common mutations in DNA repair genes. PARP inhibitors have been found to work exceptionally well in women carrying such mutations, either acquired or inherited. But investigators believe that mutations in other DNA repair genes also may make patients susceptible to these treatments.

QUADRA aimed to test that, and included 461 patients with either BRCA mutations, mutations in homologous DNA repair genes, or both. Participants had received three to four prior lines of chemotherapy, and those with homologous recombination deficiency (HRD) had responded to their last platinum-based chemotherapy.

The women were treated with a starting dose of 300 milligrams of Zejula once a day, in a cycle of 28 days.

Results showed that 28% of patients with HRD-positive cancers responded to Zejula, with the study meeting its primary goal. These women – which included patients with and without BRCA mutations – responded to treatment for a median of 9.2 months, and lived for a median of 5.5 months without disease worsening.

A similar proportion of participants with BRCA mutations (29%) also responded to treatment.

Overall, the median overall survival was 26 months for women with BRCA mutations, 19 months for those with HRD mutations, and 15.5 months for HRD-negative patients.

“We know Zejula plays an important role in helping women with ovarian cancer whose disease has progressed despite initial therapy. Our hope is that over time, our ongoing clinical trials will demonstrate that this medicine can benefit even more patients,” said Hal Barron, chief scientific officer and president of research and development at GSK. 

In addition to QUADRA, the ongoing development program for Zejula includes the PRIMA Phase 3 trial (NCT02655016) in patients with first-line ovarian cancer; the TOPACIO Phase 2 trial (NCT02657889) testing Zejula plus Keytruda (pembrolizumab) in patients with platinum-resistant ovarian cancer or triple-negative breast cancer; and the ENGOT-OV24/AVANOVA trial (NCT02354131) evaluating Zejula-Avastin (bevacizumab) in recurrent, platinum-sensitive ovarian cancer.