FDA Grants Maintenance Olaparib Priority Review for Ovarian Cancer

Andrew Coop, MBChB, vice president, US Medical Affairs, Oncology, at AstraZeneca

Andrew Coop, MBChB

The FDA has granted a priority review to a new drug application (NDA) for olaparib (Lynparza) as a maintenance therapy in relapsed patients with platinum-sensitive ovarian cancer, according to AstraZeneca, the manufacturer of the PARP inhibitor.

The NDA is based on data from the phase III SOLO2 trial, in which maintenance olaparib showed a 70% reduction in the risk of progression or death compared with placebo for patients with platinum-sensitive, relapsed, BRCA-mutant ovarian cancer, according to findings reported at the 2017 Society of Gynecologic Oncology Annual Meeting.

Patients randomized to olaparib had a median investigator-assessed progression-free survival (PFS) of 19.1 months compared with 5.5 months in the placebo arm (HR, 0.30; 95% CI, 0.22-0.41; P <.0001). A prespecified analysis of PFS by a blinded central review committee showed a median PFS of 30.2 months for the olaparib group versus 5.5 months for placebo, a 75% reduction in the hazard for progression and death (HR, 0.25; 95% CI, 0.18-0.35; P <.0001).

The NDA for maintenance olaparib is for an investigational tablet formulation of the PARP inhibitor that patients would receive at 300 mg twice daily. Olaparib is currently approved by the FDA as a capsule formulation (400 mg twice daily) for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with 3 or more prior lines of chemotherapy. Under the Prescription Drug User Fee Act, the FDA will make a final approval decision on the NDA by the third quarter of 2017, according to AstraZeneca.

“If approved as a maintenance therapy for patients with advanced ovarian cancer, LYNPARZA tablets would help address the unmet medical need and limited treatment options for women living with this disease, and offer patients a potential reduced pill burden for LYNPARZA. Additionally, the US FDA filing acceptance shows how we are progressing the science behind LYNPARZA — the first PARP inhibitor approved in the US more than two years ago – while also investigating LYNPARZA in other tumor types, including breast, pancreatic and prostate,” Andrew Coop, MBChB, vice president, US Medical Affairs, Oncology, at AstraZeneca, said in a statement.

Eligible patients for the phase III SOLO2 trial had relapsed ovarian cancer, confirmed BRCA1/2 mutation, and were in response to their most recent platinum-containing regimen following 2 or more prior systemic regimens. Investigators in the multicenter international trial randomized patients 2:1 to olaparib (300-mg tablet twice daily) or to matching placebo. Treatment continued until disease progression. The primary endpoint was investigator-assessed PFS. The trial protocol included a sensitivity analysis of PFS, performed by a blinded independent central review committee. Secondary endpoints included second PFS (PFS2), overall survival, and safety and tolerability.

Data analysis included 294 randomized patients who received the assigned study treatment. Baseline characteristics did not differ substantively between treatment groups, as 53% to 54% of patients in each group had attained a partial remission at enrollment; 40% of each group had a platinum-free interval of 6 to 12 months; and about 40% of patients had received 3 or more prior lines of therapy.

Olaparib was generally well tolerated, as no new or unexpected treatment-associated adverse events (AEs) occurred in patients who received the PARP inhibitor. The most common AEs of any grade were nausea (75.9% vs 33.3%), fatigue/asthenia (65.6% vs 39.4%), anemia (43.6% vs 8.1%), vomiting (37.4% vs 19.2%), and diarrhea (32.8% vs 20.2%). Neutropenia occurred in 19.5% of the olaparib group versus 6.1% of the placebo group, and thrombocytopenia in 13.8% versus 3.0%.

Grade ≥3 AEs included anemia (19.5% vs 2.0%), neutropenia (5.1% vs 4.0%), and thrombocytopenia (1.0% in both groups).

The results confirmed and extended those of a phase II trial that demonstrated a PFS advantage for olaparib maintenance therapy in relapsed, platinum-sensitive ovarian cancer (N Engl J Med. 2012;366:1382-1392). The earlier study did not select patients based on BRCA status, and patients received a different formulation of olaparib.

Although the earlier trial showed a PFS benefit in the overall population and across various subgroups, patients with BRCA-mutated ovarian cancer had the most prolonged PFS. Additionally, the capsule formulation of olaparib used in the phase II trial required patients to take as many as 16 pills a day whereas the 300-mg tablet formulation reduced the pill burden to 2 per day.

The secondary endpoint of median time to first subsequent therapy or death was 27.9 months with olaparib and 7.1 months with placebo (P <.0001). The median PFS2 had yet to be reached in the olaparib group, whereas the placebo group had median of 18.4 months, representing a 50% reduction in the hazard ratio in favor of the PARP inhibitor (P = .0002). Time to second subsequent therapy or death also had yet to be reached in the olaparib arm compared with a median of 18.2 months in the placebo group (P <.0001). Data remained too immature for an analysis of overall survival.