The FDA has granted a priority review to a supplemental New Drug Application (sNDA) for olaparib (Lynparza) for the treatment of patients with germline BRCA
-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy in the neoadjuvant, adjuvant, or metastatic settings, according to AstraZeneca and Merck, the co-developers of the PARP inhibitor.UPDATE 1/12/2018: FDA Approves Olaparib for BRCA+ Breast Cancer
This application is based on results from the phase III OlympiAD trial, which showed that olaparib reduced the risk of disease progression or death by 42% and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patients with BRCA-positive, HER2-negative breast cancer.
OlympiAD findings were presented at the 2017 ASCO Annual Meeting and recently published in the New England Journal of Medicine
. A Prescription Drug User Fee Act date for a final FDA decision is set for early next year.
The OlympiAD trial included 302 patients with HER2-negative metastatic breast cancer who harbored germline BRCA1
mutations. The study was conducted in 19 countries across Europe, Asia, North America, and South America. Patients were allowed to have received up to 2 prior lines of chemotherapy in the metastatic setting.
The median patient age was around 45 and about one-third of patients were non-white (mainly Asian). In both arms, there was a nearly even number of patients who were hormone-receptor positive and triple negative. Across the overall study population, 71% had received prior chemotherapy in the metastatic setting, and 28% had received prior platinum-based therapy in the neoadjuvant, adjuvant, or metastatic setting. Patients who received prior platinum regimens had to have completed the therapy within 12 months of starting the OLYMPIAD trial.
Patients were randomly assigned to 21-day cycles of 300 mg twice daily oral olaparib (n = 205) or physician’s choice of standard chemotherapy (n= 97; capecitabine, vinorelbine, or eribulin). The primary endpoint of the trial was PFS per a blinded independent review.
The PFS analysis occurred after 163 events in the olaparib cohort and 71 events in the chemotherapy group. The median PFS was 7.0 months in the olaparib arm versus 4.2 months with standard chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P
At 12 months, 25.9% of the patients in the olaparib group and 15.0% of the patients in the standard-therapy group were free from progression or death. Overall, 52% of patients had a second progression event or had died after a first progression event. The median time from randomization to a second progression event or death after a first progression event was 13.2 months in the olaparib group and 9.3 months in the standard-therapy group (HR, 0.57; 95% CI, 0.40-0.83; P
Ninety-four patients (45.9%) in the olaparib group and 46 patients (47.4%) in the standard-therapy group died by the time of the primary analysis. Median time to death was 19.3 months in the olaparib group and 19.6 months in the standard-therapy group. Overall survival (OS) was similar between the two groups (HR for death, 0.90; 95% CI, 0.63 to 1.29; P
According to blinded independent central review, 100 of the 167 patients who had measurable disease responded to treatment. The response rate was 59.9% (95% CI, 52.0-67.4) in the olaparib arm compared with 28.8% (95% CI, 18.3-41.3) in the standard-therapy group. Investigators observed complete response (CR) in 9.0% of the patients who had measurable disease in the olaparib group and in 1.5% in the standard-therapy group.
The median duration of response was 6.4 months in the olaparib group and 7.1 months in the standard-therapy group. The median time to the onset of response was 47 days and 45 days, respectively.
Olaparib was well-tolerated overall, with less than 2.0% of patients discontinuing treatment due to toxicity, compared with 2.2% in the chemotherapy arm. The main adverse events (AEs) associated with the PARP inhibitor were nausea, anemia, and fatigue.
Notably, in the olaparib arm versus the chemotherapy arm, there were fewer grade ≥3 AEs (36.6% vs 50.5%, respectively) and fewer AE-related discontinuations (4.9% vs 7.7%). The PARP inhibitor also had less of a negative impact on white blood cells compared with chemotherapy.
There was 1 death in each treatment group, a case of sepsis in the olaparib group and a case of dyspnea in the standard-therapy group. No cases of myelodysplastic syndrome or acute myeloid leukemia were noted in either treatment group.