The European Medicine Agency’s Committee for Medicinal Products for Human Use has granted a positive opinion to olaparib tablets as monotherapy for the treatment of adult patients with germline BRCA1/2-mutant, HER2-negative locally advanced or metastatic breast cancer.
Roy Baynes, MD, PhD
The European Medicine Agency’s Committee for Medicinal Products for Human Use has granted a positive opinion to olaparib (Lynparza) tablets as monotherapy for the treatment of adult patients with germline BRCA1/2-mutant, HER2-negative locally advanced or metastatic breast cancer.1
If approved, olaparib would be indicated for those who were previously been treated with an anthracycline and a taxane in the neoadjuvant, adjuvant, or metastatic setting unless they weren’t suitable for these therapies. Additionally, patients with hormone receptor (HR)—positive breast cancer should also have progressed on or after prior endocrine therapy, or be considered unsuitable for endocrine therapy, said AstraZeneca, the company that co-develops olaparib with Merck, in a press release.
The decision is based on findings from the open-label, randomized, phase III OlympiAD trial, in which olaparib demonstrated a 42% risk in the reduction of disease progression or death and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patients with BRCA-positive, HER2-negative breast cancer.
“The positive opinion from CHMP for Lynparza in this patient population is an important milestone,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “This decision brings us one step closer to offering a new treatment option to patients with advanced breast cancer and further underscores the critical need to identify patients’ BRCA status, in addition to hormone receptor and HER2 expression status, as part of the management of this disease.”
In the international OlympiAD trial, 302 patients with HER2-negative metastatic breast cancer who harbored germline BRCA1/2 mutations were randomized to either 21-day cycles of 300 mg twice daily oral olaparib (n = 205) or physician’s choice of standard chemotherapy (n= 97), which consisted of capecitabine, vinorelbine, or eribulin (Halaven).
Patients were permitted to have received up to 2 prior lines of chemotherapy in the metastatic setting. The median age was approximately 45 and about one-third of patients were non-white (mainly Asian). In both groups, there was a nearly even number of patients who had HR-positive disease and triple-negative breast cancer. Across the overall study population, 71% of patients had received prior chemotherapy in the metastatic setting, and 28% had received prior platinum-based therapy in the neoadjuvant, adjuvant, or metastatic setting. Those who received prior platinum regimens must have completed such treatment within 12 months of starting on the OlympiaAD trial. 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. Results showed that the median PFS was 7.0 months in the olaparib arm versus 4.2 months with standard chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P = .001).
At 12 months, 25.9% of the patients on the olaparib arm and 15.0% of those who received standard therapy 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 treatment arm (HR, 0.57; 95% CI, 0.40-0.83; P = .003).
Moreover, 94 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 2 groups (HR, 0.90; 95% CI, 0.63-1.29; P = .57).
Additionally, according to blinded independent central review, 100 of the 167 patients who had measurable disease responded to olaparib. The overall 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 a complete response (CR) in 9.0% of those who had measurable disease in the olaparib group and in 1.5% of those in the chemotherapy group.
The median duration of response was 6.4 months in the olaparib group and 7.1 months with standard treatment. The median time to onset of response was 47 days and 45 days, respectively.
Regarding safety, olaparib was well tolerated overall; less than 2.0% of patients discontinued treatment due to toxicity versus 2.2% in the chemotherapy arm. The main adverse events (AEs) associated with the PARP inhibitor were nausea, anemia, and fatigue.
Moreover, there were fewer grade ≥3 AEs in the olaparib arm (36.6%) versus the chemotherapy arm (50.5%) and fewer AE-related discontinuations at 4.9% vs 7.7%, respectively. Olaparib also had less of a negative impact on white blood cells versus chemotherapy.
There was 1 death in each treatment group, which was a case of sepsis in the olaparib group and a case of dyspnea in the chemotherapy arm. There were no cases of myelodysplastic syndrome or acute myeloid leukemia noted in either group.