FDA Approves Lynparza for BRCA-Positive Breast Cancer

Lynparza (olaparib), a PARP inhibitor, was granted approval by the Food and Drug Administration (FDA) for the treatment of patients with BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Also, patients who have HR-positive disease should have prior endocrine therapy or they would not be considered appropriate for such treatment.

This approval is based on results from the phase 3 OlympiAD trial, which showed that Lynparza reduced the risk of disease progression or death by 42 percent and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patients with BRCA-positive, HER2-negative breast cancer.

Treatment selection for Lynparza is based on the BRACAnalysis CDx genetic test, which today had its FDA approval expanded to include the detection of BRCA mutations in patients with breast cancer.

“This class of drugs has been used to treat advanced, BRCA-mutated ovarian cancer and has now shown efficacy in treating certain types of BRCA-mutated breast cancer,” Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval demonstrates the current paradigm of developing drugs that target the underlying genetic causes of a cancer, often across cancer types.”

The OlympiAD trial included 302 patients with HER2-negative metastatic breast cancer who harbored germline BRCA1 or BRCA2 mutations. The study was conducted in 19 countries across Europe, Asia, North America and South America. Patients were allowed to have received up to two 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 percent had received prior chemotherapy in the metastatic setting, and 28 percent 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 Lynparza (205 patients) or physician’s choice of standard chemotherapy (97 patients; 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 Lynparza cohort and 71 events in the chemotherapy group. The median PFS was seven months in the Lynparza arm versus 4.2 months with standard chemotherapy.

At 12 months, 25.9 percent of the patients in the Lynparza group and 15 percent of the patients in the standard-therapy group were free from progression or death. Overall, 52 percent 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 Lynparza group and 9.3 months in the standard-therapy group.

Ninety-four patients (45.9 percent) in the Lynparza group and 46 patients (47.4 percent) in the standard-therapy group died by the time of the primary analysis. Median time to death was 19.3 months in the Lynparza group and 19.6 months in the standard-therapy group. Overall survival (OS) was similar between the two groups.

According to blinded independent central review, 100 of the 167 patients who had measurable disease responded to treatment. The response rate was 59.9 percent in the Lynparza arm compared with 28.8 percent in the standard-therapy group. Investigators observed complete response (CR) in 9.0 percent of the patients who had measurable disease in the Lynparza group and in 1.5 percent in the standard-therapy group.

The median duration of response was 6.4 months in the Lynparza 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.

Lynparza was well-tolerated overall, with less than 2 percent of patients discontinuing treatment due to toxicity, compared with 2.2 percent in the chemotherapy arm. The main adverse events (AEs) associated with the PARP inhibitor were nausea, anemia, and fatigue.

Notably, in the Lynparza arm versus the chemotherapy arm, there were fewer grade 3 or higher AEs (36.6 percent vs 50.5 percent, respectively) and fewer AE-related discontinuations (4.9 percent vs 7.7 percent). 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 Lynparza 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.