Extending Progression-Free Survival in BRCA-Positive Breast Cancer

The PARP inhibitor Lynparza (olaparib) reduce the risk of disease progression by 42 percent versus standard chemotherapy in patients with BRCA-positive, HER2-negative breast cancer, according to findings from the phase 3 OLYMPIAD trial presented at the 2017 ASCO Annual Meeting.

The median progression-free survival (PFS) was improved by 2.8 months with Lynparza. The objective response rate (ORR) was 59.9 percent with Lynparza versus 28.8 percent with chemotherapy.

“This is the first phase 3 study to show an advantage of a PARP inhibitor over standard of care chemotherapy in breast cancer patients with a BRCA mutation,” said principal OLYMPIAD investigator Mark E. Robson, M.D., Clinic Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center.

“Olaparib could be an effective treatment option for women with BRCA mutations and metastatic HER2-negative breast cancer, including women with BRCA mutations and triple-negative breast cancer,” added Robson.

The phase 3 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 receive up to two prior lines of chemotherapy in the metastatic setting.

The median patient age was around 45, about one-third of patients were non-white (mainly Asian), 49 percent were HR-positive and 51 percent were triple-negative. Seventy-one 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 randomized in a 2:1 ratio to oral Lynparza (205 patients; 300 mg twice daily) 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. Secondary endpoints included overall survival, time to second progression or death, ORR, and effect on health-related quality of life.

The PFS analysis occurred after 163 events in the Lynparza cohort and 71 events in the chemotherapy group. The median PFS was 7 months in the olaparib arm versus 4.2 months with standard chemotherapy. Lynparza also demonstrated an improvement in PFS2, defined as the time until second progression or death.

Lynparza was well-tolerated overall, with less than 4.9 percent of patients discontinuing treatment due to toxicity, compared with 7.7 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 and fewer AE-related discontinuations (36.6 percent vs 50.5 percent, respectively). The PARP inhibitor also had less of a negative impact on white blood cells compared with chemotherapy.

Positive results for Lynparza in this setting were previously shown in a phase 2 proof-of-concept trial (NCT00494234) published in the The Lancet in 2010.² The study was conducted at 16 centers in Australia, Germany, Spain, Sweden, the United Kingdom and the United States.

The study assigned women with recurrent, advanced breast cancer and BRCA1 or BRCA2 mutations to two sequential cohorts. The first cohort (27 patients) received continuous oral Lynparza at the maximum-tolerated dose (400 mg twice daily) and the second cohort (27 patients) received 100 mg twice daily.

The median number of prior chemotherapy regimens was 3 (range, 1-5 in cohort 1, and 2-4 in cohort 2). The primary efficacy endpoint was ORR. Among patients in the 400-mg cohort, the ORR was 41 percent (11/27), and the ORR was 22 percent (6/27; 95 percent CI, 11-41) for the 100-mg cohort.

Most of the reported adverse events (AEs) were low grade. In the 400-mg cohort, the most common AEs included fatigue (grade 1/2, 11 patients [41 percent]; grade 3 or 4, four patients [15 percent]), nausea (grade 1/2, 11 patients [41 percent]; grade 3/4, four patients [15 percent]), vomiting (grade 1/2, three patients [11 percent]; grade 3/4, three patients [11 percent]), and anemia (grade 1/2, one patient [4 percent]; grade ¾, three patients [11 percent]).

In the 100-mg short, the most common AEs were nausea (grade 1/21; 11 patients [41 percent]; no grade 3/4) and fatigue (grade 1/2, seven patients[26 percent]; grade 3/4, one patient [4 percent]).

BRCA testing in the OLYMPIAD trial was done using Myriad Genetics BRACAnalysis CDx test. The test detected positive germline BRCA1/2 mutations in 98 percent (297/302) of the patients enrolled in the trial.

The FDA approved Lynparza in December 2014 for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy. The BRACAnalysis CDx test was simultaneously approved as a companion diagnostic.