Olaparib (Lynparza®) in patients with BRCA-mutated metastatic breast cancer

Approximately 5% of unselected breast cancer patients carry a germline mutation (gBRCAm) in the BRCA1 and BRCA2 genes that repairs double-strand DNA breaks through homologous recombination. Olaparib, an oral poly ADP-ribose polymerase inhibitor (PARPi), provokes selective synthetic lethality in BRCA-deficient tumour cells by inhibiting single-strand DNA repair. Currently, olaparib is not approved for the treatment of breast cancer. However, in 2014 olaparib was approved in Europe and USA for the treatment of BRCA-mutated ovarian cancer. The safety and efficacy of olaparib in patients with gBRCAm and HER2-negative metastatic breast cancer (MBC), who had received no more than two previous chemotherapy regimens for metastatic disease, were assessed in the OlympiAD trial, an open-label, randomised, multicentre, phase III study. 302 patients were enrolled and randomly assigned in a 2:1 ratio to receive either olaparib tablets (n=205; 300mg twice daily) or 21-day cycles of physician’s choice chemotherapy (n=97) with capecitabine (2,500mg/m2 oral daily for 14 days), eribulin (1.4mg/m2 IV on days 1 and 8) or vinorelbine (30mg/m2 IV on days 1 and 8). The stratification of randomisation was based on the previous use of chemotherapy for metastatic disease, hormone receptor (HR) status (HR-positive versus triple negative breast cancer, TNBC), and previous use of platinum-based therapy. The primary outcome of the study was progression-free survival (PFS). At 14-months follow-up, overall survival did not show a statistically significant difference between groups. Compared with chemotherapy, olaparib increased median PFS by 2.8 months, as monitored by blinded independent central review (BICR). It also reduced the risk of disease progression and death by 42%, as well as the risk of investigator-assessed second progression by 43%. BICR-assessed objective response rate was 59.9% for olaparib versus 28.8% for chemotherapy. At 15.3 months, chemotherapy improved disease-specific quality of life. Adverse events (AEs), primarily anaemia, caused a dose interruption, reduction or discontinuation in 50%, 27% and 5% of olaparib patients, respectively. Overall, olaparib improves PFS and reduces the risk of progression in HER2-negative BRCA-mutated MBC relative to physicians' choice chemotherapy. OlympiAD results hold limited internal and external validity, and follow-up may be insufficient to capture the risk of recurrence or second primary development. While patients are selected based on a confirmed deleterious gBRCAm, there is currently no established biomarker for response to PARPi. Clinical utility of olaparib may be limited as three mechanisms of resistance have already been established. Increasing use of platinum therapy in early TNBC may furthermore influence PARPi use, whilst the optimal PARPi-chemotherapy drug combination remains to be established.