Mutations to the BRCA gene can result in a lifetime risk of developing breast cancer of up to 84%. Additionally, when BRCA-associated cancer does develop, the phenotype is typically more aggressive, such as triple-negative breast cancer. More recently, targeted therapy with poly(ADP-ribose) polymerase (PARP) inhibitors have offered better survival outcomes compared to chemotherapy. BRCA-associated breast tumours rely on the base-exicision repair pathway for survival, which is mediated by PARP enzymes. Inhibition of this enzyme induces cell death in these cancer cells, whilst sparing healthy cells.1 Investigating the PARP inhibitor Olaparib in an adjuvant setting following chemotherapy, the phase III OlympiA trial has recently published encouraging results.
Enrolling 1836 human epidermal growth factor receptor 2 (HER2)-negative, early breast cancer patients with BRCA1 or BRCA2 mutations, this phase III, double-blind randomised trial randomised patients to receive olaparib (300mg twice daily) or placebo up to one year, following local therapy and subsequent chemotherapy. Patients were also required to have an ECOG PS of 0-1, and patients with evidence of second primary malignancy or metastatic disease were excluded. The primary endpoint of this study was invasive disease-free survival (IDFS), with key secondary endpoints of overall survival (OS), distant disease-free survival (DDFS) and safety.
At a median follow-up of 2.5 years, the 3-year IDFS was statistically better with olaparib compared to placebo (85.9% vs. 77.1%; HR[99.5%CI]: 0.58[0.41-0.82], P< 0.001). 3-year DDFS also followed a similar trend, with olaparib offering a statistically superior outcome (87.5% vs. 80.4%; HR[99.5%CI]: 0.57[0.39-0.83], P< 0.001). Treatment with olaparib also reduced the risk of death by 32%, with 59 and 86 deaths occurring in the olaparib and placebo arms, respectively (HR[99%CI]: 0.68[0.44-1.05], P= 0.02). Safety data was also consistent with the known profile of olaparib, with no excess serious adverse events (AEs) or AEs of special interest being reported.2
This study offers compelling evidence that following standard local therapy and chemotherapy, adjuvant olaparib offers significantly superior outcomes in disease-free survival. Combined with no new safety concerns, this could represent a new standard in treatment.