The side effects were consistent with the safety profile of olaparib. Adverse events of grade 3 or higher more common with olaparib included anemia (8.7%), leukopenia (3%), and fatigue (1.8%). Early discontinuation of trial regimen due to adverse events of disease recurrence occurred in 25.9% in the olaparib group and 20.7% in the placebo group. Blood transfusions were required in 5.8% of patients in the olaparib group. Myelodysplasia or acute myleoid leukemia was observed in 2 patients in the olaparib group and 3 patients in the placebo group. Adverse events leading to death occurred in 1 patient in the olaparib group and 2 patients in the placebo group.
Conclusion. Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer invasive disease-free and distant disease-free survival compared with placebo.
Commentary
The results from the current OlympiA trial provide the first evidence that adjuvant therapy with poly adenosine diphosphate-ribose polymerase (PARP) inhibitors can improve outcomes in high-risk, HER2-negative breast cancer in patients with pathogenic BRCA1 and BRCA2 mutations. The OS, while favoring olaparib, is not yet mature at the time of this analysis. Nevertheless, these results represent an important step forward in improving outcomes in this patient population. The efficacy and safety of PARP inhibitors in BRCA-mutated breast cancer has previously been shown in patients with advanced disease leading to FDA approval of both olaparib and talazoparib in this setting.1,2 With the current results, PARP inhibitors will certainly play an important role in the adjuvant setting in patients with deleterious BRCA1 or BRCA2 mutations at high risk for relapse. Importantly, the side effect profile appears acceptable with no unexpected events and a very low rate of secondary myeloid malignancies.
Subgroup analysis appears to indicate a benefit across all groups including hormone receptor–positive disease and triple negative breast cancer. Interestingly, approximately 25% of patients in both cohorts received platinum-based chemotherapy. The efficacy of adjuvant olaparib did not appear to be impacted by prior use of platinum-containing chemotherapy regimens. It is important to consider that postneoadjuvant capecitabine, per the results of the CREATE-X trial, in triple-negative patients was not permitted in the current study. Although, this has been widely adopted in clinical practice.3 The CREATE-X trial did not specify the benefit of adjuvant capecitabine in the BRCA-mutated cohort, thus, it is not clear how this subgroup fares with this approach. Thus, one cannot extrapolate the relative efficacy of olaparib compared with capecitabine, as pointed out by the authors, and whether we consider the use of capecitabine and/or olaparib in triple-negative patients with residual invasive disease after neoadjuvant chemotherapy is not clear at this time.
Nevertheless, the magnitude of benefit seen in this trial certainly provide clinically relevant and potentially practice changing results. It will be imperative to follow these results as the survival data matures and ensure no further long-term toxicity, particularly secondary myeloid malignancies, develop. These results should be discussed with each patient and informed decisions regarding the use of adjuvant olaparib should be considered for this patient population. Lastly, these results highlight the importance of germline testing for patients with breast cancer in accordance with national guideline recommendations. Moreover, these results certainly call into question whether it is time to consider expansion of our current germline testing guidelines to detect all potential patients who may benefit from this therapy.
Application for Clinical Practice
Adjuvant olaparib in high-risk patients with germline BRCA1 or BRCA2 mutations improves invasive and distant disease-free survival and should be considered in patients who meet the enrollment criteria of the current study. Furthermore, this highlights the importance of appropriate germline genetic testing in patients with breast cancer.
Financial disclosures: None.