Overall Survival and Tolerance of Olaparib in the OlympiAD Study – Results of Extended Follow-up

Introduction

Approximately 5% of all breast cancer patients have a germline mutation in the BRCA1 and/or BRCA2 gene, with a higher proportion of this mutation found in HER2-negative tumors. The Phase III OlympiAD study confirmed the efficacy of the PARP inhibitor olaparib specifically in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. This drug is currently approved for the treatment of these patients. The study demonstrated a statistically significant increase in progression-free survival compared with those treated with chemotherapy. Further follow-up allowed the evaluation of the treatment effect from the perspective of overall survival and olaparib's tolerability.

OlympiAD Study Extended Follow-up

OlympiAD was a randomized, controlled, open-label Phase III clinical trial. Participants were randomized in a 2:1 ratio to receive either olaparib or chemotherapy (capecitabine, vinorelbine, or eribulin in monotherapy). Overall, 205 patients were randomized to the olaparib arm and 97 were in the chemotherapy arm. The first analysis of overall survival (OS) data occurred in September 2017, with a follow-up duration of 25.3 months, and the subsequent analysis at 26.3 months. The results of a continued exploratory extended follow-up lasting four years were announced in 2019 at the San Antonio Breast Cancer Symposium (SABCS).

Efficacy of Olaparib

The median overall survival (OS) was 19.3 months with olaparib compared to 17.1 months with chemotherapy (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.63–1.12). The 4-year OS rate was 18.9% compared to 14.2%. 

Subgroup analysis revealed the highest benefit of olaparib therapy for patients with metastatic breast cancer who received olaparib as a first-line treatment, without prior chemotherapy for metastatic disease (median OS 22.6 vs. 14.7 months; HR 0.54). The 4-year OS was 24.6% for olaparib compared to 12.8% for chemotherapy. For patients pre-treated with one or two lines of chemotherapy, the median OS with olaparib was 18.8 vs. 17.2 months (HR 1.13), with a 4-year OS of 17.1% vs. 14.8%. The median OS was 17.2 months with olaparib compared to 13.3 months with chemotherapy in patients who had received prior platinum-based chemotherapy (HR 0.74); for patients without prior platinum chemotherapy, the median OS was 20.3 months compared to 19.6 months (HR 0.86).

For hormone-receptor-positive breast cancers, the median OS was 21.8 vs. 21.3 months (HR 0.79), and for triple-negative breast cancer, the median OS was 17.4 months with olaparib compared to 14.9 months with chemotherapy (HR 0.87).

Safety Profile

Adverse events observed with olaparib were generally less severe and manageable with supportive care or dose modification. These primarily included nausea, vomiting, and anemia. Between the 2017 OS analysis and the extended follow-up, no new serious adverse events associated with olaparib were identified. The discontinuation rate was low (4.9% in the initial analysis), and the risk of developing anemia did not increase with prolonged olaparib exposure.

Conclusion

Extended follow-up confirmed the benefit of olaparib for overall survival in patients with BRCA-mutated metastatic breast cancer. Since April 2019, olaparib has been approved in the EU for patients with HER2-negative locally advanced or metastatic breast cancer (for HR-positive, the indication is specified after exhausting hormonal therapy options), provided their prior chemotherapy included anthracyclines and taxanes. Subgroup analysis also indicated significant improvement in overall survival for patients who had not previously been treated with chemotherapy for metastatic breast cancer. Olaparib's tolerance was good, with no evidence of cumulative toxicity with extended administration.

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Sources:
1. Robson M. E., Tung N., Conte P. et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019 Apr; 30 (4): 558–566, doi: 10.1093/annonc/mdz012.
2. Broderick J. M. Extended follow-up shows continued olaparib benefit in BRCA⁺ MBC. San Antonio Breast Cancer Symposium, 2019. Available at: www.onclive.com/conference-coverage/sabcs-2019/extended-followup-shows-continued-olaparib-benefit-in-brca-mbc