The OlympiA trial of adjuvant olaparib in patients with HER2-negative, high-risk early breast cancer and BRCA1 and BRCA2 mutations has demonstrated a significant overall survival benefit, reducing the risk of death over placebo by 32%. Andrew Tutt, MBChB, PhD, Director of Breast Cancer Now at the Toby Robins Research Centre, Institute of Cancer Research and Royal Marsden Hospital London, and Guy’s Hospital King’s College, London, presented the prespecified event-driven analysis of overall survival during the March 2022 ESMO Virtual Plenary (Abstract VP1-2022). 

Andrew Tutt, MBChB, PhD

“Adjuvant olaparib improves overall survival, with a hazard ratio of 0.68 and P value of .009 at 3.5 years median follow-up, meeting the significance threshold (P < .015) for overall survival at this second planned interim analysis,” Dr. Tutt said.   In the study, patients received 1 year of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, or placebo after local treatment and adjuvant or neoadjuvant chemotherapy. After a median follow-up of 3.5 years, survival rates at 3 years were 92.0% with olaparib vs 89.1% with placebo. In a previous first interim analysis presented at the 2021 ASCO Annual Meeting after a median follow-up of 2.5 years, the hazard ratio was 0.68, but the P value of .024 did not meet the significance threshold of .010.

“OlympiA is clearly a practice-changing trial, and olaparib should be offered to patients meeting the entry criteria for the study,” said invited discussant Mark Robson, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center.

Invasive disease–free survival, the primary endpoint, and distant disease–free survival, another secondary endpoint, also remained consistent with the prior analysis, “with a tightening of the confidence intervals,” said Dr. Tutt.

Based on these data, olaparib has just been approved by the U.S. Food and Drug Administration for the adjuvant treatment of adult patients with germline BRCA1/2 mutations and HER2-negative high-risk early breast cancer who have received neoadjuvant or adjuvant chemotherapy.

Approximately 5% of patients with early breast cancer have BRCA mutations. The results from OlympiA underscore the importance of genomic testing to reveal these, as this now affects adjuvant treatment decisions, Dr. Tutt said.

About OlympiA

OlympiA is a randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III study comparing olaparib to placebo in 1,836 patients who completed local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned 1:1 to receive olaparib at 300 mg twice daily or placebo for 1 year, stratified by hormone receptor–positive status, receipt of neoadjuvant or adjuvant chemotherapy, and receipt of prior platinum-based chemotherapy.

Patient characteristics were evenly balanced. Median age was approximately 42 years, and most patients had BRCA1 mutations. Approximately 18% had hormone receptor–positive, HER2-negative disease and approximately 82% had triple-negative disease.

Improved Overall Survival

After a median follow-up of 3.5 years, there were 75 deaths in the olaparib arm and 109 in the placebo arm, amounting to 3-year overall survival rates of 92.0% and 89.1%, respectively (hazard ratio [HR] = 0.68; 98.5% confidence interval [CI] = 0.47–0.97, P = .009). Dr. Tutt reported the difference between the arms (after rounding) was 3.8% at 3 years and 3.4% at 4 years.  

“The interpretation of treatment effect in subgroups remains constrained by low numbers of events, or what remains short follow-up for olaparib treatment, but it was consistent and without evidence of significant heterogeneity across major subgroups,” he continued.

In the second preplanned interim analysis, invasive disease–free survival and distant disease–free survival endpoints remained consistent with previous estimates.

Invasive disease–free survival events numbered 134 in the olaparib arm and 207 in the placebo arm (HR = 0.63, 95% CI = 0.50–0.78). At 3 years, 86.1% and 77.3% of patients, respectively, were free of invasive disease, reflecting an 8.8% improvement. Distant disease–free survival events numbered 107 and 172, respectively, and the 3-year rate was 88.0% and 81.0%, respectively (HR = 0.61, 95% CI = 0.48–0.77). The rate difference was 7.0% at 3 years and 7.4% at 4 years.

Safety Profile Upheld

The adverse event profile of olaparib did not change between the first and second analyses. The most common toxicities of any grade in the olaparib arm vs the placebo arm were nausea (57% vs 24%, respectively) and fatigue (40% vs 27%), which were mostly mild. Serious adverse events occurred in about 9% of each arm.

Adverse events of special interest included myelodysplastic syndrome and acute myeloid leukemia, pneumonitis, and new primary malignancies, which altogether occurred in 3.4% of patients in the olaparib arm and 5.6% of the placebo arm. Grade ≥ 3 events occurred in 24.5% and 11.3%, respectively, while those leading to treatment discontinuation occurred in 10.8% vs 4.6%, respectively.

In closing, Dr. Tutt called attention to the international efforts that culminated in the global OlympiA trial.  

“The trial has been a huge team effort involving women with genetic forms of breast cancer, scientists understanding the biology of BRCA1 and BRCA2 genes, and clinicians from hundreds of hospitals across the world. It is a real example of cooperation between fundamental science, cancer genetics, clinical trialists, and pharma to work with patients to try to develop and test individualized medicines.” 

Disclosure: Dr. Tutt has financial relationships with AstraZeneca, Artios Pharma, Gilead, Inbiomotion, Merck KGaA, Pfizer, Prime Oncology, Vertex, and MD Anderson. For full disclosures of the study authors, visit oncologypro.esmo.org.

This article was revised on April 5, 2022.