The OlympiA trial of adjuvant olaparib in patients with HER2-negative, high-risk early-stage breast cancer and BRCA1 and BRCA2 mutations has now demonstrated a significant overall survival benefit, reducing the risk of death over placebo by 32% and yielding an absolute improvement of 3.8% at 3 years. Andrew Tutt, MBChB, PhD, Head of the Division of Breast Cancer Research and Director of the Breast Cancer Now Toby Robins Research Centre at the 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 European Society for Medical Oncology (ESMO) Virtual Plenary.1
“Adjuvant olaparib improves overall survival, with a hazard ratio [HR] of 0.68 and a P value of .009 at 3.5 years of median follow-up, meeting the significance threshold [P < .015] for overall survival at this second planned interim analysis,” Dr. Tutt announced.
The results from OlympiA underscore the importance of genomic testing to reveal BRCA1/2 mutations, as this now affects adjuvant treatment decisions.— Andrew Tutt, MBChB, PhD
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In the study, patients received 1 year of olaparib, a PARP (poly [ADP-ribose] polymerase) 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 ASCO 2021 at 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.
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,” he said.2
Based on these data, olaparib has just been approved by the U.S. Food and Drug Administration for the adjuvant treatment of adults with germline BRCA1/2 mutations and HER2-negative high-risk early-stage breast cancer who have received neoadjuvant or adjuvant chemotherapy.
Approximately 5% of patients with early-stage breast cancer have BRCA mutations. The results from OlympiA underscore the importance of genomic testing to reveal these mutations, as this now affects adjuvant treatment decisions, Dr. Tutt said.
OlympiA is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase III study comparing olaparib with placebo in 1,836 patients who completed local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned 1:1 to olaparib (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 between the treatment arms. Median age of patients was approximately 42, and most patients had BRCA1 mutations. Approximately 18% had hormone receptor–positive, HER2-negative disease, and approximately 82% had triple-negative breast cancer.
“Patients were young, and the mastectomy rate was high (75%) for an early-stage breast cancer trial, but this was expected in this BRCA1/2 mutation–carrier context,” he said. Most of the 20% of patients with hormone receptor–positive tumors were enrolled following a protocol amendment in 2015, Dr. Tutt added.
Improved Overall Survival
After a median follow-up of 3.5 years, there were 75 deaths in the olaparib arm and 109 deaths in the placebo arm, amounting to 3-year overall survival rates of 92.0% and 89.1%, respectively (HR = 0.68; 98.5% confidence interval [CI] = 0.47–0.97; P = .009). He 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,” Dr. Tutt said. Subgroup hazard ratio point estimates for the olaparib effect were less than 1, and the confidence intervals include the hazard ratio for the olaparib treatment effect in the overall intent-to-treat population, he explained.
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 with olaparib and 207 with placebo (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 the olaparib arm and 5.6% of the placebo arm. Grade ≥ 3 adverse events occurred in 24.5% and 11.3%, respectively, and those leading to treatment discontinuation occurred in 10.8% vs 4.6%, respectively. “Of note,” he added, “there have been no additional adverse events leading to death reported since our previous report.”
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 among fundamental science, cancer genetics, clinical trialists, and pharma to work with patients to try to develop and test individualized medicines.”
DISCLOSURE: Dr. Tutt disclosed financial relationships with AstraZeneca, Artios Pharma, Gilead, Inbiomotion, Merck KGaA, Pfizer, Prime Oncology, Vertex, and MD Anderson.
1. Tutt ANJ, Garber J, Gelber RD, et al: Prespecified event-driven analysis of overall survival in the OlympiA phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. ESMO Virtual Plenary. Abstract VP1-2022. Presented March 16, 2022.
2. Tutt ANJ, Garber JE, Kaufman B, et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.
“OlympiA is clearly a practice-changing trial, and olaparib should be offered to patients meeting the entry criteria for the study,” said Mark E. Robson, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York. Dr. Robson was invited to discuss the findings of...