Three and a half-year follow-up in the OlympiA trial showed continued survival improvement and underscores the vitality of germline BRCA testing.
Olaparib (Lynparza) has displayed a statistically significant improvement in overall survival (OS) compared with placebo in patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer, according to a prespecified event-driven analysis of OS presented during the March 2022 ESMO Virtual Plenary.
After a median follow-up of 3.5 years, adjuvant olaparib achieved a 32% reduction in the risk of death compared with placebo (stratified HR, 0.68; 98.5% CI, 0.47-0.97; P = .0009). The result exceeded the boundary for statistical significance by 0.006. The read-out of this result comes on the heels of news that olaparib improved invasive disease-free survival (iDFS) by 42% versus placebo and decreased distant disease-free survival (DDFS) by 43%.
“Olaparib after local treatment and neoadjuvant or adjuvant chemotherapy significantly improved iDFS, DDFS, and overall survival with limited and manageable toxicity and without new safety signals,” said AndrewTutt, MD, head of the Division of Breast Cancer Research and director of the Breast Cancer Now Toby Robins Research Centre at the ICR and Guy’s Hospital King’s College London, during his presentation of the data.
OlympiA (NCT02032823) is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, phase 3 study comparing olaparib to placebo in patients who have had complete local treatment and neoadjuvant or adjuvant chemotherapy. Preclinical research showed significant residual recurrence among patients with higher-risk breast cancer who carry BRCA1/2 mutations, and investigators hypothesized that olaparib would be a beneficial treatment for this patient population based on its progression-free survival results in BRCA1/2-associated breast, ovarian, prostate, and pancreatic cancers.
A total of 1836 patients were enrolled in the study and randomized 1:1 to olaparib (n = 921) or placebo (n = 915). Patients were treated with olaparib 300 mg twice daily for 1 year or a matching placebo. Patients were stratified by hormone receptor-positive status, receipt of neoadjuvant or adjuvant chemotherapy, and whether or not they received prior platinum-based chemotherapy.
At baseline, patients in the olaparib arm had a median age of 42 years (range, 36-49) and 43 years (range, 36-50) in the placebo arm. More patients in both arms had germline BRCA1 than BRCA2 mutations. In the olaparib group, 18.2% of patients had estrogen receptor (ER)-positive, PgR-positive/HER2-negative disease and 81.5% had triple-negative breast cancer. In comparison, 17.2% of patients in the placebo arm had ER- and/pr PgR-positive/HER2-negative breast cancer and 82.8% had triple-negative breast cancer.
Considering the significance boundary was crossed in the study, Tutt et al compared OS at 3 years to OS at 4 years, the rates were 3.8% versus 3.4%, respectively.
In addition to the intention-to-treat (ITT) population, treatment with olaparib appeared to be favored across most subgroups. The exceptions were patients who received adjuvant chemotherapy, those who received prior platinum-based chemotherapy, and patients with HR-positive/HER2-negative disease.
At the second OS analysis, investigators also looked longer follow-up data for iDFS and DFFS. Tutt explained that iDFS events remained lower in the olaparib arm at the second analysis with 134 events compared with 207 events in the placebo arm (stratified HR, 0.63; 95% CI, 0.50-0.78). The majority of the subgroups also had a more favorable iDFS result with olaparib versus placebo, excluding those who received platinum-based chemotherapy, patients with HR-positive/HER2-negative disease, and those with a germline BRCA2 mutation.
DDFS benefit with olaparib was also sustained at the second analysis. There were 107 DDFS events in the olaparib arm compared with 172 in the placebo arm (stratified HR, 0.61; 95% CI, 0.48-0.77). Similar to the other subgroups and the ITT populations, patients who had prior platinum-based chemotherapy, HR-positive/HER2-negative disease, and those with a germline BRCA2 mutation.
The adverse event (AE) profile of olaparib did not change between the first and second analyses. Any-grade AEs were observed in 91.8% of the olaparib arm compared with 83.8% of the placebo arm. AEs of special interest included myelodysplastic syndrome or acute myeloid leukemia, pneumonitis, and new primary malignancy. These AEs of special interest were found in 3.4% of the olaparib arm compared with 5.6% of the placebo arm. Grade 3 or higher AEs occurred in 24.5% of the olaparib arm versus 11.3% of the placebo arm.
AEs led to treatment discontinuation in 10.8% of patients who received olaparib versus 4.6% who were given a placebo. Death caused by AEs occurred once in the olaparib arm versus twice in the placebo arm.
The most common AEs of any grade in the olaparib arm versus the placebo arm were nausea (57% vs 24%, respectively) and fatigue (40% vs 27%).
Results from OlympiA underscore the importance of genomic testing, Tutt explained, stating; “Germline BRCA1 and BRCA2 sequencing is an important companion diagnostic for adjuvant treatment decisions in breast cancer. Based on these data, olaparib has just been licensed by the FDA for the adjuvant treatment of adult patients with germline BRCA1/2 mutations and HER2-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.”
Tutt A, Garber J, Gelber RD, et al. Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer. Presented at ESMO Virtual Plenary; March 16, 2022.