The second interim analysis of OlympiA showed olaparib to improve overall survival, invasive-disease-free survival, distant-disease-free survival, and revealed no new safety signals in patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer.
Adjuvant olaparib (Lynparza) showed statistically significant improved overall survival (OS) compared with placebo in patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer, according to findings of the OlympiA trial (NCT02032823) published in Annals of Oncology.1
In addition to an improvement in OS, olaparib improved 4-year invasive-disease-free survival (IDFS) vs placebo (83% vs 75%) and 4-year distant-disease-free survival (DDFS; 87% vs 79%). ‘
With a median follow-up of 3.5 years, there were 2 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cases (0.2%) with olaparib and 3 (0.3%) with placebo. At an additional 1-year of follow-up, there were no new safety signals identified with olaparib vs placebo.
“The pre-specified second [interim analysis] of OS in the OlympiA trial demonstrates that 1 year of adjuvant olaparib relative to placebo provided a statistically significant improvement in OS [HR 0.68; 98.5.% CI 0.47-0.97; P = .009] with an absolute improvement in 4-year OS of 3.4% [89.8% olaparib; 86.4% placebo] in patients with high-risk early breast cancer and pathogenic variants in germline BRCA1/2 following standard of care chemotherapy, surgery, and radiation therapy, which if indicated, had been completed at least 2 weeks prior to randomization,” wrote the study authors led by Charles E. Geyer, Jr., MD, professor of medicine, Virginia Commonwealth University School of Medicine; associate director for clinical research and Harrigan, Haw, Luck Families chair in Cancer Research, Massey Cancer Center.
The randomized, double-blind OlympiA trial compared olaparib with placebo when used as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 and HER2-negative, early breast cancer.
A total of 1836 patients were enrolled and randomized in a 1:1 ratio to olaparib (n = 921) or placebo (n = 915). Patients were administered olaparib or a matching placebo at 300 mg twice daily. Patients were stratified by hormone receptor-positive status, receipt of neoadjuvant or adjuvant chemotherapy, and whether they received prior platinum-based chemotherapy.
At baseline, those enrolled in the olaparib arm had a median age of 42 years (range, 36-49) while the placebo arm had a median age of 43 years (range, 36-50). In both arms, more patients 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 compared with 17.2% and 82.8% in the placebo arm having ER-positive, PgR-positive/HER2-negative disease and triple-negative breast cancer.
The primary end point of the trial was IDFS with secondary end points including DDFS, OS, number of patients with contralateral breast cancers, new primary ovarian cancer, new primary fallopian tube cancer, and new primary peritoneal cancer, change from baseline for functional assessment of chronic illness therapy-fatigue score for patients who completed neoadjuvant and adjuvant chemotherapy, and quality of life.
A prespecified event-driven analysis of OS was presented during the March 2022 ESMO Virtual Plenary which showed there to be a statistically significant improvement in IDFS and DDFS with olaparib vs placebo. Patients given olaparib had fewer deaths than those in the placebo. However, the difference did not reach statistical significance for the OS.
With median follow-up of 3.5 years (range, 2.5-4.5), the second interim analysis of OS showed there to be a significant improvement in the olaparib arm relative to the placebo arm (HR 0.68; 98.5% CI, 0.47-0.97; P = .009). The 4-year OS in the olaparib arm was 89.8% vs 86.4% in the placebo arm (95% CI, -0.1%-6.8%). Additionally, the 4-year IDFS for those given olaparib was 82.7% versus 75.4% for those given placebo (95% CI, 3.0%-11.5%). The 4-year DDFS was 86.5% for the olaparib group vs 79.1% for the placebo group (95% CI, 3.6%-11.3%), respectively.
The subset analyses which looked at OS, IDFS, and DDFS demonstrated a benefit across major subgroups. Additionally, no new safety signals were identified including no new cases of AML or MDS.
By the time of this safety analysis, the median exposure duration was 364 days on olaparib and 365 days on placebo, and the median percentage of intended dose delivered was 94.5% in the olaparib group vs 98.9% in the placebo group. Of the patients given olaparib, 228 (25.0%) required a dose reduction vs 47 (5.2%) given placebo. Dose interruptions which lasted 3 days or more occurred in 405 (44.5%) patients given olaparib and 279 (30.9%) given placebo.
Adverse events (AEs) which led to permanent discontinuation occurred in 98 patients (10.8%) in the olaparib arm and 42 (4.6%) in the placebo arm. The most common AEs which led to discontinuation of olaparib were nausea (2.2%), anemia (1.8%), fatigue (1.6%), and neutrophil count decreased (1%).
AEs which were grade 3 or higher all occurred in the olaparib group and included anemia (8.7%), neutropenia (4.9%), leukopenia (3.0%), fatigue (1.8%), and lymphopenia (1.3%). Serious AEs were observed in 79 patients (8.7%) who received olaparib, and 78 (8.6%) who received placebo. One patient given olaparib died due to cardiac arrest. AEs, including AML and ovarian cancer also led to death in the placebo arm in 1 patient each.
Overall, the median follow-up of 3.5 years in the OlympiA showed a statistically significant improvement in OS with adjuvant olaparib vs placebo for patients with germline BRCA-mutated, HER2-negative, high-risk early breast cancer. Patients maintained improvements in OS regarding the statistically significant end points of IDFS and DDFS, and no new safety signals were observed.
“Although the key long-term safety end point of AML/MDS will require longer follow-up for complete assessment, the low incidence of 0.2% in the olaparib-group and 0.3% in the placebo-group with a median follow-up of 3.5 years coupled with the absence of new cases since the initial report is reassuring,” wrote the study authors.