SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 319,750 new cases of breast cancer will be diagnosed in 2025 and about 42,680 individuals will die of the disease, largely due to metastatic recurrence.
DNA can be damaged due to errors during its replication or as a result of environmental exposure to UV radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Patients with BRCA mutations can present with aggressive, high-risk disease and are at a high risk of recurrence following completion of multimodality therapy including surgery, radiation, and chemotherapy. This is an area of unmet need, warranting identification of additional novel and effective therapies.
BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive.
Olaparib (LYNPARZA®) is a PARP inhibitor, that traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.
OlympiA is a multicenter, randomized, placebo-controlled, double-blind, Phase III trial of adjuvant Olaparib after neoadjuvant/adjuvant chemotherapy, in patients with germline BRCA1/2 mutations, and high risk HER2-negative early breast cancer. This trial enrolled 1836 patients, including triple-negative and Hormone Receptor positive (HR-positive) breast cancer. All enrolled patients had already received standard adjuvant or neoadjuvant chemotherapy, surgery and if needed, radiation therapy, for early stage breast cancer (Stage II-III). Inclusion criteria required that patients have a high risk of disease recurrence. Patients with triple-negative breast cancer who received adjuvant chemotherapy were required to have axillary node–positive disease or an invasive primary tumor measuring at least 2 cm. Patients who were treated with neoadjuvant chemotherapy were required to have residual invasive breast cancer in the breast or resected lymph nodes (no pathological Complete Response from neoadjuvant therapy). Patients who were treated with adjuvant chemotherapy for HR-positive, HER2-negative breast cancer were required to have 4 or more pathologically confirmed positive lymph nodes. Patients were randomized 1:1 to receive Olaparib 300 mg PO BID continuously for 1 year (N=921) or placebo (N=915). Endocrine therapy and bisphosphonates were allowed. Treatment groups were well balanced. The median age was 42 years, germline mutations were present in BRCA1 in 72% of the patients, in BRCA2 in 27% of the patients, 82% of the patients had triple-negative breast cancer, 18% had HR-positive and HER2 negative disease, 62% were premenopausal and 38% were postmenopausal, 50% of the patients had received adjuvant chemotherapy and 50% had received neoadjuvant chemotherapy. The Primary endpoint was Invasive Disease Free Survival (IDFS) and Secondary endpoints included Distant DFS (DDFS), Overall Survival (OS) and Safety. At the pre-specified interim analysis (2.5 years), the estimated 3-year Invasive DFS was 85.9% for patients who received Olaparib compared with 77.1% for those who received placebo (HR=0.58; P<0.001), representing a 42% reduction in the risk of Invasive DFS with Olaparib compared to placebo. The 3-year Distant DFS was 87.5% versus 80.4% respectively (HR=0.57; P<0.001). The researchers in this updated analysis reported the results of the third pre-specified interim analysis with median follow-up of 6.1 years (maximum follow-up of 9.6 years).
The treatment benefit with Olaparib was maintained with longer follow up, and was similar to previously reported results. The Invasive DFS at 6 years was 79.6% in the Olaparib-treated group versus 70.3% in the placebo group, with an absolute difference of 9.3%, favoring the addition of Olaparib (HR=0.65). The Distant DFS at 6 years was 83.5% versus 75.7%, respectively, with an absolute difference of 7.8% (HR=0.65). The 6-year Overall Survival rate was 87.5% in the Olaparib group versus 83.2% in the placebo group, with a 28% reduction in the risk of death (HR=0.72). The benefit with adjuvant Olaparib was consistent across all key subgroups, including for patients with high risk and HR-positive disease.
Fewer cases of BRCA-associated cancers such as contralateral invasive and non-invasive breast cancers, new primary ovarian cancer and new primary fallopian tube cancer were reported, with adjuvant Olaparib versus placebo. Further, there was no increase in the risk of developing secondary myelodysplastic syndrome or acute myeloid leukemia.
It was concluded that at 6.1 years median follow-up, one year of adjuvant treatment with Olaparib after neoadjuvant or adjuvant chemotherapy continues to demonstrate meaningful improvements in Invasive DFS, Distant DFS and OS in patients with germline BRCA pathogenic variants and high risk, HER2-negative breast cancer, including those with HR-positive tumors. This study highlights the importance of BRCA testing in early stage breast cancer. Perhaps considering one year of adjuvant Olaparib followed by a CDK4/6 inhibitor in HR-positive, BRCA-positive, high risk HER2-negative early stage breast cancer patients, may be a reasonable approach.
Garber J: OlympiA-Phase 3, multicenter, randomized placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/BRCA2 pathogenic variants and high-risk HER2-negative primary breast cancer: Longer-term follow-up. 2024 San Antonio Breast Cancer Symposium. Abstract GS1-09. Presented December 11, 2024.
