Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
The most common mutations that impact breast cancer are in the BRCA1 and BRCA2 genes. Mutations in BRCA1/2 are associated with aggressive clinical and biological manifestations of the disease. Results from real-world observational studies show that gBRCA mutations are found in approximately 10% of hormone receptor (HR)-positive, HER2-negative breast cancers and approximately 10% to 20% of triple-negative breast cancer (TNBC). Prevalence differs by ethnicity, race, and age.1-4
BRCA1 and 2 proteins promote the timely and accurate repair of double-strand breaks in DNA and are important in maintaining genomic stability. BRCA mutations disrupt homologous recombination repair of DNA breaks, thus causing genomic instability.5-7
PARPs are a family of nuclear enzymes that help maintain DNA integrity during replication with a function to repair single-strand breaks.8 PARP inhibition in cells with BRCA1 and BRCA2 mutations leads to synthetic lethality. PARP inhibitors are approved for several types of BRCA-associated cancers, including breast cancer.9,10
The efficacy and safety of PARP inhibitors as adjuvant therapy for patients with high-risk EBC and gBRCA mutations were examined in the phase III OlympiA trial (N = 1836). The trial had 2 subgroups of HER2-negative patients: those with TNBC and those with HR-positive/HER2-negative disease. Patients were randomly assigned to receive 1 year of the PARP inhibitor olaparib or placebo following the completion of local therapy and neoadjuvant or adjuvant chemotherapy.11
Baseline characteristics were well balanced between both arms, including age, menopausal status, gBRCA mutations, and previous therapy.
The primary endpoint of OlympiA was iDFS. In an event-driven prespecified analysis, the 3-year iDFS rate was 85.9% for patients in the olaparib arm vs 77.1% for patients in the placebo arm—an absolute difference of 8.8%, favoring olaparib (hazard ratio: 0.58; 99.5% CI: 0.41-0.82; P <.001).
The iDFS benefit with olaparib was consistent without evidence of significant heterogeneity across major subgroups, including gBRCA mutations and HR status.
Secondary endpoints for OlympiA included distant DFS, OS, and safety. Adjuvant olaparib significantly improved distant DFS vs placebo. At the first interim analysis, the 3-year rate of distant DFS was 87.5% for patients who received olaparib vs 80.4% for patients who received placebo. An absolute difference of 7.1% favored olaparib (hazard ratio: 0.57; CI: 0.39-0.83; P <.001).
OS data were presented at the second interim analysis with a median follow-up of 3.5 years.12 The 4-year OS rate was 89.8% for olaparib vs 86.4% for placebo—a statistically significant improvement in OS of 3.4% (hazard ratio: 0.68; 98.5% CI: 0.47-0.97; P = .009). On the olaparib arm, there were 75 deaths (70 due to breast cancer) vs 109 deaths in the placebo arm (103 due to breast cancer).
The safety profile of olaparib at the second interim analysis remained consistent with few serious adverse events (AEs).12 AEs of special interest—including myelodysplastic syndromes, acute myeloid leukemia, pneumonitis, or new primary malignancies—were low. Grade 4 AEs occurred in fewer than 2% of patients.
The rate of discontinuation due to AEs was higher with olaparib (10.8%) vs placebo (4.6%). Discontinuations mainly were due to nausea, anemia, and fatigue.
This figure shows AEs reported by ≥10% of patients at the second interim analysis of the OlympiA study.12 The most common any-grade AEs associated with olaparib were nausea (57%), fatigue (40%), and anemia (24%). Grade 3 events were infrequent; anemia (9%) was the most common.
Data on dose reductions and quality of life in the OlympiA study were reported in the first interim analysis (median follow-up: 2.5 years).11 Dose reduction was required for 25% of patients receiving olaparib vs 5.2% of patients receiving placebo. Results from the QLQ-C30 Global Health Status and Quality of Life score indicated that there were no differences in global health quality between the arms.
The FDA granted approval to olaparib in March 2022 for the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCA-mutated, HER2-negative, high-risk EBC who have received neoadjuvant or adjuvant chemotherapy. A companion diagnostic for the detection of gBRCA mutations also was approved.13
Receptor status should be determined as part of any diagnostic workup for newly diagnosed or recurrent EBC. That includes HER2 status by immunohistochemistry, plus or minus in situ hybridization, if needed, and HR status including ER and PR.14-16
In addition, several validated gene expression assays can help predict risk of recurrence and response to systemic therapy.
More recently, germline mutation testing for BRCA mutations should be ordered based on guideline recommendations, including when considering adjuvant olaparib therapy.
For patients with HR-positive disease, Ki-67 expression by immunohistochemistry can help assess risk of recurrence and is a factor in considering adjuvant abemaciclib therapy.
Who should be tested for BRCA1 or BRCA2 mutations? Patients with a personal history of breast cancer who have 1 or more of the age- and family-related factors listed in current guidelines. This includes men or women diagnosed with breast cancer at any age who have either a) TNBC histology, b) lobular breast cancer and a history of diffuse gastric cancer, or c) 1 or more close male relatives with breast cancer. Patients with high-risk EBC at any age for whom adjuvant treatment with olaparib is being considered should be tested. Testing also can aid in systemic treatment decisions using PARP inhibitors in the metastatic setting.17
Testing for gBRCA1/2 mutations requires blood or saliva samples from patients, and the turnaround time for results can be 3-4 weeks. Most health insurance companies cover the cost of genetic tests if patients meet specified criteria, and some labs may offer special financial terms if testing is not covered by insurance.18
Genetic counseling with patients considering genetic testing is an important aspect of the diagnostic workup and can help patients decide what steps they should take to reduce breast cancer risk. The genetic counselor will collect details about medical and family health history to help address important questions on understanding and implications of testing for both patients and their families.19
Most AEs associated with PARP inhibitors occur during the first cycles of PARP inhibitor treatment, and the most common include anemia, neutropenia, and thrombocytopenia. Other toxicities include those of the gastrointestinal system, renal impairment, fatigue, and sometimes alopecia.20,21
Grade 1 or 2 AEs are typically managed with supportive care. However, in grade 3 and 4 toxicities, dose interruptions and reductions also may be needed and should be monitored carefully. If AEs of grade 3 or 4 last longer than 1 month, discontinuation of PARP inhibitor therapy is recommended.21
The recommended starting dose for olaparib is 300 mg twice daily. If dose modifications are needed, the first dose reduction is to 250 mg twice daily, and the second is to 200 mg twice daily. After that, if further dose reduction is needed, the drug should be discontinued. Patients who experience renal impairment with a creatinine clearance of 31-50 mL/minute should reduce the olaparib dose to 200 mg twice daily.13
Healthcare professionals should discuss potential benefits and common AEs associated with PARP inhibitors, including anemia, neutropenia, thrombocytopenia, nausea, and fatigue. More severe hematologic toxicities should be managed with supportive measures or dose modification—or both. Patients should be counseled in advance about the toxicities they may experience and how they may be treated. Patients should understand potential AEs or toxicity that would require immediate consultation with their medical team. Healthcare professionals should adjust or simplify the treatment regimen and encourage adherence to the strategy.