What is the role of olaparib (Poly (ADP-ribose) polymerase (PARP) inhibitor) in the treatment of breast cancer?

Role of Olaparib in Breast Cancer

Olaparib should be offered to patients with HER2-negative breast cancer who have germline BRCA1/2 mutations in both early-stage high-risk disease (as adjuvant therapy) and metastatic settings, as it significantly improves survival outcomes compared to standard treatments. 1

Metastatic Breast Cancer Setting

Patient Selection

• Olaparib is indicated for patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations who have been previously treated with chemotherapy 1
• Testing for germline BRCA1/2 mutations is essential to identify eligible patients for PARP inhibitor therapy 1
• Patients can receive olaparib in first-line through third-line settings rather than chemotherapy when they are no longer benefiting from endocrine therapy (for hormone receptor-positive disease) 1

Efficacy in Metastatic Setting

• In the OlympiAD trial, olaparib monotherapy demonstrated significantly longer progression-free survival compared to standard chemotherapy (7.0 months vs. 4.2 months; hazard ratio 0.58) 2, 3
• Response rates were substantially higher with olaparib (59.9%) compared to standard chemotherapy (28.8%) 2
• While final overall survival analysis showed no statistically significant improvement (19.3 vs 17.1 months; HR 0.90), there was a potential meaningful benefit in first-line metastatic setting (HR 0.51) 3
• Beyond germline BRCA1/2, patients with somatic BRCA1/2 mutations (50% response rate) and germline PALB2 mutations (82% response rate) also show significant benefit from olaparib 4, 5

Safety Profile in Metastatic Setting

• Olaparib has a more favorable safety profile than chemotherapy with lower rates of grade 3 or higher adverse events (36.6% vs 50.5%) 2
• Common side effects include anemia, nausea, and fatigue, but they are generally manageable with supportive care or dose modifications 3
• Treatment discontinuation rates due to adverse events are low (4.9%) 3
• Quality of life measures are superior with olaparib compared to chemotherapy, with the exception of nausea/vomiting symptoms 2

Early-Stage Breast Cancer Setting

Patient Selection for Adjuvant Therapy

• For patients with early-stage, HER2-negative breast cancer with high risk of recurrence and germline BRCA1/2 mutations, one year of adjuvant olaparib should be offered after completion of (neo)adjuvant chemotherapy and local treatment 1
• For patients who had surgery first:
  • Triple-negative breast cancer: offer olaparib if tumor size ≥2 cm or any involved axillary nodes 1
  • Hormone receptor-positive disease: offer olaparib if at least four involved axillary lymph nodes 1
• For patients who had neoadjuvant chemotherapy:
  • Triple-negative breast cancer: offer olaparib if any residual cancer is present 1
  • Hormone receptor-positive disease: offer olaparib if residual disease and a clinical stage, pathologic stage, estrogen receptor, and tumor grade score ≥3 1

Efficacy in Early-Stage Setting

• The OlympiA trial showed that one year of adjuvant olaparib following completion of local treatment and (neo)adjuvant chemotherapy significantly improved invasive and distant disease-free survival 1
• While 3-year estimated overall survival was greater with olaparib, the difference was not statistically significant at the interim analysis (2.5-year median follow-up) 1

Special Considerations

Emerging Combinations

• Combination of olaparib with immunotherapy (durvalumab) has shown promising antitumor activity with manageable safety profile in patients with germline BRCA-mutated metastatic breast cancer 6
• Disease control rate at 12 weeks was 80% with the combination therapy 6

Common Pitfalls and Caveats

• Olaparib is not effective in patients with mutations in ATM or CHEK2 alone, despite these being homologous recombination repair genes 4
• PARP inhibitors are DNA-interacting drugs with potential to induce hematologic malignancies; long-term follow-up for myelodysplastic syndrome and acute myelogenous leukemia is needed 1
• In the adjuvant setting, the OlympiA trial did not assess olaparib's efficacy compared to capecitabine in the post-neoadjuvant setting for triple-negative breast cancer 1
• Resistance mechanisms can develop, including secondary BRCA2 mutations that restore the reading frame, leading to treatment failure 5