Olaparib in Adult Women with BRCA1/2 Mutations and Breast or Ovarian Cancer History
Primary Recommendation
For women with germline or somatic BRCA1/2 mutations and newly diagnosed advanced ovarian cancer (stage III-IV) who achieve complete or partial response to first-line platinum-based chemotherapy, olaparib maintenance therapy at 300 mg orally every 12 hours for 2 years is strongly recommended. 1
Ovarian Cancer: First-Line Maintenance Therapy
Eligibility Criteria
- Stage III-IV high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer 1
- Confirmed germline or somatic BRCA1/2 mutation (FDA-approved companion diagnostic required) 1
- Complete or partial response to first-line platinum-based chemotherapy 1
Strength of Recommendation by Mutation Type
- Germline BRCA1/2 mutations: Category 1 recommendation (highest level of evidence based on SOLO-1 trial) 1
- Somatic BRCA1/2 mutations: Category 2A recommendation (limited data; only 2 patients in SOLO-1 had somatic mutations with wild-type germline) 1
Dosing and Duration
- Olaparib 300 mg orally every 12 hours for 2 years 1
- Longer duration may be considered in selected individuals 1
- Continue until disease progression or unacceptable toxicity 2
Alternative First-Line Maintenance Options
- Niraparib 200-300 mg orally daily for 3 years is approved for all women with advanced ovarian cancer regardless of BRCA status, based on PRIMA trial 1, 3
- Olaparib plus bevacizumab may be offered if bevacizumab was used in first-line therapy and patient has BRCA1/2 mutation or genomic instability (Myriad myChoice CDx positive) 1
Ovarian Cancer: Recurrent Platinum-Sensitive Disease
When to Use
- Patients with recurrent epithelial ovarian cancer in complete or partial response to platinum-based chemotherapy 2
- No prior PARP inhibitor exposure 2
- BRCA1/2 mutation (germline or somatic) confirmed 1
Evidence Base
- Four major trials (Study 19, SOLO2, NOVA, ARIEL3) demonstrated 62-68% reduction in risk of progression or death (HR 0.32-0.38) 2
- FDA-approved indication: Treatment of patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy 1
Dosing
- Olaparib 300 mg orally every 12 hours 2
Breast Cancer: Current Evidence and Limitations
Available Evidence
- Phase II trials showed 41% response rate and 5.7-month progression-free survival in heavily pre-treated BRCA-mutated advanced breast cancer patients at 400 mg twice daily 1
- Proof of concept established for efficacy and tolerability in BRCA-mutated breast cancer 1
Critical Limitation
- No FDA approval for breast cancer indication as of the guideline dates provided 1
- Evidence suggests BRCA-deficient breast cancers are chemosensitive, particularly to DNA-damaging agents like platinum and anthracyclines 1
Current Recommendation
- Standard prognostic features should guide treatment decisions in BRCA mutation carriers with breast cancer 1
- Consider enrollment in clinical trials evaluating PARP inhibitors for breast cancer 1
- Platinum-based chemotherapy may be particularly effective in BRCA1-associated breast cancer (83% pathological complete response to cisplatin in neoadjuvant setting) 1
Safety Profile and Monitoring
Common Adverse Events
- Nausea (60% any grade), fatigue, vomiting, and diarrhea are most frequent 2
- Anemia (6-17% grade ≥3) requires hematologic monitoring 1, 2
- Neutropenia can occur and sometimes leads to discontinuation 1
Serious Adverse Events
- 18-29.4% of patients experience serious adverse events, mainly hematologic toxicities 2
- Discontinuation rates due to toxicity: higher with olaparib versus placebo 1
Quality of Life
- Health-related quality-of-life scores remained stable during olaparib treatment in SOLO-1 1
Critical Pitfalls to Avoid
Testing Requirements
- BRCA1/2 testing must be initiated early in the diagnostic workup for ovarian cancer to guide maintenance therapy decisions 1
- Use FDA-approved companion diagnostic for patient selection 1
- Distinguish between germline and somatic mutations, as evidence strength differs 1
Variant of Uncertain Significance (VUS)
- Do not base clinical decisions on VUS 1
- Clinical features and family history should guide management until reclassification occurs 1
Drug Interactions
- Avoid concurrent use with strong or moderate CYP3A inducers or inhibitors, as they alter olaparib plasma concentrations 4