PARP Inhibitor Treatment Recommendations
Ovarian Cancer
For patients with newly diagnosed stage III-IV high-grade serous or endometrioid ovarian cancer who achieve complete or partial response to first-line platinum-based chemotherapy, offer olaparib 300 mg orally every 12 hours for 2 years (for those with germline or somatic BRCA1/2 mutations) or niraparib 200-300 mg orally daily for 3 years (for all patients regardless of BRCA status). 1
First-Line Maintenance Therapy
BRCA1/2-mutated disease: Olaparib 300 mg every 12 hours is strongly recommended based on high-quality evidence from the SOLO1 trial, which demonstrated substantial progression-free survival benefit 1
All patients (BRCA-mutated or wild-type): Niraparib 200-300 mg once daily is approved for all women with advanced ovarian cancer in response to first-line chemotherapy, with significant benefit even in patients without BRCA mutations but with HRD-positive status (HR 0.71) 1, 2
Genomic instability without BRCA mutation: Olaparib plus bevacizumab maintenance may be offered to patients with genomic instability determined by Myriad myChoice CDx (genomic instability score ≥42) who received bevacizumab during first-line therapy 1, 2
Recurrent Platinum-Sensitive Disease
PARP inhibitor maintenance therapy should be offered to all patients with recurrent epithelial ovarian cancer who achieve complete or partial response to platinum-based chemotherapy and have not previously received a PARP inhibitor. 1
Dosing options: Olaparib 300 mg every 12 hours, rucaparib 600 mg every 12 hours, or niraparib 200-300 mg once daily 1
Evidence strength: Four major trials (SOLO2, NOVA, ARIEL3, Study 19) demonstrated significant progression-free survival improvements across all studies 1
BRCA-mutated patients show the most robust benefit: SOLO2 demonstrated olaparib extended overall survival by approximately 13-15 months compared to placebo in germline BRCA-mutated patients (51.7 vs 38.8 months; HR 0.74) 1
HRD-positive patients without BRCA mutations: Still derive significant benefit, though magnitude is greatest in BRCA-mutated patients 1
Recurrent Disease Treatment (Not Maintenance)
BRCA-mutated recurrent disease: Olaparib is FDA-approved for treatment of patients with germline BRCA-mutated ovarian cancer who have received ≥3 prior lines of chemotherapy 1
Rucaparib: Approved for treatment of patients with germline BRCA-mutated ovarian cancer treated with ≥2 chemotherapy regimens 1
Niraparib: Approved for patients with advanced ovarian cancer treated with ≥3 prior chemotherapy regimens who are PARP inhibitor-naïve and HRD-positive (including tumor BRCA-mutated or genomic instability score ≥42), with platinum-sensitive disease (progression ≥6 months after last platinum dose) 1
Critical Caveats for Ovarian Cancer
Platinum-resistant disease: PARP inhibitor treatment is not generally recommended, with <5% activity in BRCA wild-type, platinum-resistant disease 1
Disease must not have recurred within 6 months of platinum-based therapy for patients without BRCA mutations but with genomic instability 1
Testing is essential: BRCA mutation testing is recommended for all patients with non-mucinous ovarian cancers, as it provides both predictive information for response and identifies mutations in family members who may benefit from prevention strategies 1
Breast Cancer
Metastatic HER2-Negative Breast Cancer
For patients with HER2-negative metastatic breast cancer and germline BRCA1/2 mutations who have been previously treated with chemotherapy, offer oral PARP inhibitor (olaparib or talazoparib) rather than chemotherapy. 1
Olaparib efficacy: OlympiAD trial demonstrated median progression-free survival of 7.0 months with olaparib versus 4.2 months with chemotherapy (HR 0.58; 95% CI 0.43-0.80; P<0.001) 1
Triple-negative subset: The progression-free survival benefit was even more pronounced in BRCA mutation carriers with metastatic triple-negative disease (PFS HR 0.39; 95% CI 0.20-0.57) 1
Talazoparib efficacy: EMBRACA trial showed median progression-free survival of 8.6 months with talazoparib versus 5.6 months with chemotherapy (HR 0.54; 95% CI 0.41-0.71; P<0.001) 1
Treatment line: Can be used in first-line through third-line settings for hormone receptor-positive disease when patients are no longer benefiting from endocrine therapy 1
Toxicity profile: Grade 3-4 adverse events were 36.6% with olaparib versus 50.5% with chemotherapy, with treatment discontinuation due to toxicity at 4.9% versus 7.7% respectively 1
Early-Stage High-Risk Breast Cancer (Adjuvant Setting)
For patients with early-stage, HER2-negative breast cancer with germline BRCA1/2 mutations and high risk of recurrence, offer 1 year of adjuvant olaparib 300 mg orally twice daily after completing (neo)adjuvant chemotherapy and all local treatments including radiation. 3
OlympiA trial results: At 3 years, invasive disease-free survival was 85.9% with olaparib versus 77.1% with placebo (HR 0.58; 99.5% CI 0.41-0.82; P<0.001) 3
Distant disease-free survival: 87.5% with olaparib versus 80.4% with placebo at 3 years (HR 0.57; 99.5% CI 0.39-0.83; P<0.001) 3
High-risk criteria for triple-negative breast cancer: Tumor size ≥2 cm or any involved axillary nodes 3
High-risk criteria for hormone receptor-positive disease: At least 4 involved axillary lymph nodes 3
Applies even with pathologic complete response: Patients with triple-negative breast cancer who achieved pCR after neoadjuvant chemotherapy but had initially locally advanced disease should still receive adjuvant olaparib 3
Important Considerations for Breast Cancer
Somatic BRCA mutations: Emerging evidence suggests biological similarities between germline and somatic BRCA-mutated breast tumors, with both demonstrating biallelic inactivation, HRD phenotypes, and PARP inhibitor sensitivity 4
No direct comparison with specific chemotherapy agents: The randomized PARP inhibitor trials did not make direct comparisons with taxanes, anthracyclines, or platinums; comparative efficacy against these compounds is unknown 1
Long-term monitoring required: PARP inhibitors are DNA-interacting drugs with potential to induce hematologic malignancies; follow-up for myelodysplastic syndrome and acute myelogenous leukemia is needed 3
Special Populations and Biomarkers
HRD-Positive Tumors Without BRCA Mutations
BRIP1 mutations: BRIP1 is associated with homologous recombination deficiency similar to BRCA1/2, suggesting potential sensitivity to PARP inhibitors 2
For ovarian cancer with HRD-positive status: Niraparib or olaparib plus bevacizumab may be offered based on genomic instability testing (Myriad myChoice CDx with genomic instability score ≥42) 2
PAOLA-1 study: Patients without BRCA mutations but with HRD-positive status showed significant progression-free survival benefit with olaparib plus bevacizumab versus bevacizumab alone 2
HRD-negative patients: Did not show significant benefit (HR 1.00; 95% CI 0.75-1.35) and should not receive olaparib as monotherapy maintenance 2
Dosing and Toxicity Management
Common adverse events: Fatigue (50-70%), nausea (62-66%), vomiting (35-39%), and decreased appetite (27-36%) 5
Hematologic toxicities: Neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%) are the most common grade 3/4 adverse events 6
Dose adjustments: Toxicity is generally manageable through dose reductions and interruptions of therapy 1
Niraparib dosing: 200-300 mg once daily with dose adjustment based on baseline body weight and platelet count to minimize toxicity 1
Drug Interactions
- Avoid concurrent use: Strong or moderate inducers or inhibitors of CYP3A should be avoided, as they may alter plasma concentrations of olaparib 7
Testing Algorithm
All patients with non-mucinous ovarian cancer: Test for germline and somatic BRCA1/2 mutations 1
All patients with HER2-negative breast cancer: Test for germline BRCA1/2 mutations to identify candidates for PARP inhibitor therapy 1, 3
If BRCA wild-type: Consider HRD testing using validated assays (Myriad myChoice CDx or FDA/CLIA-approved tests) for ovarian cancer patients 2
Confirm platinum sensitivity: For recurrent ovarian cancer without BRCA mutations, ensure disease has not progressed within 6 months of last platinum-based therapy before offering PARP inhibitors 1, 2