What is Olaparib (Olaparib) used for in patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative breast cancer?

Olaparib for Hormone Receptor-Positive, HER2-Negative Breast Cancer

Olaparib is a PARP inhibitor used specifically for patients with hormone receptor-positive, HER2-negative breast cancer who have germline BRCA1 or BRCA2 mutations, and it can be offered in both the metastatic setting (when no longer benefiting from endocrine therapy) and as adjuvant therapy in high-risk early-stage disease. 1, 2

What Olaparib Does

Olaparib is an oral poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor that exploits a vulnerability in cancer cells with BRCA mutations. 3 These mutations impair DNA repair through homologous recombination, and PARP inhibition creates a "synthetic lethality" that preferentially kills cancer cells while sparing normal cells. 4

Indications in Metastatic Disease

When to Use Olaparib

For patients with HR-positive, HER2-negative metastatic breast cancer and germline BRCA1/2 mutations who are no longer benefiting from endocrine therapy, olaparib should be offered in the first-line through third-line setting rather than chemotherapy. 1

• This recommendation is based on the OlympiAD trial, which demonstrated median progression-free survival of 7.0 months with olaparib versus 4.2 months with chemotherapy (hazard ratio 0.58; P<0.001). 1, 3
• The response rate with olaparib was 59.9% compared to 28.8% with chemotherapy. 3
• Olaparib causes fewer grade 3 or higher adverse events (36.6%) compared to chemotherapy (50.5%). 1, 3

Important Caveats for Metastatic Use

A critical limitation is that olaparib did not improve overall survival compared to chemotherapy in the final OlympiAD analysis (19.3 months versus 17.1 months; HR 0.90; P=0.513). 5 However, there was a suggestion of meaningful benefit in patients receiving olaparib as first-line therapy for metastatic disease (HR 0.51 in the first-line subgroup). 5

The randomized trials did not compare olaparib directly with taxanes, anthracyclines, or platinum agents, so comparative efficacy against these chemotherapies is unknown. 1

Indications in Early-Stage Disease

Adjuvant Olaparib

For patients with early-stage, HER2-negative breast cancer with germline BRCA1/2 mutations and high risk of recurrence, one year of adjuvant olaparib (300 mg orally twice daily) should be offered after completing neoadjuvant or adjuvant chemotherapy and all local treatments including radiation. 2

• The OlympiA trial showed invasive disease-free survival at 3 years of 85.9% with olaparib versus 77.1% with placebo (HR 0.58; P<0.001). 2
• Distant disease-free survival at 3 years was 87.5% with olaparib versus 80.4% with placebo (HR 0.57; P<0.001). 2

High-Risk Criteria for HR-Positive Disease

For hormone receptor-positive, HER2-negative breast cancer, adjuvant olaparib is indicated if the patient has at least four involved axillary lymph nodes. 2

Who Needs Testing

All patients with HER2-negative breast cancer should undergo germline BRCA1/2 mutation testing to identify candidates for olaparib therapy. 1, 2 Small studies also show response rates with somatic BRCA mutations and germline PALB2 mutations, though these are not yet standard FDA-approved indications. 1, 4

Practical Considerations

Dosing and Administration

• Standard dose: 300 mg orally twice daily. 2, 3
• Duration in adjuvant setting: 1 year. 2
• Duration in metastatic setting: Until disease progression. 3

Toxicity Management

• Most common adverse events are low-grade and manageable with supportive care or dose modification. 5, 3
• Anemia is the most significant hematologic toxicity but does not increase with extended exposure. 5
• Treatment discontinuation due to toxicity occurs in only 4.9% of patients. 5, 3

Long-Term Safety Concern

PARP inhibitors are DNA-interacting drugs with potential to induce myelodysplastic syndrome and acute myelogenous leukemia, requiring long-term surveillance. 2

Positioning in Treatment Algorithm

For HR-positive, HER2-negative metastatic breast cancer with germline BRCA mutations:

1. Continue endocrine therapy with CDK4/6 inhibitors as first-line. 1
2. When no longer benefiting from endocrine therapy, offer olaparib rather than chemotherapy (first-line through third-line setting). 1
3. Given lower toxicity and similar or better efficacy compared to non-taxane/non-platinum chemotherapy, olaparib is strongly preferred. 1