Background
Phase 3, double-blind, placebo-controlled trial; third prespecified interim analysis at median follow-up 6.1 yrs. N=1836 patients with germline pathogenic/likely pathogenic BRCA1/2 variants and high-risk HER2-negative early breast cancer (TNBC or HR+) after definitive local therapy and (neo)adjuvant chemotherapy. Olaparib = oral PARP inhibitor.
Results
Interventions and follow up: Arm A: Olaparib 300 mg PO BID for 12 months
Arm B: Placebo for 12 months
Primary endpoint: Invasive disease-free survival (IDFS)
mFollow up: 6.1 years
Results: IDFS: HR 0.65, 95% CI 0.53–0.78
DDFS: HR 0.65, 95% CI 0.53–0.81
OS: HR 0.72, 95% CI 0.56–0.93; 6-yr OS 87.5% vs 83.2% (difference 4.4%, 95% CI 0.9–6.7)
Subgroups: Benefit consistent across key subgroups, including high-risk HR+ disease
Second cancers: Fewer BRCA-associated new breast and ovarian/fallopian tube cancers with olaparib
Arm B: Placebo for 12 months
Primary endpoint: Invasive disease-free survival (IDFS)
mFollow up: 6.1 years
Results: IDFS: HR 0.65, 95% CI 0.53–0.78
DDFS: HR 0.65, 95% CI 0.53–0.81
OS: HR 0.72, 95% CI 0.56–0.93; 6-yr OS 87.5% vs 83.2% (difference 4.4%, 95% CI 0.9–6.7)
Subgroups: Benefit consistent across key subgroups, including high-risk HR+ disease
Second cancers: Fewer BRCA-associated new breast and ovarian/fallopian tube cancers with olaparib
Adverse events
AESIs (any): 6.3% vs 9.3%
MDS/AML: 0.4% vs 0.7% — no increase with olaparib at extended follow-up
New safety signals: None with longer follow-up
MDS/AML: 0.4% vs 0.7% — no increase with olaparib at extended follow-up
New safety signals: None with longer follow-up
Conclusions
At 6.1 years, 1 year of adjuvant olaparib maintained clinically meaningful IDFS, DDFS, and OS benefits in gBRCA1/2-mutated high-risk HER2-negative early breast cancer, with no late excess of MDS/AML. These mature data cement adjuvant olaparib as standard of care in this population.
Key Limitations
Descriptive interim analysis (no formal significance testing at this data cut); high-risk-only eligibility limits extrapolation to lower-risk gBRCA disease; predates and does not address sequencing/combination with adjuvant abemaciclib (HR+) or pembrolizumab (TNBC); requires germline testing to identify eligible patients.
Clinical Context
FDA approved adjuvant olaparib (March 2022) for gBRCA-mutated high-risk HER2-negative early breast cancer based on OlympiA; NCCN, ASCO, and ESMO recommend 1 year of adjuvant olaparib in this setting and germline BRCA testing for all high-risk early breast cancer. These 6-yr data, with OS benefit and reassuring MDS/AML rates, reinforce that positioning.