Background
Phase II expansion cohorts. N=54 (24 germline BRCA-mutated, 30 somatic-mutated) with metastatic breast cancer of any subtype, measurable disease, and ≥1 germline or somatic BRCA mutation. Histology: 78% HR+/HER2-, 13% TNBC, 9% HER2+.
Interventions and follow up
Arm A: Olaparib 300mg twice daily (germline BRCA mutation carriers)
Arm B: Olaparib 300mg twice daily (somatic BRCA mutation carriers)
Primary endpoint: Overall response rate (ORR)
mFollow up: 9.4mo (germline), 5.5mo (somatic)
Arm B: Olaparib 300mg twice daily (somatic BRCA mutation carriers)
Primary endpoint: Overall response rate (ORR)
mFollow up: 9.4mo (germline), 5.5mo (somatic)
Results
ORR (germline): 75% (80% CI 60.2–86.3)
CBR (germline): 83.3% (90% CI 65.8–94.1)
ORR (somatic): 36.7% (80% CI 24.7–50)
CBR (somatic): 53.3% (90% CI 37–69.1)
CBR (germline): 83.3% (90% CI 65.8–94.1)
ORR (somatic): 36.7% (80% CI 24.7–50)
CBR (somatic): 53.3% (90% CI 37–69.1)
Adverse events
Hematologic: anemia (most common)
Gastrointestinal: nausea
Constitutional: fatigue
Overall: grade 3–4 rates modest; well tolerated
Gastrointestinal: nausea
Constitutional: fatigue
Overall: grade 3–4 rates modest; well tolerated
Conclusions
Olaparib monotherapy showed substantial activity in germline BRCA-mutated MBC and clinically meaningful (though suboptimal) activity in somatic-mutation carriers, expanding the population likely to benefit from PARP inhibition beyond germline carriers.
Key Limitations
Small sample (N=54); somatic-mutation ORR did not meet prespecified target; mixed MBC histology; limited cross-disease and biomarker subgroup analyses; single-arm (no comparator).
Clinical Context
Proof-of-concept for PARP inhibitor benefit in somatic BRCA-mutation carriers, though germline carriers remain the primary FDA-approved indication (olaparib, OlympiAD). Informs patient selection for PARP-targeted strategies; supports broader genomic testing.
References