Phase 2 trial of olaparib monotherapy for patients with metastatic breast cancer with germline mutations in PALB2 or somatic mutations in BRCA1/2

Translational Breast Cancer Research Consortium (TBCRC) 048 was a proof-of-principle trial demonstrating responses to the PARP inhibitor olaparib in patients with metastatic breast cancer (mBC) with germline (g) PALB2 or somatic (s) BRCA mutations. Results from the expansion cohorts with a larger sample of patients with gPALB2m (n=24) or sBRCAm (n=30) have now been published. Patients received olaparib 300 mg twice daily until progression. The primary endpoint was overall response rate. Among patients with a gPALB2m, the ORR was 75% (80% CI 60.2-86.3), while the clinical benefit rate was 83.3% (90% CI 65.8-94.1), the median progression-free survival was 9.4 months (90% CI 8.3-13.1), and the median duration of response was 7.0 months (90% CI 5.6-10.4). Among patients with sBRCAm (15 sBRCA1m and 15 sBRCA2m), the ORR was 36.7% (80% CI 24.7-50), the CBR was 53.3% (90% CI 37-69.1), the median PFS was 5.5 months (90% CI 2.8-8.3), and the median DOR was 11.2 months (4.4-NR), with one additional patients with an unconfirmed partial response. Although clinically meaningful, the ORR in patients with sBRCAm did not achieve the prespecified target. The authors conclude that olaparib is active in patients with mBC with gPALB2m and sBRCAm, expanding the population of patients likely to benefit from PARP inhibitors beyond gBRCA1/2m carriers.