TBCRC 048 (Olaparib Expanded) Expansion Cohorts: Phase II Study of Olaparib Monotherapy for Patients With Metastatic Breast Cancer With Germline Mutations in PALB2 or Somatic Mutations in BRCA1 or BRCA2

PURPOSE Translational Breast Cancer Research Consortium 048 was a proof-of-principle trial demonstrating responses to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients (pts) with metastatic breast cancer (MBC) with germline (g) PALB2 or somatic (s) BRCA mutations (s BRCA m). Here we report results from the expansion cohorts in a larger sample of pts with g PALB2 m or s BRCA m. METHODS Eligible pts had MBC of any subtype with measurable disease and a g PALB2 m or s BRCA m. Pts received olaparib 300 mg twice a day until progression. The primary end point was overall response rate. Secondary end points include clinical benefit rate (CBR) at 18 weeks, progression-free survival (PFS), duration of response (DOR), and whether among s BRCA m carriers the mutant allele frequency (MAF) is significantly higher in responders than in nonresponders. RESULTS Fifty-four pts with g PALB2 m (N = 24) or s BRCA m (N = 30) were enrolled. Forty-two (78%) had estrogen receptor–positive human epidermal growth factor receptor 2–negative (HER2–) MBC, seven (13%) had triple-negative breast cancer, and five (9%) had HER2+ disease. Among pts with a g PALB2 m, the overall response rate (ORR) was 75% (80% CI, 60.2 to 86.3), CBR was 83.3% (90% CI, 65.8 to 94.1), the median PFS was 9.4 months (90% CI, 8.3 to 13.1), and the median DOR was 7.0 months (90% CI, 5.6 to 10.4). Among pts with s BRCA m (15 s BRCA1 and 15 s BRCA2 ), the ORR was 36.7% (80% CI, 24.7 to 50), CBR was 53.3% (90% CI, 37 to 69.1), the median PFS was 5.5 months (90% CI, 2.8 to 8.3), and the median DOR was 11.2 months (90% CI, 4.4 to not reached). One additional pt had an unconfirmed partial response. Although clinically meaningful, the ORR in pts with s BRCA m did not achieve the prespecified target. Among s BRCA m carriers, the mean MAF did not differ significantly between responders (46%) and nonresponders (39%; P = .7). CONCLUSION Olaparib is active in pts with MBC with g PALB2 m and s BRCA m, significantly expanding the population of pts with breast cancer likely to benefit from PARP inhibitors beyond g BRCA1/2 m carriers.