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

Abstract

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) <i>PALB2</i> or somatic (s) <i>BRCA</i> mutations (s<i>BRCA</i>m). Here we report results from the expansion cohorts in a larger sample of pts with g<i>PALB2</i>m or s<i>BRCA</i>m. Eligible pts had MBC of any subtype with measurable disease and a g<i>PALB2</i>m or s<i>BRCA</i>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<i>BRCA</i>m carriers the mutant allele frequency (MAF) is significantly higher in responders than in nonresponders. Fifty-four pts with g<i>PALB2</i>m (N = 24) or s<i>BRCA</i>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<i>PALB2</i>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<i>BRCA</i>m (15 s<i>BRCA1</i> and 15 s<i>BRCA2</i>), 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<i>BRCA</i>m did not achieve the prespecified target. Among s<i>BRCA</i>m carriers, the mean MAF did not differ significantly between responders (46%) and nonresponders (39%; <i>P</i> = .7). Olaparib is active in pts with MBC with g<i>PALB2</i>m and s<i>BRCA</i>m, significantly expanding the population of pts with breast cancer likely to benefit from PARP inhibitors beyond g<i>BRCA1/2</i>m carriers.