TBCRC 048 (olaparib expanded) expansion cohorts: Phase 2 study of olaparib monotherapy in patients (pts) with metastatic breast cancer (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2.

1021 Background: TBCRC 048 is an investigator-initiated proof of principle phase II trial that demonstrated responses with monotherapy olaparib in MBC pts with g PALB2 or s BRCA mutations. Here we report results of the expansion cohorts for additional pts with g PALB2(Cohort 1a) or s BRCA (Cohort 2a) mutations. Methods: 24 MBC pts with g PALB2m and 30 pts with s BRCAm were enrolled in the expansion cohorts from Sept 2020 to Oct 2023.Eligibility included: MBC with measurable disease; documented g PALB2m or s BRCAm (with normal g BRCA testing); progression on 13 responses were seen. Secondary endpoints include clinical benefit rate (CBR) at 18 weeks, progression-free survival (PFS), duration of response (DOR) and whether the mutant allele frequency (MAF) is significantly higher in responders than in non-responders. Enrollment to the g PALB2 cohort was closed early due to slow enrollment. PFS and DOR were estimated using the Kaplan-Meier method. Association between MAF and response status was assessed using Wilcoxon rank sum test. Results: In Cohort 1a (g PALB2, n=24), median age was 52.5 years (range: 26-86). 19 pts had ER+ HER2-negative, 2 HER2-positive, and 3 triple-negative breast cancer (TNBC). There were 18 confirmed responses for ORR of 75% (80% CI: 60.2%-86.3%); CBR at 18 weeks was 83.3% (90% CI: 65.8%-94.1%). Median PFS was 9.6 months (90% CI: 8.3-12.4). Median DOR was 7.1 months (90% CI: 5.6-11.0). In Cohort 2a (s BRCA1/2, n=30) 15 pts had s BRCA1m and 15 s BRCA2m. 23 pts had ER+ HER2-negative, 3 HER2-positive, and 4 TNBC. There were 11 confirmed responses for ORR of 36.7% (80% CI: 24.8%-50%). CBR was 53.3% (90% CI: 37%-69.2%) and median PFS was 5.6 months (90% CI: 3.0-8.3). Median DOR was 12.4 months (90% CI: 4.3-not reached). One additional pt with a s BRCAm had a PR, which was not confirmed. Clinical and molecular factors associated with response to olaparib are being evaluated. MAF was available and evaluable for 33 of the 46 pts in Cohorts 2 plus 2a who had s BRCAm identification by tumor biopsy. The mean MAF was 43% in responders and 39 % in non-responders (p=0.7), which was not significantly different. Conclusions: The notable ORR (75%) with olaparib in this second cohort of women with MBC and g PALB2m was again demonstrated.Olaparib activity inMBC pts with s BRCAm was also confirmed, though identifying predictors of response for these pts is of critical importance to distinguish those more likely to respond to PARP inhibition. Clinical trial information: NCT02032823 .