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.
Authors: Tung Nadine M. , Robson Mark E. , Nanda Rita , Li Tianyu , Vinayak Shaveta , Shah Payal Deepak , Khoury Katia , Kimmick Gretchen Genevieve , Santa-Maria Cesar Augusto , Brufsky Adam , DeMeo Michelle , Vieira Joao Pedro , Carey Lisa A. , Wulf Gerburg M. , Domchek Susan M. , Krop Ian E. , Wolff Antonio C. , Winer Eric P. , Garber Judy Ellen 
Published: June 2024

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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 < 2 metastatic chemotherapy regimens. Prior PARP inhibitor or progression on platinum was not allowed. Patients received olaparib 300 mg bid until progression or unacceptable toxicity. The null hypothesis for each expansion cohort [≤ 30% objective response rate (ORR)] would be rejected if > 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 .