A phase II clinical trial to analyze olaparib response in patients with <i>BRCA1</i> and/or <i>BRCA</i>2 promoter methylation with advanced breast cancer (GEICAM/2015-06 COMETA-Breast study).

TPS1114 Background: Identification of targeted therapies for advanced triple negative breast cancer (TNBC) remains as an important clinical challenge. TNBC frequently shows BRCA dysfunction and 80% of germline BRCA1 mutation (gBRCAm) carriers with BC diagnosis are TNBC patients (pts). In addition to germline mutations, epigenetic silencing by aberrant methylation of BRCA1/2 promoters can be responsible for a dysfunctional BRCA protein. Methylation of BRCA1 promoter occurs in 15-57% of TNBCs. Interestingly, BRCA1-methylated sporadic breast tumors display pathologic features and gene expression profiles similar to those of gBRCAm carriers, a phenotype called “BRCAness”. Olaparib (O) is an oral poly (ADP-ribose) polymerase (PARP) inhibitor approved by the FDA for treatment of gBRCA-mutated HER2-negative metastatic BC. Tutt et al. have shown antitumor activity in gBRCA-mutated advanced TNBC (54% Objective Response Rate [ORR]). We report an ongoing phase II clinical trial to analyze the O efficacy in advanced TNBC pts with BRCA1/2 promoter methylation (NCT03205761). Methods: Eligible pts are advanced TNBC cases with ≥ 1 prior treatment for advanced disease, without germline BRCA1/2 mutations and centrally confirmed somatic BRCA1/2 promoter methylation in metastatic lesions. Pts receive O 300 mg b.i.d. orally. Primary objective is to analyze O efficacy in terms of ORR according to RECIST 1.1 by investigator assessment. Secondary objectives include safety, other efficacy endpoints, and biomarker analyses. Sequential tumor and blood samples are collected to a) explore changes in methylation status, b) correlate BRCA-methylation status both in blood vs. tumor and in primary vs. metastatic counterpart lesions, and c) correlate methylation status with BRCA1/2 expression and outcome. Thirty-four evaluable pts are required based on an optimal two-stage Simon model (α error = 0.05, power = 80%, dropout rate = 10%). Recruitment started in October 2017, with 17 pts screened for methylation status, 3 pts enrolled by 31th January 2018, and 14 active sites out of 16 participants. Primary endpoint analysis is planned for Q2 2020. Clinical trial information: NCT03205761.