Background: Rucaparib, a potent oral PARP-1, -2 and -3 inhibitor, has shown activity in a phase 3 study in patients (pts) with ovarian carcinoma (ARIEL 3) harbouring a BRCA mutation or an homologous recombination deficient (HRD) profile defined by high percentage of genome-wide loss of heterozygosity and in a phase 1 study that included breast cancer pts with germline BRCA mutation (Kristeleit et al, Clin Can Res, 2017). High genomic LOH score identified HRD tumors (also known as BRCAness tumors), including both known BRCA1 methylation and unknown genetic/epigenetic mechanisms and somatic BRCA1/2 mutations. This single arm, open-label, multicenter phase II RUBY study (NCT02505048) is evaluating the efficacy and safety of rucaparib in pts with HER2- metastatic breast cancer (MBC) associated with a “high tumor genomic LOH” score and/or a somatic BRCA mutation (excluding BRCA1 and/or BRCA2 germline mutation). Methods: Women with HER2- MBC with a HRD phenotype who received at least 1 prior chemotherapy regimens are eligible. ECOG PS 0-1 and adequate organ function is required. HRD phenotype is defined by a “high tumor genomic LOH” score, generated from the CytoScan HD SNP array, which is available from the SAFIR02 (NCT02299999) or SAFIR-TOR (NCT02444390) protocols. Pts received oral rucaparib 600 mg BID continuously in 21-day cycles until disease progression. The primary endpoint is clinical benefit rate (CBR), defined by complete and partial response and stable disease lasting for at least 16 weeks. If CBR is significant the objective response rate (ORR) will be considered as well. Secondary endpoints include progression-free survival, overall survival, safety, and the prognostic value of the HRD signature. This trial design is intended to establish proof-of-concept that rucaparib can improve ORR in HER2- MBC with HRD. Targeted enrollment is 41 pts using a Simon two-stage design, 19 pts in the first step and 22 pts in the second one. The prespecified goal of the first step was achieved; enrollment into the second step is ongoing. Clinical trial information: NCT02505048