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PURPOSE: We explored the efficacy of PARP inhibition combined with sapacitabine, an orally bioavailable prodrug of the deoxycytidine analog 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine, in patients with germline BRCA1/2-mutated HER2-negative metastatic breast cancer.PATIENTS AND METHODS: In this phase Ib investigator-sponsored study of sapacitabine and olaparib, patients who were PARP inhibitor-naïve were enrolled. The primary objective was determination of the recommended phase 2 dose (RP2D) of sapacitabine with olaparib. Archival samples were subjected to IHC for biomarkers of homologous recombination repair (HRR) deficiency and replication stress. Serial blood samples were collected for ctDNA analysis.RESULTS: Ten patients (3 BRCA1 and 7 BRCA2) were enrolled. The RP2D was not determined due to hematologic toxicities. The objective response rate (ORR) was 50% (95% confidence interval, 18.7%-81.3%), with median progression-free survival (mPFS) of 9.7 months (95% confidence interval, 8.02-not estimable). Three patients had clinical benefit greater than 15 months, including two who remained on trial for more than 40 months. Tumors from responding patients demonstrated HRR deficiency and/or replication stress by IHC. At progression, ctDNA from two patients had evidence of BRCA reversion mutations associated with a microhomology-mediated end-joining signature, and three patients had acquired putative nonreversion mechanisms of resistance.CONCLUSIONS: Sapacitabine with olaparib produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of response in some patients suggest possible combinatorial benefit. Further exploration of olaparib with different sapacitabine schedules or substitution of a PARP1-selective inhibitor to potentially decrease hematologic toxicity is warranted.