Abstract 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 (CNDAC), in patients with germline BRCA1/2 (gBRCA1/2)-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-naive were enrolled. The primary objective was determination of the recommended phase 2 dose (RP2D) of sapacitabine with olaparib. Archival samples were subjected to immunohistochemistry (IHC) for biomarkers of homologous recombination repair (HRR) deficiency and replication stress. Serial blood samples were collected for circulating tumor DNA (ctDNA) analysis. Results: Ten patients (3 BRCA1, 7 BRCA2) were enrolled. The RP2D was not determined due to hematological toxicities. The objective response rate (ORR) was 50% (95% CI: 18.7% - 81.3%) with median progression-free survival (mPFS) of 9.7 months (95% CI: 8.02 – NA). Three patients had clinical benefit greater than 15 months, including 2 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 2 patients had evidence of BRCA reversion mutation associated with a microhomology-mediated end-joining (MMEJ) signature, and 3 patients had acquired putative non-reversion 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 hematological toxicity is warranted.
Poorvu et al. (Wed,) studied this question.