<p>PARP inhibitors significantly extend progression-free survival (PFS), compared to chemotherapy in patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative metastatic breast cancer, but responses are not durable. Preclinical studies suggest that sapacitabine, an oral nucleoside analog, is synergistic with PARP inhibition in cell lines harboring homologous recombination repair (HRR) defects. </p><p>To translate these findings, this phase Ib study combining sapacitabine and olaparib enrolled ten patients with gBRCA1/2-mutated HER2-negative metastatic breast cancer. The recommended phase 2 dose was not determined due to hematological toxicities, mainly neutropenia and anemia. Archival tumors from responders demonstrated evidence of HRR deficiency or of high replication stress. At progression, BRCA1/2 reversion mutations associated with a microhomology-mediated end-joining (MMEJ) signature and other acquired putative non-reversion mechanisms of resistance were identified. The median PFS observed of 9.7 months, with three patients experiencing clinical benefit greater than 15 months, suggests that the addition of sapacitabine to PARP inhibition merits further investigation.</p>

A Phase Ib Study of Sapacitabine and Olaparib in Patients With BRCA1/2-Mutated (BRCA1/2m) Metastatic Breast Cancer