Phase II study of olaparib plus ATR inhibitor ceralasertib in patients with metastatic breast cancer and germline BRCA1/2 pathogenic variants who progressed on prior PARP inhibitor therapy.

1142 Background: PARP inhibitors (PARPi) olparib and talazoparib improve objective response rate (ORR) and disease-free survival (DFS) compared with chemotherapy in patients with metastatic breast cancer and germline BRCA 1/2 pathogenic variants (gBRCA 1/2 PVs). Although the ORR is approximately 60%, about 40% of patients do not respond, and nearly all responders eventually develop progressive disease. Therefore, new strategies to overcome PARPi resistance are needed. Preclinical studies suggest that ATR inhibition combined with olaparib may restore PARPi sensitivity. Phase I studies have shown that olaparib (Ola) plus the ATR inhibitor ceralasertib (Cerala) is safe and have established the recommended phase II dose. This prospective phase II study evaluated the ORR of Ola plus Cerala in patients with metastatic breast cancer with gBRCA 1/2 PVs who previously progressed on PARPi therapy. Methods: Eligible patients had metastatic breast cancer (HER2- negative), prior PARPi exposure, and no more than two prior lines of chemotherapy. After informed consent, all patients underwent the baseline research biopsy of a metastatic lesion and provided blood samples for exploratory analysis aimed at identifying mechanisms of PARPi resistance. Treatment consisted of olaparib 150 mg orally twice daily on days 1-28 plus ceralasertib 80 mg orally twice daily on days 1-14 of each 28-day cycle. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included safety, DFS, and duration of response. Exploratory endpoints focused on biomarker analysis of PARPi resistance. This abstract reports the primary end point. Results: Fifteen patients were enrolled. The median age was 39 years. Eight patients had hormone receptor-positive disease; 6 of these had received endocrine therapy before first-line PARPi. Two patients achieved a partial response (PR) and two had stable disease (SD), resulting and an ORR of 13.3% and a clinical benefit rate of 26.7%. No grade 4 toxicities were observed. Grade 3 adverse events included anemia (N=5), neutropenia (N=1), decreased white blood cell count (N=1), lymphopenia (N=1), and thrombocytopenia (N=1). Conclusions: The combination of olaparib plus ceralasertib is well tolerated and demonstrates clinical activity in patients with metastatic breast cancer with gBRCA 1/2 PVs who have progressed on prior PARPi therapy. A study of this combination in the first-line setting may help determine whether ATR inhibition can overcome or delay PARPi resistance. Biomarker analysis to identify mechanisms of resistance are ongoing and will be reported separately. Clinical trial information: NCT04090567 .