Ceralasertib (ATR inhibitor) + Olaparib (PARP inhibitor) hits 37.8% ORR in PARPi‑naïve BRCA‑mut HER2‑neg breast cancer

Ceralasertib is an oral ATR kinase inhibitor that amplifies replication stress and is hypothesized to resensitize tumors to PARP inhibition; here it was combined with olaparib (PARPi) in a modular Phase 1 dose-escalation/expansion study (NCT02264678) across advanced solid tumors, with breast cancer expansion cohorts. The recommended Phase 2 dose (RP2D) was ceralasertib 160mg QD days 1–7 + olaparib 300mg BID continuously (28‑day cycles), selected due to hematologic safety in combination; 142 patients were treated overall. In the PARPi‑naïve BRCA1/2-mutant HER2‑negative breast cancer expansion (Part B3; n=37), ORR was 37.8% (14/37) with grade ≥3 TEAEs in 43.2% and discontinuations in 5.4% (dose reductions: 18.9%); in contrast, Part B4 (BRCA1/2 wild-type TNBC; n=25) had 0% ORR despite similar AE rates (grade ≥3: 36.0%, discontinuations: 4.0%), and the all‑comers escalation cohorts showed 0% ORR with ceralasertib monotherapy (Part A1) and 16.4% ORR with the combination (Part A2; 10/61). For benchmark context, single‑agent PARP inhibitors are already a standard option for germline BRCA-mutated, HER2‑negative metastatic breast cancer (per ASCO guidance), and in OlympiAD (olaparib vs physician’s choice chemo) olaparib improved ORR vs chemo—so a 37.8% ORR in a small Phase 1 expansion looks broadly in-family rather than clearly additive vs PARPi alone without a randomized comparator.