Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer

Ceralasertib, an ATR inhibitor, is known to exacerbate replication stress induced by the PARP inhibitor (PARPi) olaparib, with the combination having the potential to overcome PARPi resistance in the clinic. This modular Phase 1 study evaluated the combination in advanced solid tumours, including breast cancer. Dose escalation of ceralasertib alone (Part A1) or with olaparib (Part A2) in patients with all solid tumours was followed by expansion in PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer (Part B3) or BRCA1/2 wt triple-negative breast cancer (Part B4). Overall, 142 patients were treated. No dose-limiting toxicities occurred in Part A1. Based on haematological safety in Part A2, the combination recommended Phase 2 dose was ceralasertib 160 mg once-daily, days 1–7, plus olaparib 300 mg twice-daily continuously (28-day cycles). In Parts B3 and B4, 36/37 (97.3%) and 24/25 (96.0%) patients had treatment-emergent adverse events (grade ≥3: 16/37 [43.2%], 9/25 [36.0%]; leading to discontinuation: 2/37 [5.4%], 1/25 [4.0%]), and 7 (18.9%) and 3 (12.0%) required ceralasertib dose reductions. Objective response rates were: Part A1, 0%; Part A2, 16.4% ( n = 10/61); Part B3, 37.8% ( n = 14/37); and Part B4, 0%. In PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer, ceralasertib-olaparib had generally manageable safety and demonstrated preliminary antitumour activity. NCT02264678.

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Journal
British Journal of Cancer
Published
2026-09-30
DOI
https://doi.org/10.1038/s41416-026-03601-z
Primary Topic
PARP inhibition in cancer therapy
Type
article
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article

Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer

Emma Jane Dean, Sophie C. Postel-Vinay, Anthony B. El-Khoueiry, Itziar Irurzun‐Arana et al.
British Journal of Cancer
PARP inhibition in cancer therapy
article

Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer

Emma Jane Dean, Sophie C. Postel-Vinay, Anthony B. El-Khoueiry, Itziar Irurzun‐Arana, Rebecca Roylance, Natalia Lukashchuk, Gemma N. Jones, Sun Young Rha, Juanita Suzanne Lopez, Conor Norris, Seock‐Ah Im, Duncan Ian Jodrell, Matthew Krebs, Keun‐Wook Lee, Mario Campone, Christine Stephens, Wassim Abida, Tobias Arkenau, Arsène-Bienvenu Loembé
article en

Abstract

Ceralasertib, an ATR inhibitor, is known to exacerbate replication stress induced by the PARP inhibitor (PARPi) olaparib, with the combination having the potential to overcome PARPi resistance in the clinic. This modular Phase 1 study evaluated the combination in advanced solid tumours, including breast cancer. Dose escalation of ceralasertib alone (Part A1) or with olaparib (Part A2) in patients with all solid tumours was followed by expansion in PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer (Part B3) or BRCA1/2 wt triple-negative breast cancer (Part B4). Overall, 142 patients were treated. No dose-limiting toxicities occurred in Part A1. Based on haematological safety in Part A2, the combination recommended Phase 2 dose was ceralasertib 160 mg once-daily, days 1–7, plus olaparib 300 mg twice-daily continuously (28-day cycles). In Parts B3 and B4, 36/37 (97.3%) and 24/25 (96.0%) patients had treatment-emergent adverse events (grade ≥3: 16/37 [43.2%], 9/25 [36.0%]; leading to discontinuation: 2/37 [5.4%], 1/25 [4.0%]), and 7 (18.9%) and 3 (12.0%) required ceralasertib dose reductions. Objective response rates were: Part A1, 0%; Part A2, 16.4% ( n = 10/61); Part B3, 37.8% ( n = 14/37); and Part B4, 0%. In PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer, ceralasertib-olaparib had generally manageable safety and demonstrated preliminary antitumour activity. NCT02264678.

British Journal of Cancer
Université Paris-Sud (FR), AstraZeneca (United Kingdom) (GB), University of Southern California (US), Royal Marsden NHS Foundation Trust (GB), Memorial Sloan Kettering Cancer Center (US), University College London Hospitals NHS Foundation Trust (GB), Seoul National University (KR), Inserm (FR), Sarah Cannon Research Institute (GB), Yonsei University (KR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Cambridge University Hospitals NHS Foundation Trust (GB), Seoul National University Hospital (KR), Seoul National University Bundang Hospital (KR), University of Manchester (GB), London Cancer (GB), AstraZeneca (Netherlands) (NL), AstraZeneca (Singapore) (SG), USC Norris Comprehensive Cancer Center (US), The Christie NHS Foundation Trust (GB), UCL Biomedical Research Centre (GB), CRUK Lung Cancer Centre of Excellence (GB), Yonsei University Health System (KR), Yonsei Cancer Hospital (KR), University College London (GB)
Good health and well-being
Openalex Percentile: Top 15%
PARP inhibition in cancer therapy
DOIOpen Access PDFOpenAlex
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