British journal of cancer · 2026
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.
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Lopez Juanita S, Im Seock-Ah, Postel-Vinay Sophie, Campone Mario, El-Khoueiry Anthony B, Abida Wassim, Arkenau Tobias, Lee Keun-Wook, Rha Sun Young, Jodrell Duncan I, Roylance Rebecca, Irurzun-Arana Itziar, Jones Gemma N, Lukashchuk Natalia, Stephens Christine, Norris Conor, Loembé Arsène-Bienvenu, Dean Emma, Krebs Matthew G
Аннотация
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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%.
CONCLUSION: In PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer, ceralasertib-olaparib had generally manageable safety and demonstrated preliminary antitumour activity.
TRIAL REGISTRATION NUMBER: NCT02264678.
METHODS: 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).
RESULTS: 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%.
CONCLUSION: In PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer, ceralasertib-olaparib had generally manageable safety and demonstrated preliminary antitumour activity.
TRIAL REGISTRATION NUMBER: NCT02264678.