Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010)

Ring, A. et al. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29(23), pp. 4751-4759. (doi: 10.1158/1078-0432.CCR-23-1696) (PMID:37773077) (PMCID:PMC10690092)

Abstract

Background Approximately 10-15% of triple negative breast cancers (TNBCs) have deleterious mutations in BRCA1 and BRCA2 and may benefit from polyadenosine 5’diphosphoribose polymerase (PARP) inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related protein (ATR). This phase II study examined the activity of the combination of PARP inhibitor, Olaparib, and ATR inhibitor, celerasertib (AZD6738), in patients with advanced TNBC. Patients and methods Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300mg twice a day continuously and celarasertib 160mg on days 1–7 on a 28 day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were pre-planned to identify predictors of response. Results 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95%CI: 10.4-25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumours with functional homologous recombination deficiency by RAD51 foci. Conclusion The response rate to olaparib and ceralasertib did not meet pre-specified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to Olaparib monotherapy.

• Item Type: Articles
• Additional Information: This research was funded by the Stand Up to Cancer Campaign for Cancer Research UK (CRUK/15/010, C30746/A19505, S. Martin, H. Johnson, L. Moretti) with additional support from AstraZeneca, Guardant Health, BioRad and Asociación Española Contra el Cáncer (AECC, INVES20095LLOP A. Llop‐Guevara). The ICR Clinical Trials and Statistics Unit is supported by the Cancer Research UK core programme grant (C1491/A25351 L Kilburn).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Iain
• Authors: Ring, A., Kilburn, L. S., Pearson, A., Moretti, L., Afshari-Mehr, A., Wardley, A. M., Gurel, B., MacPherson, I. R., Riisnaes, R., Baird, R. D., Martin, S., Roylance, R., Johnson, H., Ferreira, A., Winter, M. C., Dunne, K., Copson, E., Hickish, T., Burcombe, R., Randle, K., Serra, V., Llop-Guevara, A., Bliss, J. M., and Turner, N. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432
• ISSN (Online): 1557-3265
• Published Online: 29 September 2023
• Copyright Holders: Copyright © 2023 by the American Association for Cancer Research
• First Published: First published in Clinical Cancer Research 29(23):4751–4759
• Publisher Policy: Reproduced under a Creative Commons license