Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)

Abstract

Olaparib; Ceralasertib; Triple-negative advanced breast cancer

Olaparib; Ceralasertib; Càncer de mama avançat triple negatiu

Olaparib; Ceralasertib; Cáncer de mama avanzado triple negativo

Purpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (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 300 mg twice a day continuously and celarasertib 160 mg 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 preplanned 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% confidence interval, 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 tumors with functional homologous recombination deficiency by RAD51 foci. Conclusions: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.

This research was funded by the Stand Up to Cancer Campaign for Cancer Research UK (CRUK/15/010, C30746/A19505; to S. Martin, H. Johnson, L. Moretti) with additional support from AstraZeneca, Guardant Health, Bio-Rad and Asociación Española Contra el Cáncer (AECC, INVES20095LLOP; to A. Llop-Guevara). The ICR Clinical Trials and Statistics Unit is supported by the Cancer Research UK core programme grant (C1491/A25351; to L.S. Kilburn). This study represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, London, UK. In addition, plasmaMATCH is supported by the NIHR Manchester Clinical Research Facility at the Christie Hospital, Manchester, UK, the NIHR UCLH Clinical Research Facility at University College London Hospitals NHS Foundation Trust, London, UK, the Cancer Research UK Cambridge Centre, Cambridge Biomedical Research Centre (BRC-1215–20014) and Cambridge Experimental Cancer Medicine Centre, Cambridge, UK. The RAD51 analysis was supported with grants from the Spanish Association of Cancer Research and Instituto de Salud Carlos III (ERAPERMED2019–215, CPII19/00033, and INVES20095LLOP). plasmaMATCH is supported at participating sites in England by the NIHR Clinical Research Network, in Scotland by the Chief Scientist Office, and in Wales by Health and Care Research Wales.