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

Abstract

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.

• Authors: Alistair Ring, Lucy S Kilburn, Alex Pearson, Laura Moretti, Angelica Afshari-Mehr, Andrew M Wardley, Bora Gurel, Iain R Macpherson, Ruth Riisnaes, Richard D Baird, Sue Martin, Rebecca Roylance, Hannah Johnson, Ana Ferreira, Matthew C Winter, Kathryn Dunne, Ellen Copson, Tamas Hickish, Russell Burcombe, Kat Randle, Violeta Serra, Alba Llop-Guevara, Judith M Bliss, Nicolas C Turner
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 29 Issue 23 Pg. 4751-4759 (Dec 01 2023) ISSN: 1557-3265 [Electronic] United States
• PMID: 37773077 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• ceralasertib
• Poly(ADP-ribose) Polymerase Inhibitors
• BRCA1 protein, human
• BRCA1 Protein
• olaparib
• BRCA2 protein, human
• BRCA2 Protein
• Antineoplastic Agents
• Phthalazines

Topics

• Humans
• Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use, pharmacology)
• BRCA1 Protein (genetics)
• Triple Negative Breast Neoplasms (drug therapy, genetics)
• BRCA2 Protein (genetics)
• Antineoplastic Agents (therapeutic use)
• Phthalazines (adverse effects)