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Clinical Trial
. 2023 Dec 1;29(23):4751-4759.
doi: 10.1158/1078-0432.CCR-23-1696.

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

Alistair Ring  1   2 , Lucy S Kilburn #  3 , Alex Pearson #  4 , Laura Moretti  3 , Angelica Afshari-Mehr  4 , Andrew M Wardley  5 , Bora Gurel  6 , Iain R Macpherson  7 , Ruth Riisnaes  6 , Richard D Baird  8 , Sue Martin  3 , Rebecca Roylance  9 , Hannah Johnson  3 , Ana Ferreira  6 , Matthew C Winter  10 , Kathryn Dunne  4   11 , Ellen Copson  12 , Tamas Hickish  13 , Russell Burcombe  14 , Kat Randle  15 , Violeta Serra  16 , Alba Llop-Guevara  16 , Judith M Bliss #  3 , Nicolas C Turner #  1   4
Affiliations
Clinical Trial

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

Alistair Ring et al. Clin Cancer Res. .

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.

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Figures

Figure 1. Best percentage change from baseline for sum of the target lesions (n = 70).
Figure 1.
Best percentage change from baseline for sum of the target lesions (n = 70).
Figure 2. Swimmer plots for evaluable population with (A) germline BRCA mutations (n = 10) and (B) no germline or somatic BRCA mutations (n = 55).
Figure 2.
Swimmer plots for evaluable population with (A) germline BRCA mutations (n = 10) and (B) no germline or somatic BRCA mutations (n = 55).
Figure 3. Activity according to biomarker subgroups: confirmed response rate.
Figure 3.
Activity according to biomarker subgroups: confirmed response rate.
Figure 4. Treatment-emergent AEs more than 10% incidence.
Figure 4.
Treatment-emergent AEs more than 10% incidence.
See this image and copyright information in PMC

References

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    1. Chopra N, Tovey H, Pearson A, Cutts R, Toms C, Proszek P, et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple-negative breast cancer. Nat Commun 2020;11:2662. - PMC - PubMed
    1. Graeser M, McCarthy A, Lord CJ, Savage K, Hills M, Salter J, et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res 2010;16:6159–68. - PMC - PubMed
    1. Staaf J, Glodzik D, Bosch A, Vallon-Christersson J, Reuterswärd C, Häkkinen J, et al. Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study. Nat Med 2019;25:1526–33. - PMC - PubMed
    1. Lecona E, Fernandez-Capetillo O. Targeting ATR in cancer. Nat Rev Cancer 2018;18:586–95. - PubMed

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