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Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer.

Publication ,  Journal Article
Wethington, SL; Shah, PD; Martin, L; Tanyi, JL; Latif, N; Morgan, M; Torigian, DA; Rodriguez, D; Smith, SA; Dean, E; Domchek, SM; Drapkin, R ...
Published in: Clin Cancer Res
August 1, 2023

PURPOSE: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC. PATIENTS AND METHODS: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)-deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). RESULTS: Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15-0.72). Median treatment duration was 8 cycles (range 4-23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity. CONCLUSIONS: Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 1, 2023

Volume

29

Issue

15

Start / End Page

2800 / 2807

Location

United States

Related Subject Headings

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Phthalazines
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Homologous Recombination
  • Female
  • Carcinoma, Ovarian Epithelial
  • BRCA2 Protein
 

Citation

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Wethington, S. L., Shah, P. D., Martin, L., Tanyi, J. L., Latif, N., Morgan, M., … Simpkins, F. (2023). Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer. Clin Cancer Res, 29(15), 2800–2807. https://doi.org/10.1158/1078-0432.CCR-22-2444
Wethington, Stephanie L., Payal D. Shah, Lainie Martin, Janos L. Tanyi, Nawar Latif, Mark Morgan, Drew A. Torigian, et al. “Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer.Clin Cancer Res 29, no. 15 (August 1, 2023): 2800–2807. https://doi.org/10.1158/1078-0432.CCR-22-2444.
Wethington SL, Shah PD, Martin L, Tanyi JL, Latif N, Morgan M, et al. Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer. Clin Cancer Res. 2023 Aug 1;29(15):2800–7.
Wethington, Stephanie L., et al. “Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer.Clin Cancer Res, vol. 29, no. 15, Aug. 2023, pp. 2800–07. Pubmed, doi:10.1158/1078-0432.CCR-22-2444.
Wethington SL, Shah PD, Martin L, Tanyi JL, Latif N, Morgan M, Torigian DA, Rodriguez D, Smith SA, Dean E, Domchek SM, Drapkin R, Shih I-M, Brown EJ, Hwang W-T, Armstrong DK, Gaillard S, Giuntoli R, Simpkins F. Combination ATR (ceralasertib) and PARP (olaparib) Inhibitor (CAPRI) Trial in Acquired PARP Inhibitor-Resistant Homologous Recombination-Deficient Ovarian Cancer. Clin Cancer Res. 2023 Aug 1;29(15):2800–2807.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

August 1, 2023

Volume

29

Issue

15

Start / End Page

2800 / 2807

Location

United States

Related Subject Headings

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Phthalazines
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Homologous Recombination
  • Female
  • Carcinoma, Ovarian Epithelial
  • BRCA2 Protein