The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
Abstract The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurab...
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47215-6 |
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| author | Elena Giudice Tzu-Ting Huang Jayakumar R. Nair Grant Zurcher Ann McCoy Darryl Nousome Marc R. Radke Elizabeth M. Swisher Stanley Lipkowitz Kristen Ibanez Duncan Donohue Tyler Malys Min-Jung Lee Bernadette Redd Elliot Levy Shraddha Rastogi Nahoko Sato Jane B. Trepel Jung-Min Lee |
| author_facet | Elena Giudice Tzu-Ting Huang Jayakumar R. Nair Grant Zurcher Ann McCoy Darryl Nousome Marc R. Radke Elizabeth M. Swisher Stanley Lipkowitz Kristen Ibanez Duncan Donohue Tyler Malys Min-Jung Lee Bernadette Redd Elliot Levy Shraddha Rastogi Nahoko Sato Jane B. Trepel Jung-Min Lee |
| author_sort | Elena Giudice |
| collection | DOAJ |
| description | Abstract The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation. |
| format | Article |
| id | doaj-art-a32a2dc2018942d5a1dda8aa8f8851d8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a32a2dc2018942d5a1dda8aa8f8851d82025-02-02T12:30:53ZengNature PortfolioNature Communications2041-17232024-03-0115111410.1038/s41467-024-47215-6The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trialElena Giudice0Tzu-Ting Huang1Jayakumar R. Nair2Grant Zurcher3Ann McCoy4Darryl Nousome5Marc R. Radke6Elizabeth M. Swisher7Stanley Lipkowitz8Kristen Ibanez9Duncan Donohue10Tyler Malys11Min-Jung Lee12Bernadette Redd13Elliot Levy14Shraddha Rastogi15Nahoko Sato16Jane B. Trepel17Jung-Min Lee18Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Center for Cancer Research Collaborative Bioinformatics Resource, CCR, NCI, NIHDepartment of Ob/Gyn, University of WashingtonDepartment of Ob/Gyn, University of WashingtonWomen’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Statistical Consulting and Scientific Programming Group, Computer and Statistical Services, Data Management Services, Inc. (a BRMI company), NCIStatistical Consulting and Scientific Programming Group, Computer and Statistical Services, Data Management Services, Inc. (a BRMI company), NCIDevelopmental Therapeutics Branch, CCR, NCI, NIHClinical Image Processing Service, Department of Radiology and Imaging Sciences, CCR, NCI, NIHInterventional Radiology, CCR, NCI, NIHDevelopmental Therapeutics Branch, CCR, NCI, NIHDevelopmental Therapeutics Branch, CCR, NCI, NIHDevelopmental Therapeutics Branch, CCR, NCI, NIHWomen’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH)Abstract The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.https://doi.org/10.1038/s41467-024-47215-6 |
| spellingShingle | Elena Giudice Tzu-Ting Huang Jayakumar R. Nair Grant Zurcher Ann McCoy Darryl Nousome Marc R. Radke Elizabeth M. Swisher Stanley Lipkowitz Kristen Ibanez Duncan Donohue Tyler Malys Min-Jung Lee Bernadette Redd Elliot Levy Shraddha Rastogi Nahoko Sato Jane B. Trepel Jung-Min Lee The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial Nature Communications |
| title | The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial |
| title_full | The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial |
| title_fullStr | The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial |
| title_full_unstemmed | The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial |
| title_short | The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial |
| title_sort | chk1 inhibitor prexasertib in brca wild type platinum resistant recurrent high grade serous ovarian carcinoma a phase 2 trial |
| url | https://doi.org/10.1038/s41467-024-47215-6 |
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