Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methyla...

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Veröffentlicht in:	Nature communications Jg. 12; H. 1; S. 2487 - 13
Hauptverfasser:	Swisher, Elizabeth M., Kwan, Tanya T., Oza, Amit M., Tinker, Anna V., Ray-Coquard, Isabelle, Oaknin, Ana, Coleman, Robert L., Aghajanian, Carol, Konecny, Gottfried E., O’Malley, David M., Leary, Alexandra, Provencher, Diane, Welch, Stephen, Chen, Lee-may, Wahner Hendrickson, Andrea E., Ma, Ling, Ghatage, Prafull, Kristeleit, Rebecca S., Dorigo, Oliver, Musafer, Ashan, Kaufmann, Scott H., Elvin, Julia A., Lin, Douglas I., Chambers, Setsuko K., Dominy, Erin, Vo, Lan-Thanh, Goble, Sandra, Maloney, Lara, Giordano, Heidi, Harding, Thomas, Dobrovic, Alexander, Scott, Clare L., Lin, Kevin K., McNeish, Iain A.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 03.05.2021 Nature Publishing Group Nature Portfolio
Schlagworte:	631/67/1517/1709 631/67/1857 Adult Aged Aged, 80 and over AKT protein Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Biomarkers BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Carcinoma, Ovarian Epithelial - drug therapy Cell cycle Cross-resistance DNA methylation DNA Methylation - genetics DNA-Binding Proteins - genetics Female Health services Homologous recombination Homology Humanities and Social Sciences Humans Indoles - adverse effects Indoles - therapeutic use Inhibitors Methylation Middle Aged Modulators multidisciplinary Mutation Neoplasm Recurrence, Local - drug therapy Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Patients Platinum Platinum - therapeutic use Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Promoter Regions, Genetic - genetics Scars Science Science (multidisciplinary)
ISSN:	2041-1723, 2041-1723
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Abstract	ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
AbstractList	ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1 / BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity. The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the authors report clinical results and exploratory biomarker analyses from the ARIEL2 phase 2 clinical trial on the safety and efficacy of the PARP inhibitor rucaparib in patients with recurrent ovarian cancers
ArticleNumber	2487
Author	Provencher, Diane Elvin, Julia A. Dominy, Erin Kristeleit, Rebecca S. Coleman, Robert L. Ma, Ling Konecny, Gottfried E. Chambers, Setsuko K. Aghajanian, Carol Goble, Sandra Ghatage, Prafull Dobrovic, Alexander Tinker, Anna V. Maloney, Lara Oza, Amit M. Dorigo, Oliver Lin, Kevin K. Chen, Lee-may O’Malley, David M. Welch, Stephen Wahner Hendrickson, Andrea E. Swisher, Elizabeth M. Oaknin, Ana Kaufmann, Scott H. Harding, Thomas Kwan, Tanya T. Vo, Lan-Thanh Ray-Coquard, Isabelle McNeish, Iain A. Scott, Clare L. Leary, Alexandra Musafer, Ashan Lin, Douglas I. Giordano, Heidi
Author_xml	– sequence: 1 givenname: Elizabeth M. orcidid: 0000-0003-2331-0434 surname: Swisher fullname: Swisher, Elizabeth M. email: swishere@uw.edu organization: University of Washington – sequence: 2 givenname: Tanya T. orcidid: 0000-0002-8109-4023 surname: Kwan fullname: Kwan, Tanya T. organization: Clovis Oncology, Inc – sequence: 3 givenname: Amit M. surname: Oza fullname: Oza, Amit M. organization: Princess Margaret Cancer Centre, University Health Network – sequence: 4 givenname: Anna V. surname: Tinker fullname: Tinker, Anna V. organization: BC Cancer—Vancouver – sequence: 5 givenname: Isabelle orcidid: 0000-0003-2472-8306 surname: Ray-Coquard fullname: Ray-Coquard, Isabelle organization: GINECO, Centre Léon Bérard and University Claude Bernard – sequence: 6 givenname: Ana surname: Oaknin fullname: Oaknin, Ana organization: Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO) – sequence: 7 givenname: Robert L. surname: Coleman fullname: Coleman, Robert L. organization: The University of Texas, MD Anderson Cancer Center – sequence: 8 givenname: Carol surname: Aghajanian fullname: Aghajanian, Carol organization: Memorial Sloan Kettering Cancer Center – sequence: 9 givenname: Gottfried E. surname: Konecny fullname: Konecny, Gottfried E. organization: University of California Los Angeles – sequence: 10 givenname: David M. surname: O’Malley fullname: O’Malley, David M. organization: The Ohio State University, James Cancer Center – sequence: 11 givenname: Alexandra surname: Leary fullname: Leary, Alexandra organization: Gustave Roussy Cancer Center and INSERM U981 – sequence: 12 givenname: Diane orcidid: 0000-0003-1902-3256 surname: Provencher fullname: Provencher, Diane organization: l’Université de Montréal (CHUM) – sequence: 13 givenname: Stephen surname: Welch fullname: Welch, Stephen organization: Lawson Health Research Institute – sequence: 14 givenname: Lee-may surname: Chen fullname: Chen, Lee-may organization: University of California San Francisco Helen Diller Family Comprehensive Cancer Center – sequence: 15 givenname: Andrea E. surname: Wahner Hendrickson fullname: Wahner Hendrickson, Andrea E. organization: Mayo Clinic – sequence: 16 givenname: Ling surname: Ma fullname: Ma, Ling organization: Rocky Mountain Cancer Centers – sequence: 17 givenname: Prafull orcidid: 0000-0002-2371-0844 surname: Ghatage fullname: Ghatage, Prafull organization: Tom Baker Cancer Center – sequence: 18 givenname: Rebecca S. orcidid: 0000-0003-3825-1326 surname: Kristeleit fullname: Kristeleit, Rebecca S. organization: Guy’s and St. Thomas NHS Foundation Trust – sequence: 19 givenname: Oliver orcidid: 0000-0002-1976-5201 surname: Dorigo fullname: Dorigo, Oliver organization: Stanford University Cancer Center and Stanford Cancer Institute – sequence: 20 givenname: Ashan surname: Musafer fullname: Musafer, Ashan organization: University of Melbourne Department of Surgery, Austin Hospital – sequence: 21 givenname: Scott H. orcidid: 0000-0002-4900-7145 surname: Kaufmann fullname: Kaufmann, Scott H. organization: Mayo Clinic – sequence: 22 givenname: Julia A. surname: Elvin fullname: Elvin, Julia A. organization: Foundation Medicine, Inc – sequence: 23 givenname: Douglas I. orcidid: 0000-0003-0105-9760 surname: Lin fullname: Lin, Douglas I. organization: Foundation Medicine, Inc – sequence: 24 givenname: Setsuko K. surname: Chambers fullname: Chambers, Setsuko K. organization: University of Arizona Cancer Center – sequence: 25 givenname: Erin surname: Dominy fullname: Dominy, Erin organization: Clovis Oncology, Inc – sequence: 26 givenname: Lan-Thanh surname: Vo fullname: Vo, Lan-Thanh organization: Clovis Oncology, Inc – sequence: 27 givenname: Sandra surname: Goble fullname: Goble, Sandra organization: Clovis Oncology, Inc – sequence: 28 givenname: Lara surname: Maloney fullname: Maloney, Lara organization: Clovis Oncology, Inc – sequence: 29 givenname: Heidi surname: Giordano fullname: Giordano, Heidi organization: Clovis Oncology, Inc – sequence: 30 givenname: Thomas surname: Harding fullname: Harding, Thomas organization: Clovis Oncology, Inc – sequence: 31 givenname: Alexander surname: Dobrovic fullname: Dobrovic, Alexander organization: University of Melbourne Department of Surgery, Austin Hospital – sequence: 32 givenname: Clare L. orcidid: 0000-0002-3689-5956 surname: Scott fullname: Scott, Clare L. organization: Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research – sequence: 33 givenname: Kevin K. surname: Lin fullname: Lin, Kevin K. organization: Clovis Oncology, Inc – sequence: 34 givenname: Iain A. orcidid: 0000-0002-9387-7586 surname: McNeish fullname: McNeish, Iain A. organization: Imperial College London
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/33941784$$D View this record in MEDLINE/PubMed
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Snippet	ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post... The identification of biomarkers of response to PARP inhibitors can enable selection of appropriate ovarian cancer patients for treatment. In this study, the...
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SubjectTerms	631/67/1517/1709 631/67/1857 Adult Aged Aged, 80 and over AKT protein Antineoplastic Agents - adverse effects Antineoplastic Agents - therapeutic use Biomarkers BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Carcinoma, Ovarian Epithelial - drug therapy Cell cycle Cross-resistance DNA methylation DNA Methylation - genetics DNA-Binding Proteins - genetics Female Health services Homologous recombination Homology Humanities and Social Sciences Humans Indoles - adverse effects Indoles - therapeutic use Inhibitors Methylation Middle Aged Modulators multidisciplinary Mutation Neoplasm Recurrence, Local - drug therapy Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - drug therapy Patients Platinum Platinum - therapeutic use Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Promoter Regions, Genetic - genetics Scars Science Science (multidisciplinary)
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Title	Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)
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