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

Elizabeth M. Swisher; Tanya T. Kwan; Amit M. Oza; Anna V. Tinker; Isabelle Ray-Coquard; Ana Oaknin; Robert L. Coleman; Carol Aghajanian; Gottfried E. Konecny; David M. O’Malley; Alexandra Leary; Diane Provencher; Stephen Welch; Lee may Chen; Andrea E. Wahner Hendrickson; Ling Ma; Prafull Ghatage; Rebecca S. Kristeleit; Oliver Dorigo; Ashan Musafer; Scott H. Kaufmann; Julia A. Elvin; Douglas I. Lin; Setsuko K. Chambers; Erin Dominy; Lan Thanh Vo; Sandra Goble; Lara Maloney; Heidi Giordano; Thomas Harding; Alexander Dobrovic; Clare L. Scott; Kevin K. Lin; Iain A. McNeish

doi:10.1038/s41467-021-22582-6

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

Elizabeth M. Swisher, Tanya T. Kwan, Amit M. Oza, Anna V. Tinker, Isabelle Ray-Coquard, Ana Oaknin, Robert L. Coleman, Carol Aghajanian, Gottfried E. Konecny, David M. O’Malley, Alexandra Leary, Diane Provencher, Stephen Welch, Lee may Chen, Andrea E. Wahner Hendrickson, Ling Ma, Prafull Ghatage, Rebecca S. Kristeleit, Oliver Dorigo, Ashan MusaferScott H. Kaufmann, Julia A. Elvin, Douglas I. Lin, Setsuko K. Chambers, Erin Dominy, Lan Thanh Vo, Sandra Goble, Lara Maloney, Heidi Giordano, Thomas Harding, Alexander Dobrovic, Clare L. Scott, Kevin K. Lin, Iain A. McNeish

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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.

Original language	English (US)
Article number	2487
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22582-6
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Swisher, E. M., Kwan, T. T., Oza, A. M., Tinker, A. V., Ray-Coquard, I., Oaknin, A., Coleman, R. L., Aghajanian, C., Konecny, G. E., O’Malley, D. M., Leary, A., Provencher, D., Welch, S., Chen, L. M., Wahner Hendrickson, A. E., Ma, L., Ghatage, P., Kristeleit, R. S., Dorigo, O., ... McNeish, I. A. (2021). Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nature communications, 12(1), Article 2487. https://doi.org/10.1038/s41467-021-22582-6

Swisher, EM, Kwan, TT, Oza, AM, Tinker, AV, Ray-Coquard, I, Oaknin, A, Coleman, RL, Aghajanian, C, Konecny, GE, O’Malley, DM, Leary, A, Provencher, D, Welch, S, Chen, LM, Wahner Hendrickson, AE, Ma, L, Ghatage, P, Kristeleit, RS, Dorigo, O, Musafer, A, Kaufmann, SH, Elvin, JA, Lin, DI, Chambers, SK, Dominy, E, Vo, LT, Goble, S, Maloney, L, Giordano, H, Harding, T, Dobrovic, A, Scott, CL, Lin, KK & McNeish, IA 2021, 'Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)', Nature communications, vol. 12, no. 1, 2487. https://doi.org/10.1038/s41467-021-22582-6

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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)",

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.",

author = "Swisher, {Elizabeth M.} and Kwan, {Tanya T.} and Oza, {Amit M.} and Tinker, {Anna V.} and Isabelle Ray-Coquard and Ana Oaknin and Coleman, {Robert L.} and Carol Aghajanian and Konecny, {Gottfried E.} and O{\textquoteright}Malley, {David M.} and Alexandra Leary and Diane Provencher and Stephen Welch and Chen, {Lee may} and {Wahner Hendrickson}, {Andrea E.} and Ling Ma and Prafull Ghatage and Kristeleit, {Rebecca S.} and Oliver Dorigo and Ashan Musafer and Kaufmann, {Scott H.} and Elvin, {Julia A.} and Lin, {Douglas I.} and Chambers, {Setsuko K.} and Erin Dominy and Vo, {Lan Thanh} and Sandra Goble and Lara Maloney and Heidi Giordano and Thomas Harding and Alexander Dobrovic and Scott, {Clare L.} and Lin, {Kevin K.} and McNeish, {Iain A.}",

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AU - Swisher, Elizabeth M.

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AU - Oza, Amit M.

AU - Tinker, Anna V.

AU - Ray-Coquard, Isabelle

AU - Oaknin, Ana

AU - Coleman, Robert L.

AU - Aghajanian, Carol

AU - Konecny, Gottfried E.

AU - O’Malley, David M.

AU - Leary, Alexandra

AU - Provencher, Diane

AU - Welch, Stephen

AU - Chen, Lee may

AU - Wahner Hendrickson, Andrea E.

AU - Ma, Ling

AU - Ghatage, Prafull

AU - Kristeleit, Rebecca S.

AU - Dorigo, Oliver

AU - Musafer, Ashan

AU - Kaufmann, Scott H.

AU - Elvin, Julia A.

AU - Lin, Douglas I.

AU - Chambers, Setsuko K.

AU - Dominy, Erin

AU - Vo, Lan Thanh

AU - Goble, Sandra

AU - Maloney, Lara

AU - Giordano, Heidi

AU - Harding, Thomas

AU - Dobrovic, Alexander

AU - Scott, Clare L.

AU - Lin, Kevin K.

AU - McNeish, Iain A.

PY - 2021/12/1

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N2 - 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.

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

Abstract

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