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

Research output: Contribution to journal › Article › peer-review

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

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-021-22582-6

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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), [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

@article{1378a390748746fbabec1ac063c022a1,

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.}",

note = "Funding Information: Funding from the National Breast Cancer Foundation of Australia (to A.D.) and the Department of Defense Ovarian Cancer Research Program (OC12056, to E.M.S. and S.H.K.) and a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACR-DT16-15, to E.M.S. and S.H.K.). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. We thank Elaina Mann, Jennifer Borrow, Jen Lenore, Jeff Isaacson, and Lindsey Rolfe for clinical development, statistical guidance, and operational support of the ARIEL2 study. In addition, we thank Vivian Chen and Mary Joyce for assistance in manuscript preparation. ARIEL2 was designed by the funder and a subgroup of investigators. Data presented and herein were collected by the funder; the funder and all authors interpreted and analyzed the data. Funding Information: E.M.S. has received funding for clinical trials from Clovis Oncology and TESARO (paid to her institution). T.T.K., E.D., L.-T.V., S.G., L. Maloney, H.G., T.H., and K.K.L. are employees of Clovis Oncology and may own stock or have stock options in that company. A.M.O. has served on advisory boards for Clovis Oncology, Amgen, Immunovaccine, and Verastem; received support for travel or accommodation from AstraZeneca; and received honoraria from WebRx. A.V.T. has served on an advisory board for and received grants from AstraZeneca. I.R.-C. has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, Merck Sharpe Dohme, PharmaMar, Roche, and Tesaro/GlaxoSmithKline and received support for travel or accommodation from AstraZeneca, GlaxoSmithKline, and Roche. A.O. has served on advisory boards for Clovis Oncology, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, and Tesaro and received support for travel or accommodation from AstraZeneca, PharmaMar, Roche, and Tesaro. R.L.C. reports grants from Clovis Oncology, AbbVie, AstraZeneca, Esperance, Janssen, Merck, Millennium, OncoMed, and Roche/Genentech and has served as an advisor to Clovis Oncology, AbbVie, AstraZeneca, Bayer, Esperance, GamaMabs, Genmab, Gradalis, Janssen, Millennium, Merck, OncoMed, Pfizer, Roche/Genentech, and Tesaro. C.A. has served on steering committees for Clovis Oncology and Mateon Therapeutics; served on advisory boards for Clovis Oncology, Bayer, Cerulean Pharma, Tesaro, and VentiRx, and received honoraria from Clovis Oncology, Bayer, Cerulean Pharma, Mateon Therapeutics, Tesaro, and VentiRx. G.E.K. has received research funding (to the University of California outside the scope of this work) from Lilly, Merck, and Pfizer, and received honorarium from Clovis Oncology, AstraZeneca, and Tesaro. D.M.O. has served on advisory boards for Clovis Oncology, AstraZeneca, Gynecologic Oncology Group, Janssen, Myriad, and Tesaro; has served on steering committees for Clovis Oncology, Amgen, and ImmunoGen; has served as a consultant to AbbVie, Ambry, AstraZeneca, Health Analytics, and Tesaro, and his institution has received research support from Clovis Oncology, Agenus, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, ERGOMED Clinical Research, Exelixis, Genentech, GlaxoSmithKline, Gynecologic Oncology Group, ImmunoGen, INC Research, inVentiv Health Clinical, Janssen Research and Development, Ludwig Institute for Cancer Research, Novartis Pharmaceuticals, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, and TRACON Pharmaceuticals. A.L. has served on advisory boards for Clovis Oncology, Ability, AstraZeneca, Biocad, Merck Serono, MSD, Pfizer, PharmaMar, Seattle Genetics, and Tesaro PharmaMar; reports institutional research grant support from GamaMabs, Inivata, Merus, and Sanofi, and reports boarding and travel expenses for congress activities from Clovis Oncology, AstraZeneca, Roche, and Tesaro. D.P. has served on advisory boards for AstraZeneca and GlaxoSmithKline, and received support for travel from AstraZeneca. S.W. has served on advisory boards for Astra-Zeneca and Roche; reports institutional research support from Clovis Oncology, AstraZeneca, Merck, Regeneron, and Tesaro, and has received honoraria from AstraZeneca. P.G. has served on an advisory board for AstraZeneca, GSK, and Merck, and received support for travel expenses for congress activities from Astra-Zeneca. R.S.K. has served on advisory boards for Clovis Oncology, Roche, and Tesaro. O.D. has served on advisory boards for Clovis Oncology, IMV, Tesaro, and Merck, and has served on the speaker bureau for AstraZeneca and Tesaro. J.A.E. and D.I.L. are employees of Foundation Medicine, Inc., which is a wholly-owned subsidiary of Roche, and may own stock or have stock options in Roche. A.D. has served on advisory boards for AstraZeneca Australia and has received travel support from Bio-Rad. C.L.S. has served on advisory boards for Clovis Oncology, AstraZeneca, Takeda, Roche Australia, MSD, Eisai Co., has received travel support from AstraZe-neca, has received in kind research support from Clovis Oncology, Roche, Beigene and Funded research support from Sierra oncology and Eisai Co. I.A.M. has served on advisory boards for Clovis Oncology, AstraZeneca, Roche, Takeda, and Tesaro and receives institutional funding from AstraZeneca. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-22582-6",

language = "English (US)",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

AU - Swisher, Elizabeth M.

AU - Kwan, Tanya T.

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.

N1 - Funding Information: Funding from the National Breast Cancer Foundation of Australia (to A.D.) and the Department of Defense Ovarian Cancer Research Program (OC12056, to E.M.S. and S.H.K.) and a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACR-DT16-15, to E.M.S. and S.H.K.). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. We thank Elaina Mann, Jennifer Borrow, Jen Lenore, Jeff Isaacson, and Lindsey Rolfe for clinical development, statistical guidance, and operational support of the ARIEL2 study. In addition, we thank Vivian Chen and Mary Joyce for assistance in manuscript preparation. ARIEL2 was designed by the funder and a subgroup of investigators. Data presented and herein were collected by the funder; the funder and all authors interpreted and analyzed the data. Funding Information: E.M.S. has received funding for clinical trials from Clovis Oncology and TESARO (paid to her institution). T.T.K., E.D., L.-T.V., S.G., L. Maloney, H.G., T.H., and K.K.L. are employees of Clovis Oncology and may own stock or have stock options in that company. A.M.O. has served on advisory boards for Clovis Oncology, Amgen, Immunovaccine, and Verastem; received support for travel or accommodation from AstraZeneca; and received honoraria from WebRx. A.V.T. has served on an advisory board for and received grants from AstraZeneca. I.R.-C. has served on advisory boards for Clovis Oncology, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, Merck Sharpe Dohme, PharmaMar, Roche, and Tesaro/GlaxoSmithKline and received support for travel or accommodation from AstraZeneca, GlaxoSmithKline, and Roche. A.O. has served on advisory boards for Clovis Oncology, AstraZeneca, ImmunoGen, Genmab/Seattle Genetics, PharmaMar, Roche, and Tesaro and received support for travel or accommodation from AstraZeneca, PharmaMar, Roche, and Tesaro. R.L.C. reports grants from Clovis Oncology, AbbVie, AstraZeneca, Esperance, Janssen, Merck, Millennium, OncoMed, and Roche/Genentech and has served as an advisor to Clovis Oncology, AbbVie, AstraZeneca, Bayer, Esperance, GamaMabs, Genmab, Gradalis, Janssen, Millennium, Merck, OncoMed, Pfizer, Roche/Genentech, and Tesaro. C.A. has served on steering committees for Clovis Oncology and Mateon Therapeutics; served on advisory boards for Clovis Oncology, Bayer, Cerulean Pharma, Tesaro, and VentiRx, and received honoraria from Clovis Oncology, Bayer, Cerulean Pharma, Mateon Therapeutics, Tesaro, and VentiRx. G.E.K. has received research funding (to the University of California outside the scope of this work) from Lilly, Merck, and Pfizer, and received honorarium from Clovis Oncology, AstraZeneca, and Tesaro. D.M.O. has served on advisory boards for Clovis Oncology, AstraZeneca, Gynecologic Oncology Group, Janssen, Myriad, and Tesaro; has served on steering committees for Clovis Oncology, Amgen, and ImmunoGen; has served as a consultant to AbbVie, Ambry, AstraZeneca, Health Analytics, and Tesaro, and his institution has received research support from Clovis Oncology, Agenus, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, ERGOMED Clinical Research, Exelixis, Genentech, GlaxoSmithKline, Gynecologic Oncology Group, ImmunoGen, INC Research, inVentiv Health Clinical, Janssen Research and Development, Ludwig Institute for Cancer Research, Novartis Pharmaceuticals, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, and TRACON Pharmaceuticals. A.L. has served on advisory boards for Clovis Oncology, Ability, AstraZeneca, Biocad, Merck Serono, MSD, Pfizer, PharmaMar, Seattle Genetics, and Tesaro PharmaMar; reports institutional research grant support from GamaMabs, Inivata, Merus, and Sanofi, and reports boarding and travel expenses for congress activities from Clovis Oncology, AstraZeneca, Roche, and Tesaro. D.P. has served on advisory boards for AstraZeneca and GlaxoSmithKline, and received support for travel from AstraZeneca. S.W. has served on advisory boards for Astra-Zeneca and Roche; reports institutional research support from Clovis Oncology, AstraZeneca, Merck, Regeneron, and Tesaro, and has received honoraria from AstraZeneca. P.G. has served on an advisory board for AstraZeneca, GSK, and Merck, and received support for travel expenses for congress activities from Astra-Zeneca. R.S.K. has served on advisory boards for Clovis Oncology, Roche, and Tesaro. O.D. has served on advisory boards for Clovis Oncology, IMV, Tesaro, and Merck, and has served on the speaker bureau for AstraZeneca and Tesaro. J.A.E. and D.I.L. are employees of Foundation Medicine, Inc., which is a wholly-owned subsidiary of Roche, and may own stock or have stock options in Roche. A.D. has served on advisory boards for AstraZeneca Australia and has received travel support from Bio-Rad. C.L.S. has served on advisory boards for Clovis Oncology, AstraZeneca, Takeda, Roche Australia, MSD, Eisai Co., has received travel support from AstraZe-neca, has received in kind research support from Clovis Oncology, Roche, Beigene and Funded research support from Sierra oncology and Eisai Co. I.A.M. has served on advisory boards for Clovis Oncology, AstraZeneca, Roche, Takeda, and Tesaro and receives institutional funding from AstraZeneca. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85105232015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85105232015&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-22582-6

DO - 10.1038/s41467-021-22582-6

M3 - Article

C2 - 33941784

AN - SCOPUS:85105232015

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2487

ER -

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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