Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.
BRCA1/2
PARP inhibition
adjuvant therapy
breast cancer
olaparib
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
14
09
2022
accepted:
22
09
2022
pubmed:
14
10
2022
medline:
6
12
2022
entrez:
13
10
2022
Statut:
ppublish
Résumé
The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.
Sections du résumé
BACKGROUND
The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety.
PATIENTS AND METHODS
One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015.
RESULTS
With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome.
CONCLUSION
With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.
Identifiants
pubmed: 36228963
pii: S0923-7534(22)04165-5
doi: 10.1016/j.annonc.2022.09.159
pmc: PMC10207856
mid: NIHMS1898247
pii:
doi:
Substances chimiques
olaparib
WOH1JD9AR8
olympia
71714-89-1
Phthalazines
0
BRCA1 protein, human
0
BRCA1 Protein
0
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase III
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1250-1268Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180822
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180868
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA189867
Pays : United States
Investigateurs
Paul Sevelda
(P)
Ferdinand Haslbauer
(F)
Monika Penzinger
(M)
Leopold Öhler
(L)
Christoph Tinchon
(C)
Richard Greil
(R)
Sonja Heibl
(S)
Rupert Bartsch
(R)
Viktor Wette
(V)
Christian F Singer
(CF)
Claudia Pasterk
(C)
Ruth Helfgott
(R)
Gunda Pristauz-Telsnigg
(G)
Herbert Stöger
(H)
Angsar Weltermann
(A)
Daniel Egle
(D)
Irene Thiel
(I)
David Fuchs
(D)
Holger Rumpold
(H)
Kathrin Strasser-Weippl
(K)
Beate Rautenberg
(B)
Volkmar Müller
(V)
Marcus Schmidt
(M)
Stefan Paepke
(S)
Mustafa Aydogdu
(M)
Christoph Thomssen
(C)
Joachim Rom
(J)
Christine Mau
(C)
Peter Fasching
(P)
Uwe-Jochen Göhring
(UJ)
Thorsten Kühn
(T)
Stefanie Noeding
(S)
Sherko Kümmel
(S)
John Hackmann
(J)
Elmar Stickeler
(E)
Abhishek Joshi
(A)
Joanna Dewar
(J)
Michael Friedlander
(M)
Kelly-Anne Phillips
(KA)
Yoland Antill
(Y)
Natasha Woodward
(N)
Ehtesham Abdi
(E)
Susan Tiley
(S)
Mathew George
(M)
David Boadle
(D)
Annabel Goodwin
(A)
Andre van der Westhuizen
(A)
George Kannourakis
(G)
Nicholas Murray
(N)
Nicole McCarthy
(N)
Judith Kroep
(J)
Maaike de Boer
(M)
Joan Heijns
(J)
Agnes Jager
(A)
Franciscus Erdkamp
(F)
Sandra Bakker
(S)
Gabe S Sonke
(GS)
Amer Sami
(A)
John Mackey
(J)
Catherine Prady
(C)
Andrea Eisen
(A)
Christine Desbiens
(C)
Erica Patocskai
(E)
Cristiano Ferrario
(C)
Karen Gelmon
(K)
Louise Bordeleau
(L)
Haji Chalchal
(H)
Saroj Niraula
(S)
None Ido Wolf
Elżbieta Senkus
(E)
François Duhoux
(F)
None Randal d'Hondt
Sylvie Luce
(S)
Daphné t'Kint de Roodenbeke
(DT)
Konstantinos Papadimitriou
(K)
Marleen Borms
(M)
Claire Quaghebeur
(C)
William Jacot
(W)
Etienne Brain
(E)
Laurence Venat-Bouvet
(L)
Alain Lortholary
(A)
Zbigniew Nowecki
(Z)
Fátima Cardoso
(F)
Richard Hayward
(R)
Santiago Bella
(S)
Mauricio Fernández Lazzaro
(MF)
Norma Pilnik
(N)
Luis E Fein
(LE)
Cesar Blajman
(C)
Guillermo Lerzo
(G)
Mirta Varela
(M)
Juan Jose Zarba
(JJ)
Diego Kaen
(D)
Maria Victoria Constanzo
(MV)
Joke Tio
(J)
Wulf Siggelkow
(W)
Christian Jackisch
(C)
Eva Maria Grischke
(EM)
Dirk Zahm
(D)
Sara Tato-Varela
(S)
Sabine Schmatloch
(S)
Peter Klare
(P)
Andrea Stefek
(A)
Kerstin Rhiem
(K)
Oliver Hoffmann
(O)
Sherko Kümmel
(S)
Mustafa Deryal
(M)
Isolde Gröll
(I)
Peter Ledwon
(P)
Christoph Uleer
(C)
Petra Krabisch
(P)
Jochem Potenberg
(J)
Maren Darsow
(M)
Tjoung-Won Park-Simon
(TW)
Heinz-Gert Höffkes
(HG)
Till-Oliver Emde
(TO)
Gerd Graffunder
(G)
Oliver Tomé
(O)
Dirk Forstmeyer
(D)
Jürgen Terhaag
(J)
Christoph Salat
(C)
Karin Kast
(K)
Steffi Weniger
(S)
Carsten Schreiber
(C)
Bernhard Heinrich
(B)
Max Dieterich
(M)
Michaela Penelope Wüllner
(MP)
Raquel Andrés Conejero
(RA)
José Ángel García Sáenz
(JÁ)
Lourdes Calvo Martinez
(LC)
Angels Arcusa Lanza
(AA)
Serafín Morales Murillo
(SM)
Fernando Henao Carrasco
(FH)
Salvador Blanch Tormo
(SB)
Isabel Álvarez López
(IÁ)
Juan Ignacio Delgado Mingorance
(JI)
Elena Álvarez Gomez
(EÁ)
Marta Santisteban
(M)
Josefina Cruz Jurado
(JC)
Vanesa Quiroga
(V)
Manuel Ruiz Borrego
(MR)
Eduardo Martínez de Dueñas
(E)
Jose Enrique Alés Martínez
(JE)
Juan De la Haba
(J)
Noelia Martínez Jañez
(NM)
Álvaro Rodríguez Lescure
(ÁR)
Antonio Antón Torres
(AA)
Gema Llort Crusades
(GL)
Santiago González-Santiago
(S)
Antonia Marquez Aragones
(AM)
Ana Laura Ortega
(AL)
Agusti Barnadas Molins
(AB)
José Ignacio Chacón López-Muñiz
(JI)
Miguel Martín Jiménez
(MM)
Ana Santaballa Bertrán
(AS)
César Rodríguez
(C)
Lucía González Cortijo
(LG)
Elisabetta Cretella
(E)
Laura Cortesi
(L)
Enzo Maria Ruggeri
(EM)
Claudio Verusio
(C)
Stefania Gori
(S)
Andrea Bonetti
(A)
Anna Maria Mosconi
(AM)
Oskar Johannsson
(O)
Guy Jerusalem
(G)
Patrick Neven
(P)
Tünde Nagy
(T)
Graziella Pinotti
(G)
Marco A Colleoni
(MA)
Antonio Bernardo
(A)
Lorenzo Gianni
(L)
Eraldo Bucci
(E)
Laura Biganzoli
(L)
Konstantin Dedes
(K)
Urban Novak
(U)
Khalil Zaman
(K)
Jeremy Braybrooke
(J)
Matthew Winter
(M)
Daniel Rea
(D)
Muireann Kelleher
(M)
Sophie Barrett
(S)
Stephen Chan
(S)
Tamas Hickish
(T)
Jane Hurwitz
(J)
John Conibear
(J)
Apurna Jegannathen
(A)
Marina Parton
(M)
Andrew Tutt
(A)
Rozenn Allerton
(R)
Annabel Borley
(A)
Anne Armstrong
(A)
Ellen Copson
(E)
Nicola Levitt
(N)
Jean Abraham
(J)
Timothy Perren
(T)
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(R)
Kazushige Ishida
(K)
Tatsuya Toyama
(T)
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(N)
Junichiro Watanabe
(J)
Eriko Tokunaga
(E)
Takayuki Kinoshita
(T)
Yoshiaki Rai
(Y)
Masahiro Takada
(M)
Yasuhiro Yanagita
(Y)
Rikiya Nakamura
(R)
Takahiro Nakayama
(T)
Yasuto Naoi
(Y)
Hiroji Iwata
(H)
Seigo Nakamura
(S)
Masato Takahashi
(M)
Kenjiro Aogi
(K)
Koichiro Tsugawa
(K)
Hirofumi Mukai
(H)
Toshimi Takano
(T)
Akihiko Osaki
(A)
Nobuaki Sato
(N)
Hideko Yamauchi
(H)
Yutaka Tokuda
(Y)
Mitsuya Ito
(M)
Takeki Sugimoto
(T)
Shakeela W Bahadur
(SW)
Patricia A Ganz
(PA)
Min J Lu
(MJ)
Min J Lu
(MJ)
Monica M Mita
(MM)
James Waisman
(J)
Jonathan A Polikoff
(JA)
Melinda L Telli
(ML)
Samantha A Seaward
(SA)
J Marie Suga
(JM)
Samantha A Seaward
(SA)
J Marie Suga
(JM)
Lara N Durna
(LN)
Jennifer Fu Carney
(JF)
Alex Menter
(A)
J Marie Suga
(JM)
Ajithkumar Puthillath
(A)
Jonathan A Polikoff
(JA)
J Marie Suga
(JM)
Nitin Rohatgi
(N)
J Marie Suga
(JM)
Jonathan A Polikoff
(JA)
Jonathan A Polikoff
(JA)
James H Feusner
(JH)
Kristie A Bobolis
(KA)
Jonathan A Polikoff
(JA)
Peter D Eisenberg
(PD)
J Marie Suga
(JM)
Jonathan A Polikoff
(JA)
Derrick Wong
(D)
Virginia F Borges
(VF)
Alexander T Urquhart
(AT)
Erin W Hofstatter
(EW)
Erin W Hofstatter
(EW)
Erin W Hofstatter
(EW)
Edward C McCarron
(EC)
Claudine Isaacs
(C)
Pia Herbolsheimer
(P)
Ramya Varadarajan
(R)
Adam Raben
(A)
Ruby Anne E Deveras
(RAE)
Frances Valdes-Albini
(F)
Reshma L Mahtani
(RL)
Reshma L Mahtani
(RL)
Jane L Meisel
(JL)
Bradley T Sumrall
(BT)
Cheryl F Jones
(CF)
Samuel N Ofori
(SN)
Kenneth N M Sumida
(KNM)
Kenneth N M Sumida
(KNM)
Mark Karwal
(M)
Deborah W Wilbur
(DW)
Joe Singh
(J)
David M Spector
(DM)
John Schallenkamp
(J)
Douglas E Merkel
(DE)
Shelly S Lo
(SS)
Pam G Khosla
(PG)
Massimo Cristofanilli
(M)
Lisa Flaum
(L)
Kent F Hoskins
(KF)
Melody A Cobleigh
(MA)
Elyse A Lambiase
(EA)
Olwen M Hahn
(OM)
Ira A Oliff
(IA)
Bryan A Faller
(BA)
James L Wade
(JL)
Nafisa D Burhani
(ND)
James L Wade
(JL)
Amaryllis Gil
(A)
Harvey E Einhorn
(HE)
Anna M V Storniolo
(AMV)
Brian K Chang
(BK)
Maitri Kalra
(M)
Erwin L Robin
(EL)
Bilal Ansari
(B)
Priyanka Sharma
(P)
Shaker R Dakhil
(SR)
Shaker R Dakhil
(SR)
Richard L Deming
(RL)
John T Cole
(JT)
John T Cole
(JT)
John T Cole
(JT)
David S Hanson
(DS)
Augusto C Ochoa
(AC)
John T Cole
(JT)
Augusto C Ochoa
(AC)
Judy E Garber
(JE)
Judy E Garber
(JE)
Harvey Zimbler
(H)
Deborah K Armstrong
(DK)
Katherine H R Tkaczuk
(KHR)
David A Riseberg
(DA)
Deborah K Armstrong
(DK)
Brian M O'Connor
(BM)
Thomas H Openshaw
(TH)
Thomas H Openshaw
(TH)
Thomas H Openshaw
(TH)
Dana Zakalik
(D)
Cynthia M Vakhariya
(CM)
Anne F Schott
(AF)
Michael S Simon
(MS)
Thomas J Doyle
(TJ)
Tareq Al Baghdadi
(T)
Amy VanderWoude
(A)
Patrick J Flynn
(PJ)
Richard T Zera
(RT)
Bret E B Friday
(BEB)
Kathryn J Ruddy
(KJ)
Richard T Zera
(RT)
Ron Smith
(R)
Patrick J Flynn
(PJ)
None Ademuyiwa
Foluso Olabisi
(F)
Robert Ellis
(R)
Jay W Carlson
(JW)
Jay W Carlson
(JW)
None Marchello
Benjamin T
(B)
Edward A Levine
(EA)
Paul K Marcom
(PK)
Cameron B Harkness
(CB)
Antoinette R Tan
(AR)
William J Charles
(WJ)
Charles S Kuzma
(CS)
Shonda Asaad
(S)
James E Radford
(JE)
Preston D Steen
(PD)
Madhu Unnikrishnan
(M)
Grant R Seeger
(GR)
Kirsten M H Leu
(KMH)
Mehmet S Copur
(MS)
Ralph J Hauke
(RJ)
Gamini S Soori
(GS)
Ralph J Hauke
(RJ)
Bradley A Arrick
(BA)
Jennifer G Reeder
(JG)
Deborah L Toppmeyer
(DL)
Zoneddy R Dayao
(ZR)
Sylvia Adams
(S)
Eleni Andreopoulou
(E)
Magnuson Allison
(M)
Jesus D Anampa Mesias
(JD)
Ruby Sharma
(R)
Bhuvaneswari Ramaswamy
(B)
Aaron T Gerds
(AT)
Robert R Shenk
(RR)
Howard M Gross
(HM)
Shruti Trehan
(S)
Howard M Gross
(HM)
Howard M Gross
(HM)
Howard M Gross
(HM)
Robert R Shenk
(RR)
Howard M Gross
(HM)
Robert R Shenk
(RR)
Wajeeha Razaq
(W)
Abdul H Mansoor
(AH)
Christie J Hilton
(CJ)
Adam M Brufsky
(AM)
Chanh Huynh
(C)
Nabila Chowdhury
(N)
Susan M Domchek
(SM)
Elin R Sigurdson
(ER)
Terrence P Cescon
(TP)
Marc A Rovito
(MA)
Albert S DeNittis
(AS)
Victor G Vogel
(VG)
Thomas B Julian
(TB)
L E Boyle
(LE)
Luis Baez-Diaz
(L)
Frank J Brescia
(FJ)
John E Doster
(JE)
Robert D Siegel
(RD)
Lucas Wong
(L)
Tejal Patel
(T)
Julie R Nangia
(JR)
Catherine A Jones
(CA)
George M Cannon
(GM)
George M Cannon
(GM)
Harry D Bear
(HD)
Hetal Vachhani
(H)
Mary Wilkinson
(M)
Marie E Wood
(ME)
Marie E Wood
(ME)
Fengting Yan
(F)
Xingwei Sui
(X)
Carol M van Haelst
(CM)
Jennifer M Specht
(JM)
Ying Zhuo
(Y)
Rubina Qamar
(R)
Matthew L Ryan
(ML)
Abigail Stockham
(A)
Shamsuddin Virani
(S)
Rubina Qamar
(R)
Arlene A Gayle
(AA)
Rubina Qamar
(R)
Rubina Qamar
(R)
Steven J Jubelirer
(SJ)
Sobha Kurian
(S)
Mohamad A Salkeni
(MA)
Niklas Loman
(N)
Barbro Linderholm
(B)
Gustav Silander
(G)
Anna-Lotta Hallbeck
(AL)
Anna von Wachenfeldt Väppling
(A)
Elsa Curtit
(E)
Catarina Cardoso
(C)
Sofia Braga
(S)
Miguel Abreu
(M)
Mafalda Casa-Nova
(M)
Mónica Nave
(M)
Eva María Ciruelos Gil
(EM)
Judith Balmaña Gelpi
(JB)
Adela Fernández Ortega
(AF)
Josep Gumà Padró
(JG)
Begoña Bermejo de Las Heras
(B)
María González Cao
(MG)
Juan Cueva Bañuelos
(JC)
Jesús Alarcon Company
(JA)
Gemma Viñas Villaró
(GV)
Laura García Estevez
(LG)
Jens Huober
(J)
Steffi Busch
(S)
Tanja Fehm
(T)
Antje Hahn
(A)
Andrea Grafe
(A)
Thomas Noesselt
(T)
Thomas Dewitz
(T)
Harald Wagner
(H)
Christina Bechtner
(C)
Michael Weigel
(M)
Hans-Christian Kolberg
(HC)
Thomas Decker
(T)
Jörg Thomalla
(J)
Tobias Hesse
(T)
Nadia Harbeck
(N)
Jan Schröder Jens-Uwe Blohmer
(JS)
Marc Wolf Sütterlin
(M)
Renske Altena
(R)
Chang-Fang Chiu
(CF)
Shin-Cheh Chen
(SC)
Ming-Feng Hou
(MF)
Yuan-Ching Chang
(YC)
Shang-Hung Chen
(SH)
Shou-Tung Chen
(ST)
Chiun-Sheng Huang
(CS)
Dah-Cherng Yeh
(DC)
Jyh-Cherng Yu
(JC)
Ling-Ming Tseng
(LM)
Wei-Pang Chung
(WP)
Audrey Mailliez
(A)
Thierry Petit
(T)
Suzette Delaloge
(S)
Christelle Lévy
(C)
Philippe Dalivoust
(P)
Jean-Marc Extra
(JM)
Marie-Ange Mouret-Reynier
(MA)
Anne-Claire Hardy-Bessard
(AC)
Hélène Simon
(H)
Tiffenn L'Haridon
(T)
Alice Mege
(A)
Sylvie Giacchetti
(S)
Camille Chakiba-Brugere
(C)
Alain Gratet
(A)
Virginie Pottier
(V)
Jean-Marc Ferrero
(JM)
Isabelle Tennevet
(I)
Christophe Perrin
(C)
Jean-Luc Canon
(JL)
Sofie Joris
(S)
Zhimin Shao
(Z)
Binghe Xu
(B)
ZeFei Jiang
(Z)
Qiang Sun
(Q)
Kunwei Shen
(K)
Da Pang
(D)
Jin Zhang
(J)
Shui Wang
(S)
Hongjian Yang
(H)
Ning Liao
(N)
Hong Zheng
(H)
Peifen Fu
(P)
Chuangui Song
(C)
Yongsheng Wang
(Y)
Zhimin Fan
(Z)
Cuizhi Geng
(C)
Olivier Tredan
(O)
László Landherr
(L)
Bella Kaufman
(B)
Rinat Yerushalmi
(R)
Beatrice Uziely
(B)
Pierfranco Conte
(P)
Claudio Zamagni
(C)
Giampaolo Bianchini
(G)
Michelino De Laurentiis
(M)
Carlo Tondini
(C)
Vittorio Gebbia
(V)
Mariangela Ciccarese
(M)
Tomasz Sarosiek
(T)
Jacek Mackiewicz
(J)
Anna Słowińska
(A)
Ewa Kalinka
(E)
Tomasz Huzarski
(T)
Seock-Ah Im
(SA)
Kyung Hae Jung
(KH)
Joo Hyuk Sohn
(JH)
Jee Hyun Kim
(JH)
Keun Seok Lee
(KS)
Yeon Hee Park
(YH)
Kyoung Eun Lee
(KE)
Yee Soo Chae
(YS)
Eun Kyung Cho
(EK)
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
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