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

OlympiA Clinical Trial Steering Committee and Investigators; C. E. Geyer; J. E. Garber; R. D. Gelber; G. Yothers; M. Taboada; L. Ross; P. Rastogi; K. Cui; A. Arahmani; G. Aktan; A. C. Armstrong; M. Arnedos; J. Balmaña; J. Bergh; J. Bliss; S. Delaloge; S. M. Domchek; A. Eisen; F. Elsafy; L. E. Fein; A. Fielding; J. M. Ford; S. Friedman; K. A. Gelmon; L. Gianni; M. Gnant; S. J. Hollingsworth; S. A. Im; A. Jager; Jóhannsson; S. R. Lakhani; W. Janni; B. Linderholm; T. W. Liu; N. Loman; L. Korde; S. Loibl; P. C. Lucas; F. Marmé; E. Martinez de Dueñas; R. McConnell; Kelly Anne Phillips; M. Piccart; G. Rossi; R. Schmutzler; E. Senkus; Z. Shao; P. Sharma; C. F. Singer; T. Španić; E. Stickeler; M. Toi; T. A. Traina; G. Viale; G. Zoppoli; Y. H. Park; R. Yerushalmi; H. Yang; D. Pang; K. H. Jung; A. Mailliez; Z. Fan; I. Tennevet; J. Zhang; T. Nagy; G. S. Sonke; Q. Sun; M. Parton; M. A. Colleoni; M. Schmidt; A. M. Brufsky; W. Razaq; B. Kaufman; D. Cameron; C. Campbell; A. N.J. Tutt; Paul Sevelda; Ferdinand Haslbauer; Monika Penzinger; Leopold Öhler; Christoph Tinchon; Richard Greil; Sonja Heibl; Rupert Bartsch; Viktor Wette; Christian F. Singer; Claudia Pasterk; Ruth Helfgott; Gunda Pristauz-Telsnigg; Herbert Stöger; Angsar Weltermann; Daniel Egle; Irene Thiel; David Fuchs; Holger Rumpold; Kathrin Strasser-Weippl; Beate Rautenberg; Volkmar Müller; Marcus Schmidt; Stefan Paepke; Mustafa Aydogdu; Christoph Thomssen; Joachim Rom; Christine Mau; Peter Fasching; Uwe Jochen Göhring; Thorsten Kühn; Stefanie Noeding; Sherko Kümmel; John Hackmann; Elmar Stickeler; Abhishek Joshi; Joanna Dewar; Michael Friedlander; Yoland Antill; Natasha Woodward; Ehtesham Abdi; Susan Tiley; Mathew George; David Boadle; Annabel Goodwin; Andre van der Westhuizen; George Kannourakis; Nicholas Murray; Nicole McCarthy; Judith Kroep; Maaike de Boer; Joan Heijns; Franciscus Erdkamp; Sandra Bakker; Gabe S. Sonke; Amer Sami; John Mackey; Catherine Prady; Andrea Eisen; Christine Desbiens; Erica Patocskai; Cristiano Ferrario; Louise Bordeleau; Haji Chalchal; Saroj Niraula; wolf ido wolf; François Duhoux; d'Hondt Randal d'Hondt; Sylvie Luce; Daphné t.Kint de Roodenbeke; Konstantinos Papadimitriou; Marleen Borms; Claire Quaghebeur; William Jacot; Etienne Brain; Laurence Venat-Bouvet; Alain Lortholary; Zbigniew Nowecki; Fátima Cardoso; Richard Hayward; Santiago Bella; Mauricio Fernández Lazzaro; Norma Pilnik; Luis E. Fein; Cesar Blajman; Guillermo Lerzo; Mirta Varela; Juan Jose Zarba; Diego Kaen; Maria Victoria Constanzo; Joke Tio; Wulf Siggelkow; Christian Jackisch; Eva Maria Grischke; Dirk Zahm; Sara Tato-Varela; Sabine Schmatloch; Peter Klare; Andrea Stefek; Kerstin Rhiem; Oliver Hoffmann; Mustafa Deryal; Isolde Gröll; Peter Ledwon; Christoph Uleer; Petra Krabisch; Jochem Potenberg; Maren Darsow; Tjoung Won Park-Simon; Heinz Gert Höffkes; Till Oliver Emde; Gerd Graffunder; Oliver Tomé; Dirk Forstmeyer; Jürgen Terhaag; Christoph Salat; Karin Kast; Steffi Weniger; Carsten Schreiber; Bernhard Heinrich; Max Dieterich; Michaela Penelope Wüllner; Raquel Andrés Conejero; Robert D. Siegel

doi:10.1016/j.annonc.2022.09.159

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

OlympiA Clinical Trial Steering Committee and Investigators, C. E. Geyer, J. E. Garber, R. D. Gelber, G. Yothers, M. Taboada, L. Ross, P. Rastogi, K. Cui, A. Arahmani, G. Aktan, A. C. Armstrong, M. Arnedos, J. Balmaña, J. Bergh, J. Bliss, S. Delaloge, S. M. Domchek, A. Eisen, F. ElsafyL. E. Fein, A. Fielding, J. M. Ford, S. Friedman, K. A. Gelmon, L. Gianni, M. Gnant, S. J. Hollingsworth, S. A. Im, A. Jager, Jóhannsson, S. R. Lakhani, W. Janni, B. Linderholm, T. W. Liu, N. Loman, L. Korde, S. Loibl, P. C. Lucas, F. Marmé, E. Martinez de Dueñas, R. McConnell, Kelly Anne Phillips, M. Piccart, G. Rossi, R. Schmutzler, E. Senkus, Z. Shao, P. Sharma, C. F. Singer, T. Španić, E. Stickeler, M. Toi, T. A. Traina, G. Viale, G. Zoppoli, Y. H. Park, R. Yerushalmi, H. Yang, D. Pang, K. H. Jung, A. Mailliez, Z. Fan, I. Tennevet, J. Zhang, T. Nagy, G. S. Sonke, Q. Sun, M. Parton, M. A. Colleoni, M. Schmidt, A. M. Brufsky, W. Razaq, B. Kaufman, D. Cameron, C. Campbell, A. N.J. Tutt, Paul Sevelda, Ferdinand Haslbauer, Monika Penzinger, Leopold Öhler, Christoph Tinchon, Richard Greil, Sonja Heibl, Rupert Bartsch, Viktor Wette, Christian F. Singer, Claudia Pasterk, Ruth Helfgott, Gunda Pristauz-Telsnigg, Herbert Stöger, Angsar Weltermann, Daniel Egle, Irene Thiel, David Fuchs, Holger Rumpold, Kathrin Strasser-Weippl, Beate Rautenberg, Volkmar Müller, Marcus Schmidt, Stefan Paepke, Mustafa Aydogdu, Christoph Thomssen, Joachim Rom, Christine Mau, Peter Fasching, Uwe Jochen Göhring, Thorsten Kühn, Stefanie Noeding, Sherko Kümmel, John Hackmann, Elmar Stickeler, Abhishek Joshi, Joanna Dewar, Michael Friedlander, Yoland Antill, Natasha Woodward, Ehtesham Abdi, Susan Tiley, Mathew George, David Boadle, Annabel Goodwin, Andre van der Westhuizen, George Kannourakis, Nicholas Murray, Nicole McCarthy, Judith Kroep, Maaike de Boer, Joan Heijns, Franciscus Erdkamp, Sandra Bakker, Gabe S. Sonke, Amer Sami, John Mackey, Catherine Prady, Andrea Eisen, Christine Desbiens, Erica Patocskai, Cristiano Ferrario, Louise Bordeleau, Haji Chalchal, Saroj Niraula, wolf ido wolf, François Duhoux, d'Hondt Randal d'Hondt, Sylvie Luce, Daphné t.Kint de Roodenbeke, Konstantinos Papadimitriou, Marleen Borms, Claire Quaghebeur, William Jacot, Etienne Brain, Laurence Venat-Bouvet, Alain Lortholary, Zbigniew Nowecki, Fátima Cardoso, Richard Hayward, Santiago Bella, Mauricio Fernández Lazzaro, Norma Pilnik, Luis E. Fein, Cesar Blajman, Guillermo Lerzo, Mirta Varela, Juan Jose Zarba, Diego Kaen, Maria Victoria Constanzo, Joke Tio, Wulf Siggelkow, Christian Jackisch, Eva Maria Grischke, Dirk Zahm, Sara Tato-Varela, Sabine Schmatloch, Peter Klare, Andrea Stefek, Kerstin Rhiem, Oliver Hoffmann, Mustafa Deryal, Isolde Gröll, Peter Ledwon, Christoph Uleer, Petra Krabisch, Jochem Potenberg, Maren Darsow, Tjoung Won Park-Simon, Heinz Gert Höffkes, Till Oliver Emde, Gerd Graffunder, Oliver Tomé, Dirk Forstmeyer, Jürgen Terhaag, Christoph Salat, Karin Kast, Steffi Weniger, Carsten Schreiber, Bernhard Heinrich, Max Dieterich, Michaela Penelope Wüllner, Raquel Andrés Conejero, Robert D. Siegel

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

283 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1250-1268
Number of pages	19
Journal	Annals of Oncology
Volume	33
Issue number	12
DOIs	https://doi.org/10.1016/j.annonc.2022.09.159
State	Published - Dec 1 2022

Keywords

BRCA1/2
PARP inhibition
adjuvant therapy
breast cancer
olaparib

Access to Document

10.1016/j.annonc.2022.09.159

Cite this

OlympiA Clinical Trial Steering Committee and Investigators, Geyer, C. E., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmaña, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., ... Siegel, R. D. (2022). 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. Annals of Oncology, 33(12), 1250-1268. https://doi.org/10.1016/j.annonc.2022.09.159

@article{d2f82fc13fd845c69e877e5d3b225274,

title = "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",

abstract = "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.",

keywords = "BRCA1/2, PARP inhibition, adjuvant therapy, breast cancer, olaparib",

author = "{OlympiA Clinical Trial Steering Committee and Investigators} and Geyer, {C. E.} and Garber, {J. E.} and Gelber, {R. D.} and G. Yothers and M. Taboada and L. Ross and P. Rastogi and K. Cui and A. Arahmani and G. Aktan and Armstrong, {A. C.} and M. Arnedos and J. Balma{\~n}a and J. Bergh and J. Bliss and S. Delaloge and Domchek, {S. M.} and A. Eisen and F. Elsafy and Fein, {L. E.} and A. Fielding and Ford, {J. M.} and S. Friedman and Gelmon, {K. A.} and L. Gianni and M. Gnant and Hollingsworth, {S. J.} and Im, {S. A.} and A. Jager and J{\'o}hannsson and Lakhani, {S. R.} and W. Janni and B. Linderholm and Liu, {T. W.} and N. Loman and L. Korde and S. Loibl and Lucas, {P. C.} and F. Marm{\'e} and {Martinez de Due{\~n}as}, E. and R. McConnell and Phillips, {Kelly Anne} and M. Piccart and G. Rossi and R. Schmutzler and E. Senkus and Z. Shao and P. Sharma and Singer, {C. F.} and T. {\v S}pani{\'c} and E. Stickeler and M. Toi and Traina, {T. A.} and G. Viale and G. Zoppoli and Park, {Y. H.} and R. Yerushalmi and H. Yang and D. Pang and Jung, {K. H.} and A. Mailliez and Z. Fan and I. Tennevet and J. Zhang and T. Nagy and Sonke, {G. S.} and Q. Sun and M. Parton and Colleoni, {M. A.} and M. Schmidt and Brufsky, {A. M.} and W. Razaq and B. Kaufman and D. Cameron and C. Campbell and Tutt, {A. N.J.} and Paul Sevelda and Ferdinand Haslbauer and Monika Penzinger and Leopold {\"O}hler and Christoph Tinchon and Richard Greil and Sonja Heibl and Rupert Bartsch and Viktor Wette and Singer, {Christian F.} and Claudia Pasterk and Ruth Helfgott and Gunda Pristauz-Telsnigg and Herbert St{\"o}ger and Angsar Weltermann and Daniel Egle and Irene Thiel and David Fuchs and Holger Rumpold and Kathrin Strasser-Weippl and Beate Rautenberg and Volkmar M{\"u}ller and Marcus Schmidt and Stefan Paepke and Mustafa Aydogdu and Christoph Thomssen and Joachim Rom and Christine Mau and Peter Fasching and G{\"o}hring, {Uwe Jochen} and Thorsten K{\"u}hn and Stefanie Noeding and Sherko K{\"u}mmel and John Hackmann and Elmar Stickeler and Abhishek Joshi and Joanna Dewar and Michael Friedlander and Yoland Antill and Natasha Woodward and Ehtesham Abdi and Susan Tiley and Mathew George and David Boadle and Annabel Goodwin and {van der Westhuizen}, Andre and George Kannourakis and Nicholas Murray and Nicole McCarthy and Judith Kroep and {de Boer}, Maaike and Joan Heijns and Franciscus Erdkamp and Sandra Bakker and Sonke, {Gabe S.} and Amer Sami and John Mackey and Catherine Prady and Andrea Eisen and Christine Desbiens and Erica Patocskai and Cristiano Ferrario and Louise Bordeleau and Haji Chalchal and Saroj Niraula and {ido wolf}, wolf and Fran{\c c}ois Duhoux and {Randal d'Hondt}, d'Hondt and Sylvie Luce and Roodenbeke, {Daphn{\'e} t.Kint de} and Konstantinos Papadimitriou and Marleen Borms and Claire Quaghebeur and William Jacot and Etienne Brain and Laurence Venat-Bouvet and Alain Lortholary and Zbigniew Nowecki and F{\'a}tima Cardoso and Richard Hayward and Santiago Bella and Lazzaro, {Mauricio Fern{\'a}ndez} and Norma Pilnik and Fein, {Luis E.} and Cesar Blajman and Guillermo Lerzo and Mirta Varela and Zarba, {Juan Jose} and Diego Kaen and Constanzo, {Maria Victoria} and Joke Tio and Wulf Siggelkow and Christian Jackisch and Grischke, {Eva Maria} and Dirk Zahm and Sara Tato-Varela and Sabine Schmatloch and Peter Klare and Andrea Stefek and Kerstin Rhiem and Oliver Hoffmann and Mustafa Deryal and Isolde Gr{\"o}ll and Peter Ledwon and Christoph Uleer and Petra Krabisch and Jochem Potenberg and Maren Darsow and Park-Simon, {Tjoung Won} and H{\"o}ffkes, {Heinz Gert} and Emde, {Till Oliver} and Gerd Graffunder and Oliver Tom{\'e} and Dirk Forstmeyer and J{\"u}rgen Terhaag and Christoph Salat and Karin Kast and Steffi Weniger and Carsten Schreiber and Bernhard Heinrich and Max Dieterich and W{\"u}llner, {Michaela Penelope} and Conejero, {Raquel Andr{\'e}s} and Siegel, {Robert D.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = dec,

day = "1",

doi = "10.1016/j.annonc.2022.09.159",

language = "English",

volume = "33",

pages = "1250--1268",

journal = "Annals of Oncology",

issn = "0923-7534",

number = "12",

}

OlympiA Clinical Trial Steering Committee and Investigators, Geyer, CE, Garber, JE, Gelber, RD, Yothers, G, Taboada, M, Ross, L, Rastogi, P, Cui, K, Arahmani, A, Aktan, G, Armstrong, AC, Arnedos, M, Balmaña, J, Bergh, J, Bliss, J, Delaloge, S, Domchek, SM, Eisen, A, Elsafy, F, Fein, LE, Fielding, A, Ford, JM, Friedman, S, Gelmon, KA, Gianni, L, Gnant, M, Hollingsworth, SJ, Im, SA, Jager, A, Jóhannsson, Lakhani, SR, Janni, W, Linderholm, B, Liu, TW, Loman, N, Korde, L, Loibl, S, Lucas, PC, Marmé, F, Martinez de Dueñas, E, McConnell, R, Phillips, KA, Piccart, M, Rossi, G, Schmutzler, R, Senkus, E, Shao, Z, Sharma, P, Singer, CF, Španić, T, Stickeler, E, Toi, M, Traina, TA, Viale, G, Zoppoli, G, Park, YH, Yerushalmi, R, Yang, H, Pang, D, Jung, KH, Mailliez, A, Fan, Z, Tennevet, I, Zhang, J, Nagy, T, Sonke, GS, Sun, Q, Parton, M, Colleoni, MA, Schmidt, M, Brufsky, AM, Razaq, W, Kaufman, B, Cameron, D, Campbell, C, Tutt, ANJ, Sevelda, P, Haslbauer, F, Penzinger, M, Öhler, L, Tinchon, C, Greil, R, Heibl, S, Bartsch, R, Wette, V, Singer, CF, Pasterk, C, Helfgott, R, Pristauz-Telsnigg, G, Stöger, H, Weltermann, A, Egle, D, Thiel, I, Fuchs, D, Rumpold, H, Strasser-Weippl, K, Rautenberg, B, Müller, V, Schmidt, M, Paepke, S, Aydogdu, M, Thomssen, C, Rom, J, Mau, C, Fasching, P, Göhring, UJ, Kühn, T, Noeding, S, Kümmel, S, Hackmann, J, Stickeler, E, Joshi, A, Dewar, J, Friedlander, M, Antill, Y, Woodward, N, Abdi, E, Tiley, S, George, M, Boadle, D, Goodwin, A, van der Westhuizen, A, Kannourakis, G, Murray, N, McCarthy, N, Kroep, J, de Boer, M, Heijns, J, Erdkamp, F, Bakker, S, Sonke, GS, Sami, A, Mackey, J, Prady, C, Eisen, A, Desbiens, C, Patocskai, E, Ferrario, C, Bordeleau, L, Chalchal, H, Niraula, S, ido wolf, W, Duhoux, F, Randal d'Hondt, DH, Luce, S, Roodenbeke, DTKD, Papadimitriou, K, Borms, M, Quaghebeur, C, Jacot, W, Brain, E, Venat-Bouvet, L, Lortholary, A, Nowecki, Z, Cardoso, F, Hayward, R, Bella, S, Lazzaro, MF, Pilnik, N, Fein, LE, Blajman, C, Lerzo, G, Varela, M, Zarba, JJ, Kaen, D, Constanzo, MV, Tio, J, Siggelkow, W, Jackisch, C, Grischke, EM, Zahm, D, Tato-Varela, S, Schmatloch, S, Klare, P, Stefek, A, Rhiem, K, Hoffmann, O, Deryal, M, Gröll, I, Ledwon, P, Uleer, C, Krabisch, P, Potenberg, J, Darsow, M, Park-Simon, TW, Höffkes, HG, Emde, TO, Graffunder, G, Tomé, O, Forstmeyer, D, Terhaag, J, Salat, C, Kast, K, Weniger, S, Schreiber, C, Heinrich, B, Dieterich, M, Wüllner, MP, Conejero, RA & Siegel, RD 2022, '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', Annals of Oncology, vol. 33, no. 12, pp. 1250-1268. https://doi.org/10.1016/j.annonc.2022.09.159

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. / OlympiA Clinical Trial Steering Committee and Investigators; Geyer, C. E.; Garber, J. E. et al.
In: Annals of Oncology, Vol. 33, No. 12, 01.12.2022, p. 1250-1268.

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

TY - JOUR

T1 - 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

AU - OlympiA Clinical Trial Steering Committee and Investigators

AU - Geyer, C. E.

AU - Garber, J. E.

AU - Gelber, R. D.

AU - Yothers, G.

AU - Taboada, M.

AU - Ross, L.

AU - Rastogi, P.

AU - Cui, K.

AU - Arahmani, A.

AU - Aktan, G.

AU - Armstrong, A. C.

AU - Arnedos, M.

AU - Balmaña, J.

AU - Bergh, J.

AU - Bliss, J.

AU - Delaloge, S.

AU - Domchek, S. M.

AU - Eisen, A.

AU - Elsafy, F.

AU - Fein, L. E.

AU - Fielding, A.

AU - Ford, J. M.

AU - Friedman, S.

AU - Gelmon, K. A.

AU - Gianni, L.

AU - Gnant, M.

AU - Hollingsworth, S. J.

AU - Im, S. A.

AU - Jager, A.

AU - Jóhannsson,

AU - Lakhani, S. R.

AU - Janni, W.

AU - Linderholm, B.

AU - Liu, T. W.

AU - Loman, N.

AU - Korde, L.

AU - Loibl, S.

AU - Lucas, P. C.

AU - Marmé, F.

AU - Martinez de Dueñas, E.

AU - McConnell, R.

AU - Phillips, Kelly Anne

AU - Piccart, M.

AU - Rossi, G.

AU - Schmutzler, R.

AU - Senkus, E.

AU - Shao, Z.

AU - Sharma, P.

AU - Singer, C. F.

AU - Španić, T.

AU - Stickeler, E.

AU - Toi, M.

AU - Traina, T. A.

AU - Viale, G.

AU - Zoppoli, G.

AU - Park, Y. H.

AU - Yerushalmi, R.

AU - Yang, H.

AU - Pang, D.

AU - Jung, K. H.

AU - Mailliez, A.

AU - Fan, Z.

AU - Tennevet, I.

AU - Zhang, J.

AU - Nagy, T.

AU - Sonke, G. S.

AU - Sun, Q.

AU - Parton, M.

AU - Colleoni, M. A.

AU - Schmidt, M.

AU - Brufsky, A. M.

AU - Razaq, W.

AU - Kaufman, B.

AU - Cameron, D.

AU - Campbell, C.

AU - Tutt, A. N.J.

AU - Sevelda, Paul

AU - Haslbauer, Ferdinand

AU - Penzinger, Monika

AU - Öhler, Leopold

AU - Tinchon, Christoph

AU - Greil, Richard

AU - Heibl, Sonja

AU - Bartsch, Rupert

AU - Wette, Viktor

AU - Singer, Christian F.

AU - Pasterk, Claudia

AU - Helfgott, Ruth

AU - Pristauz-Telsnigg, Gunda

AU - Stöger, Herbert

AU - Weltermann, Angsar

AU - Egle, Daniel

AU - Thiel, Irene

AU - Fuchs, David

AU - Rumpold, Holger

AU - Strasser-Weippl, Kathrin

AU - Rautenberg, Beate

AU - Müller, Volkmar

AU - Schmidt, Marcus

AU - Paepke, Stefan

AU - Aydogdu, Mustafa

AU - Thomssen, Christoph

AU - Rom, Joachim

AU - Mau, Christine

AU - Fasching, Peter

AU - Göhring, Uwe Jochen

AU - Kühn, Thorsten

AU - Noeding, Stefanie

AU - Kümmel, Sherko

AU - Hackmann, John

AU - Stickeler, Elmar

AU - Joshi, Abhishek

AU - Dewar, Joanna

AU - Friedlander, Michael

AU - Antill, Yoland

AU - Woodward, Natasha

AU - Abdi, Ehtesham

AU - Tiley, Susan

AU - George, Mathew

AU - Boadle, David

AU - Goodwin, Annabel

AU - van der Westhuizen, Andre

AU - Kannourakis, George

AU - Murray, Nicholas

AU - McCarthy, Nicole

AU - Kroep, Judith

AU - de Boer, Maaike

AU - Heijns, Joan

AU - Erdkamp, Franciscus

AU - Bakker, Sandra

AU - Sonke, Gabe S.

AU - Sami, Amer

AU - Mackey, John

AU - Prady, Catherine

AU - Eisen, Andrea

AU - Desbiens, Christine

AU - Patocskai, Erica

AU - Ferrario, Cristiano

AU - Bordeleau, Louise

AU - Chalchal, Haji

AU - Niraula, Saroj

AU - ido wolf, wolf

AU - Duhoux, François

AU - Randal d'Hondt, d'Hondt

AU - Luce, Sylvie

AU - Roodenbeke, Daphné t.Kint de

AU - Papadimitriou, Konstantinos

AU - Borms, Marleen

AU - Quaghebeur, Claire

AU - Jacot, William

AU - Brain, Etienne

AU - Venat-Bouvet, Laurence

AU - Lortholary, Alain

AU - Nowecki, Zbigniew

AU - Cardoso, Fátima

AU - Hayward, Richard

AU - Bella, Santiago

AU - Lazzaro, Mauricio Fernández

AU - Pilnik, Norma

AU - Fein, Luis E.

AU - Blajman, Cesar

AU - Lerzo, Guillermo

AU - Varela, Mirta

AU - Zarba, Juan Jose

AU - Kaen, Diego

AU - Constanzo, Maria Victoria

AU - Tio, Joke

AU - Siggelkow, Wulf

AU - Jackisch, Christian

AU - Grischke, Eva Maria

AU - Zahm, Dirk

AU - Tato-Varela, Sara

AU - Schmatloch, Sabine

AU - Klare, Peter

AU - Stefek, Andrea

AU - Rhiem, Kerstin

AU - Hoffmann, Oliver

AU - Deryal, Mustafa

AU - Gröll, Isolde

AU - Ledwon, Peter

AU - Uleer, Christoph

AU - Krabisch, Petra

AU - Potenberg, Jochem

AU - Darsow, Maren

AU - Park-Simon, Tjoung Won

AU - Höffkes, Heinz Gert

AU - Emde, Till Oliver

AU - Graffunder, Gerd

AU - Tomé, Oliver

AU - Forstmeyer, Dirk

AU - Terhaag, Jürgen

AU - Salat, Christoph

AU - Kast, Karin

AU - Weniger, Steffi

AU - Schreiber, Carsten

AU - Heinrich, Bernhard

AU - Dieterich, Max

AU - Wüllner, Michaela Penelope

AU - Conejero, Raquel Andrés

AU - Siegel, Robert D.

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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.

AB - 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.

KW - BRCA1/2

KW - PARP inhibition

KW - adjuvant therapy

KW - breast cancer

KW - olaparib

UR - http://www.scopus.com/inward/record.url?scp=85141805158&partnerID=8YFLogxK

U2 - 10.1016/j.annonc.2022.09.159

DO - 10.1016/j.annonc.2022.09.159

M3 - Article

C2 - 36228963

AN - SCOPUS:85141805158

SN - 0923-7534

VL - 33

SP - 1250

EP - 1268

JO - Annals of Oncology

JF - Annals of Oncology

IS - 12

ER -

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

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