Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer

I.D. Davis, A.J. Martin, M.R. Stockler, S. Begbie, K.N. Chi, S. Chowdhury, X. Coskinas, M. Frydenberg, W.E. Hague, L.G. Horvath, A.M. Joshua, N.J. Lawrence, G. Marx, J. McCaffrey, R. McDermott, M. McJannett, S.A. North, F. Parnis, W. Parulekar, D.W. Pook & 13 others M.N. Reaume, S.K. Sandhu, A. Tan, T.H. Tan, A. Thomson, E. Tu, F. Vera-Badillo, S.G. Williams, S. Yip, A.Y. Zhang, R.R. Zielinski, C.J. Sweeney, for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P=0.002). Kaplan–Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.)
Original languageEnglish
Number of pages11
JournalNew England Journal of Medicine
DOIs
Publication statusAccepted/In press - 2 Jun 2019

Cite this

Davis, I. D., Martin, A. J., Stockler, M. R., Begbie, S., Chi, K. N., Chowdhury, S., ... for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (Accepted/In press). Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1903835
Davis, I.D. ; Martin, A.J. ; Stockler, M.R. ; Begbie, S. ; Chi, K.N. ; Chowdhury, S. ; Coskinas, X. ; Frydenberg, M. ; Hague, W.E. ; Horvath, L.G. ; Joshua, A.M. ; Lawrence, N.J. ; Marx, G. ; McCaffrey, J. ; McDermott, R. ; McJannett, M. ; North, S.A. ; Parnis, F. ; Parulekar, W. ; Pook, D.W. ; Reaume, M.N. ; Sandhu, S.K. ; Tan, A. ; Tan, T.H. ; Thomson, A. ; Tu, E. ; Vera-Badillo, F. ; Williams, S.G. ; Yip, S. ; Zhang, A.Y. ; Zielinski, R.R. ; Sweeney, C.J. ; for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. / Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. In: New England Journal of Medicine. 2019.
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title = "Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer",
abstract = "BACKGROUND Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95{\%} confidence interval [CI], 0.52 to 0.86; P=0.002). Kaplan–Meier estimates of overall survival at 3 years were 80{\%} (based on 94 events) in the enzalutamide group and 72{\%} (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1{\%}) and in no patients in the standard-care group. CONCLUSIONS Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.)",
author = "I.D. Davis and A.J. Martin and M.R. Stockler and S. Begbie and K.N. Chi and S. Chowdhury and X. Coskinas and M. Frydenberg and W.E. Hague and L.G. Horvath and A.M. Joshua and N.J. Lawrence and G. Marx and J. McCaffrey and R. McDermott and M. McJannett and S.A. North and F. Parnis and W. Parulekar and D.W. Pook and M.N. Reaume and S.K. Sandhu and A. Tan and T.H. Tan and A. Thomson and E. Tu and F. Vera-Badillo and S.G. Williams and S. Yip and A.Y. Zhang and R.R. Zielinski and C.J. Sweeney and {for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group}",
note = "doi: 10.1056/NEJMoa1903835",
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doi = "10.1056/NEJMoa1903835",
language = "English",
journal = "New England Journal of Medicine",
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Davis, ID, Martin, AJ, Stockler, MR, Begbie, S, Chi, KN, Chowdhury, S, Coskinas, X, Frydenberg, M, Hague, WE, Horvath, LG, Joshua, AM, Lawrence, NJ, Marx, G, McCaffrey, J, McDermott, R, McJannett, M, North, SA, Parnis, F, Parulekar, W, Pook, DW, Reaume, MN, Sandhu, SK, Tan, A, Tan, TH, Thomson, A, Tu, E, Vera-Badillo, F, Williams, SG, Yip, S, Zhang, AY, Zielinski, RR, Sweeney, CJ & for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group 2019, 'Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer' New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1903835

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. / Davis, I.D.; Martin, A.J.; Stockler, M.R.; Begbie, S.; Chi, K.N.; Chowdhury, S.; Coskinas, X.; Frydenberg, M.; Hague, W.E.; Horvath, L.G.; Joshua, A.M.; Lawrence, N.J.; Marx, G.; McCaffrey, J.; McDermott, R.; McJannett, M.; North, S.A.; Parnis, F.; Parulekar, W.; Pook, D.W.; Reaume, M.N.; Sandhu, S.K.; Tan, A.; Tan, T.H.; Thomson, A.; Tu, E.; Vera-Badillo, F.; Williams, S.G.; Yip, S.; Zhang, A.Y.; Zielinski, R.R.; Sweeney, C.J.; for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group.

In: New England Journal of Medicine, 02.06.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer

AU - Davis, I.D.

AU - Martin, A.J.

AU - Stockler, M.R.

AU - Begbie, S.

AU - Chi, K.N.

AU - Chowdhury, S.

AU - Coskinas, X.

AU - Frydenberg, M.

AU - Hague, W.E.

AU - Horvath, L.G.

AU - Joshua, A.M.

AU - Lawrence, N.J.

AU - Marx, G.

AU - McCaffrey, J.

AU - McDermott, R.

AU - McJannett, M.

AU - North, S.A.

AU - Parnis, F.

AU - Parulekar, W.

AU - Pook, D.W.

AU - Reaume, M.N.

AU - Sandhu, S.K.

AU - Tan, A.

AU - Tan, T.H.

AU - Thomson, A.

AU - Tu, E.

AU - Vera-Badillo, F.

AU - Williams, S.G.

AU - Yip, S.

AU - Zhang, A.Y.

AU - Zielinski, R.R.

AU - Sweeney, C.J.

AU - for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

N1 - doi: 10.1056/NEJMoa1903835

PY - 2019/6/2

Y1 - 2019/6/2

N2 - BACKGROUND Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P=0.002). Kaplan–Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.)

AB - BACKGROUND Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P=0.002). Kaplan–Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.)

U2 - 10.1056/NEJMoa1903835

DO - 10.1056/NEJMoa1903835

M3 - Article

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

ER -