Apalutamide treatment and metastasis-free survival in prostate cancer

Matthew R. Smith, Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A. Hadaschik, Julie Graff, David Olmos, Paul N. Mainwaring, Ji Youl Lee, Hiroji Uemura, Angela Lopez-Gitlitz, Géralyn C. Trudel, Byron M. Espina, Youyi Shu, Youn C. Park, Wayne R. Rackoff, Margaret K. Yu, Eric J. Small

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Abstract

BACKGROUND Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204.)

Original languageEnglish (US)
Pages (from-to)1408-1418
Number of pages11
JournalNew England Journal of Medicine
Volume378
Issue number15
DOIs
StatePublished - Apr 12 2018

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Prostatic Neoplasms
Placebos
Neoplasm Metastasis
Survival
Castration
Therapeutics
Random Allocation
Confidence Intervals
Androgen Receptors
Prostate-Specific Antigen
Hypothyroidism
Exanthema
Androgens
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Smith, M. R., Saad, F., Chowdhury, S., Oudard, S., Hadaschik, B. A., Graff, J., ... Small, E. J. (2018). Apalutamide treatment and metastasis-free survival in prostate cancer. New England Journal of Medicine, 378(15), 1408-1418. https://doi.org/10.1056/NEJMoa1715546

Apalutamide treatment and metastasis-free survival in prostate cancer. / Smith, Matthew R.; Saad, Fred; Chowdhury, Simon; Oudard, Stéphane; Hadaschik, Boris A.; Graff, Julie; Olmos, David; Mainwaring, Paul N.; Lee, Ji Youl; Uemura, Hiroji; Lopez-Gitlitz, Angela; Trudel, Géralyn C.; Espina, Byron M.; Shu, Youyi; Park, Youn C.; Rackoff, Wayne R.; Yu, Margaret K.; Small, Eric J.

In: New England Journal of Medicine, Vol. 378, No. 15, 12.04.2018, p. 1408-1418.

Research output: Contribution to journalArticle

Smith, MR, Saad, F, Chowdhury, S, Oudard, S, Hadaschik, BA, Graff, J, Olmos, D, Mainwaring, PN, Lee, JY, Uemura, H, Lopez-Gitlitz, A, Trudel, GC, Espina, BM, Shu, Y, Park, YC, Rackoff, WR, Yu, MK & Small, EJ 2018, 'Apalutamide treatment and metastasis-free survival in prostate cancer', New England Journal of Medicine, vol. 378, no. 15, pp. 1408-1418. https://doi.org/10.1056/NEJMoa1715546
Smith, Matthew R. ; Saad, Fred ; Chowdhury, Simon ; Oudard, Stéphane ; Hadaschik, Boris A. ; Graff, Julie ; Olmos, David ; Mainwaring, Paul N. ; Lee, Ji Youl ; Uemura, Hiroji ; Lopez-Gitlitz, Angela ; Trudel, Géralyn C. ; Espina, Byron M. ; Shu, Youyi ; Park, Youn C. ; Rackoff, Wayne R. ; Yu, Margaret K. ; Small, Eric J. / Apalutamide treatment and metastasis-free survival in prostate cancer. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 15. pp. 1408-1418.
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abstract = "BACKGROUND Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95{\%} confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95{\%} CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6{\%} in the apalutamide group and 7.0{\%} in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8{\%} vs. 5.5{\%}), hypothyroidism (8.1{\%} vs. 2.0{\%}), and fracture (11.7{\%} vs. 6.5{\%}). CONCLUSIONS Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204.)",
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AU - Smith, Matthew R.

AU - Saad, Fred

AU - Chowdhury, Simon

AU - Oudard, Stéphane

AU - Hadaschik, Boris A.

AU - Graff, Julie

AU - Olmos, David

AU - Mainwaring, Paul N.

AU - Lee, Ji Youl

AU - Uemura, Hiroji

AU - Lopez-Gitlitz, Angela

AU - Trudel, Géralyn C.

AU - Espina, Byron M.

AU - Shu, Youyi

AU - Park, Youn C.

AU - Rackoff, Wayne R.

AU - Yu, Margaret K.

AU - Small, Eric J.

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N2 - BACKGROUND Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204.)

AB - BACKGROUND Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204.)

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