Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer

Matthew R Smith; Fred Saad; Simon Chowdhury; Stéphane Oudard; Boris A Hadaschik; Julie N 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; SPARTAN Investigators; Paul Mainwaring; Lisa Horvath; Louise Nott; Klaus Brasso; Niels Harving; Anders Holm-Nielsen; Mads Poulsen; Russell Pachynski; Chiledum Ahaghotu; Margaret Kemeny

doi:10.1056/nejmoa1715546

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer

Matthew R Smith, Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A Hadaschik, Julie N 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, SPARTAN Investigators, Paul MainwaringLisa Horvath, Louise Nott, Klaus Brasso, Niels Harving, Anders Holm-Nielsen, Mads Poulsen, Russell Pachynski, Chiledum Ahaghotu, Margaret Kemeny

Institut for Klinisk Medicin

499 Citationer (Scopus)

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.)

Originalsprog	Engelsk
Tidsskrift	The New England Journal of Medicine
Vol/bind	378
Udgave nummer	15
Sider (fra-til)	1408-1418
ISSN	0028-4793
DOI	https://doi.org/10.1056/nejmoa1715546
Status	Udgivet - 12 apr. 2018

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Smith, M. R., Saad, F., Chowdhury, S., Oudard, S., Hadaschik, B. A., Graff, J. N., Olmos, D., Mainwaring, P. N., Lee, J. Y., Uemura, H., Lopez-Gitlitz, A., Trudel, G. C., Espina, B. M., Shu, Y., Park, Y. C., Rackoff, W. R., Yu, M. K., Small, E. J., SPARTAN Investigators, ... Kemeny, M. (2018). Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. The New England Journal of Medicine, 378(15), 1408-1418. https://doi.org/10.1056/nejmoa1715546

Smith, MR, Saad, F, Chowdhury, S, Oudard, S, Hadaschik, BA, Graff, JN, 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, SPARTAN Investigators, Mainwaring, P, Horvath, L, Nott, L, Brasso, K, Harving, N, Holm-Nielsen, A, Poulsen, M, Pachynski, R, Ahaghotu, C & Kemeny, M 2018, 'Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer', The New England Journal of Medicine, bind 378, nr. 15, s. 1408-1418. https://doi.org/10.1056/nejmoa1715546

@article{0ee7071ded4f420a9488f6cda3ed1c97,

title = "Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer",

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.)",

keywords = "Adenocarcinoma/drug therapy, Aged, Aged, 80 and over, Androgen Antagonists/adverse effects, Disease Progression, Disease-Free Survival, Double-Blind Method, Exanthema/chemically induced, Humans, Male, Middle Aged, Neoplasm Metastasis/prevention & control, Proportional Hazards Models, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant/drug therapy, Thiohydantoins/adverse effects",

author = "Smith, {Matthew R} and Fred Saad and Simon Chowdhury and St{\'e}phane Oudard and Hadaschik, {Boris A} and Graff, {Julie N} and David Olmos and Mainwaring, {Paul N} and Lee, {Ji Youl} and Hiroji Uemura and Angela Lopez-Gitlitz and Trudel, {G{\'e}ralyn C} and Espina, {Byron M} and Youyi Shu and Park, {Youn C} and Rackoff, {Wayne R} and Yu, {Margaret K} and Small, {Eric J} and {SPARTAN Investigators} and Paul Mainwaring and Lisa Horvath and Louise Nott and Klaus Brasso and Niels Harving and Anders Holm-Nielsen and Mads Poulsen and Russell Pachynski and Chiledum Ahaghotu and Margaret Kemeny",

year = "2018",

month = apr,

day = "12",

doi = "10.1056/nejmoa1715546",

language = "English",

volume = "378",

pages = "1408--1418",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "15",

}

TY - JOUR

T1 - Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer

AU - Smith, Matthew R

AU - Saad, Fred

AU - Chowdhury, Simon

AU - Oudard, Stéphane

AU - Hadaschik, Boris A

AU - Graff, Julie N

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

AU - SPARTAN Investigators

AU - Mainwaring, Paul

AU - Horvath, Lisa

AU - Nott, Louise

AU - Brasso, Klaus

AU - Harving, Niels

AU - Holm-Nielsen, Anders

AU - Poulsen, Mads

AU - Pachynski, Russell

AU - Ahaghotu, Chiledum

AU - Kemeny, Margaret

PY - 2018/4/12

Y1 - 2018/4/12

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.)

KW - Adenocarcinoma/drug therapy

KW - Aged

KW - Aged, 80 and over

KW - Androgen Antagonists/adverse effects

KW - Disease Progression

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Exanthema/chemically induced

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasm Metastasis/prevention & control

KW - Proportional Hazards Models

KW - Prostate-Specific Antigen

KW - Prostatic Neoplasms, Castration-Resistant/drug therapy

KW - Thiohydantoins/adverse effects

U2 - 10.1056/nejmoa1715546

DO - 10.1056/nejmoa1715546

M3 - Journal article

C2 - 29420164

SN - 0028-4793

VL - 378

SP - 1408

EP - 1418

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 15

ER -

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer

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