ARCHES: A Randomized, Phase III Study of

original reports
Androgen Deprivation Therapy With
Enzalutamide or Placebo in Men With Metastatic
Hormone-Sensitive Prostate Cancer
Andrew J. Armstrong, MD, ScM1; Russell Z. Szmulewitz, MD2; Daniel P. Petrylak, MD3; Jeffrey Holzbeierlein, MD4; Arnauld Villers, MD5;
Arun Azad, MBBS, PhD6; Antonio Alcaraz, MD, PhD7; Boris Alekseev, MD8; Taro Iguchi, MD, PhD9; Neal D. Shore, MD10;
Brad Rosbrook, MS11; Jennifer Sugg, MS12; Benoit Baron, MS13; Lucy Chen, MD12; and Arnulf Stenzl, MD14
abstract

PURPOSE Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in met-
astatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of
enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).
METHODS ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial,
wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus
androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The
primary end point was radiographic progression-free survival.
RESULTS As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with
enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P , .001; median
not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were
reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide
plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic
therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men
achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus
ADT (P , .001). Patients in both treatment groups reported a high baseline level of quality of life, which was
maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received
enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse
ASSOCIATED events.
CONTENT
CONCLUSION Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time
See accompanying
Editorial on versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel,
page 2957 with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in
See accompanying castration-resistant prostate cancer.
article on page 2961
J Clin Oncol 37:2974-2986. © 2019 by American Society of Clinical Oncology
Appendix
Creative Commons Attribution Non-Commercial No Derivatives 4.0 License
Data Supplement
Protocol
Author affiliations
INTRODUCTION hormone therapy, accounts for up to 5% of annual
and support prostate cancer incidence in the United States.4 An-
information (if
Globally, prostate cancer was the most common drogen deprivation therapy (ADT) with a luteinizing
applicable) appear cancer for men, with 1.4 million patients in 2016; hormone-releasing hormone agonist/receptor antag-
at the end of this mortality was 381,000.1 In the United States, 174,650 onist or bilateral orchiectomy has been the standard of
article. new cases of prostate cancer are expected in 2019, care (SOC) for men with mHSPC.5 However, the
Accepted on June 6, with 31,620 anticipated deaths.2 The majority of
2019 and published at
majority of men with mHSPC who receive ADT alone
jco.org on July 22,
deaths from prostate cancer are due to metastatic progress to castration-resistant disease within 1 to
2019: DOI https://doi. disease, identified either at diagnosis or after relapse 3 years, despite experiencing an initial response.5-7
org/10.1200/JCO.19. following local therapies.3
00799
Previous trials in men with mHSPC combining ADT with
Clinical trial
Metastatic hormone-sensitive prostate cancer (mHSPC), other treatments such as docetaxel chemotherapy6,8
information: defined as patients with metastatic disease who have or the selective androgen biosynthesis inhibitor abir-
NCT02677896. not yet received, or are continuing to respond to, aterone acetate,9-11 hereafter referred to as abiraterone,

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

have demonstrated significant clinical benefits, including imaging. Enrollment was based on investigator-assessed
significantly improved overall survival (OS), and these metastases; after study entry, metastasis was evaluated by
combinations are now included in treatment guidelines as independent central review. Prior ADT and up to six cycles
part of the SOC.12,13 Abiraterone plus ADT is approved in of prior docetaxel chemotherapy were permitted. Patients
combination with prednisone for men with metastatic who experienced disease progression prior to randomiza-
high-risk castration-sensitive prostate cancer,14,15 on the tion while receiving ADT and/or docetaxel were excluded.
basis of the LATITUDE trial (ClinicalTrials.gov identifier: Additional details regarding inclusion/exclusion criteria are
NCT01715285),10 which exclusively enrolled men with provided in the Data Supplement.
high-risk mHSPC and excluded previous chemotherapy. Patients were centrally randomized 1:1 to enzalutamide
The efficacy and safety of enzalutamide, a potent (160 mg/day) plus ADT or placebo plus ADT, stratified by
androgen-receptor (AR) inhibitor,16 has been demon- disease volume (low v high) and prior docetaxel chemo-
strated across the spectrum of castration-resistant therapy for prostate cancer (no cycles, one to five cycles, or
prostate cancer (CRPC) by numerous, large-scale, six cycles). High-volume disease was defined as presence
randomized, controlled clinical trials.17-21 In addition, of metastases involving the viscera, or in the absence of
a phase II, open-label, single-arm study investigating visceral lesions, four or more bone lesions, one or more of
enzalutamide monotherapy in patients with hormone- which must have been in a bony structure beyond the
naı̈ve prostate cancer demonstrated long-term re- vertebral column and pelvic bone, per CHAARTED (Clin-
ductions in prostate-specific antigen (PSA) levels, with icalTrials.gov identifier: NCT00309985) criteria.6 Treat-
minimal changes in overall bone mineral density and ment continued until occurrence of unacceptable toxicity,
global health status.22-24 radiographic progression (confirmed by independent cen-
Two recent studies that investigated abiraterone in addition tral review), or initiation of an investigational agent or
to ADT excluded men with prior docetaxel chemotherapy new prostate cancer therapy. Subsequent therapy after
and did not include prospective evaluation of results by treatment discontinuation was permitted per local practice.
disease volume (high v low).10,11 ARCHES (Clinical- On the basis of the primary analysis results and DSMB
Trials.gov identifier: NCT02677896) aimed to assess recommendation of study continuation, eligible patients
efficacy and safety of enzalutamide plus ADT in men with were offered the opportunity to transition to an open-label
mHSPC, regardless of prior docetaxel or disease volume. extension.
We hypothesized that enzalutamide, in combination with End Points
ADT, would prolong radiographic progression-free sur- The primary end point was rPFS, defined as the time from
vival (rPFS) in men with mHSPC, compared with randomization to the first objective evidence of radiographic
ADT alone. disease progression, as assessed by independent central
review or death (defined as death from any cause within
METHODS 24 weeks from study drug discontinuation), whichever
Study Design and Conduct occurred first. The cutoff of 24 weeks from study drug
ARCHES is a multinational, double-blind, randomized, discontinuation (ie, the second long-term follow-up visit) for
placebo-controlled, phase III trial. The study protocol was deaths (in the absence of disease progression) ensured
approved by local independent review boards and con- a similar follow-up period as for monitoring of radiographic
ducted according to provisions of the Declaration of progression (ie, two 12-week radiologic assessment cycles
Helsinki and Good Clinical Practice Guidelines of the post-treatment discontinuation). In addition, sensitivity
International Conference on Harmonisation. All patients analyses for rPFS were performed, including all deaths (in
provided written informed consent. An independent Data the absence of evidence of radiographic progression) re-
Safety Monitoring Board (DSMB) evaluated unblinded gardless of timing, and radiographic progression docu-
safety data on an ongoing basis. Please refer to the Dis- mented by central review according to Prostate Cancer
closures for full information on data sharing. Working Group 2 criteria,25 to assess the robustness of the
primary analysis; additional details are provided in Data
Patients and Treatments Supplement Table A1. Key secondary end points were time
Eligible patients were adult (defined according to local to PSA progression, time to initiation of new antineoplastic
regulation) males with pathologically confirmed prostate therapy (including cytotoxic and hormone therapies), PSA
adenocarcinoma, without neuroendocrine differentiation, undetectable rate, objective response rate, time to de-
signet-cell, or small-cell features, and an Eastern Co- terioration in urinary symptoms, and OS. Other secondary
operative Oncology Group performance status score of 0 or end points included time to first symptomatic skeletal
1. Eligible patients had hormone-sensitive metastatic dis- event, time to castration resistance, patient-reported out-
ease, either de novo or after recurrence after prior local comes (PROs), time to deterioration of quality of life (QoL),
therapy, documented by a positive bone scan, or metastatic and time to pain progression. Additional prespecified an-
lesions on computed tomography or magnetic resonance alyses, per a separate PRO statistical analysis plan (SAP),

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 Armstrong et al

included QoL over time and sensitivity analyses of time 34 patients (5.9%) in the enzalutamide plus ADT group and
to pain progression (using other clinically meaningful 43 patients (7.5%) in the placebo plus ADT group.
threshold criteria). Safety was also assessed. End point As of the data cutoff on October 14, 2018, median follow-up
definitions are provided in Data Supplement Table A1. time was 14.4 months. Overall, 377 patients (32.8%) dis-
Assessments continued study treatment (enzalutamide plus ADT, n = 135
[23.5%]; placebo plus ADT, n = 242 [42.0%]). The primary
Efficacy assessments included sequential radiographic reason for treatment discontinuation was progressive dis-
imaging performed at screening, at week 13, and every ease (enzalutamide plus ADT, n = 65 [11.3%] v placebo plus
subsequent 12 weeks. Radiographic progression events ADT, n = 171 [29.7%]), followed by patient withdrawal
were confirmed by independent central review; details (n = 25 [4.4%] v n = 30 [5.2%], respectively; Fig 1).
regarding the definition of radiographic progression, in-
cluding confirmatory scans required for new bone lesions rPFS
observed over time, are provided in Data Supplement At data cutoff, 292 radiographic disease progression events
Table A2. PSA levels were measured at screening, at weeks or deaths without radiographic disease progression within
1, 5, and 13, every subsequent 12 weeks, and 30 days after 24 weeks of treatment discontinuation had occurred
the last dose or prior to initiation of new antineoplastic (enzalutamide plus ADT, n = 91 [15.9%]; placebo plus
therapy for prostate cancer, whichever occurred first. PRO ADT, n = 201 [34.9%]; Table 2). Overall, enzalutamide plus
assessments, such as Functional Assessment of Cancer ADT significantly reduced the risk of radiographic disease
Therapy–Prostate,26 Quality of Life Prostate-Specific progression or death compared with placebo plus ADT by
questionnaire 25,27 and Brief Pain Inventory–Short 61% (HR, 0.39; 95% CI, 0.30 to 0.50; P , .001; Fig 2A).
Form (BPI-SF), were completed at baseline, week 13, Median rPFS was not reached (NR) with enzalutamide plus
and every 12 weeks thereafter. Adverse events (AEs) were ADT (95% CI, NR to NR) versus 19.0 months (95% CI, 16.6
graded by the investigator according to the National to 22.2 months) with placebo plus ADT. The treatment
Cancer Institute Common Terminology Criteria for Ad- effect of enzalutamide plus ADT was consistent across all
verse Events (version 4.03). prespecified subgroups, including disease volume and
prior docetaxel chemotherapy (Fig 2B). A sensitivity
Statistical Analysis
analysis of rPFS, including all deaths (in the absence of
The final rPFS analysis was planned to occur after evidence of radiographic disease progression) regardless of
262 events, to detect a hazard ratio (HR) of 0.67 with 90% timing, and a sensitivity analysis of radiographic progres-
power, on the basis of a two-sided log-rank test and 5% sion documented by central review according to Prostate
significance level. To adjust for multiplicity, a parallel testing Cancer Working Group 2 criteria25 were both consistent
strategy was applied to the key secondary end points with the primary analysis (Table 2).
(Appendix Fig A1, online only). Key secondary end
points, other than OS, were sequentially tested at a 1% Secondary End Points
significance level. A final OS analysis will be performed The superiority of enzalutamide plus ADT over placebo plus
when 342 deaths have occurred to provide 80% power to ADT was shown for the key secondary end points of time to
detect an HR of 0.73 at a 4% significance level. An interim PSA progression, time to initiation of new antineoplastic
OS analysis was performed at the time of the final rPFS therapy, PSA undetectable rate, and objective response
analysis at a significance level calculated using the O’Brien- rate (Table 2; Fig 3). Although the median time to initiation
Fleming function to control the overall alpha. Additional of a new antineoplastic agent of 30.2 months in the
details regarding the statistical analyses (original and final) enzalutamide arm is not a reliable estimate because it
are provided in the Data Supplement (Fig A1 and Table A1) resulted from an event observed in the only remaining
and Protocol (including SAP). patient at risk, the treatment effect was robust, as evi-
denced by the HR of 0.28 (95% CI, 0.20 to 0.40; P , .001).
RESULTS Of the patients who initiated new antineoplastic therapy, the
most common therapy was abiraterone (n = 13; 28.3%)
Patients and Treatment followed by docetaxel (n = 11; 23.9%) in the enzalutamide
From March 21, 2016, to January 12, 2018, a total of 1,150 plus ADT group and docetaxel (n = 52; 39.1%) followed by
patients were randomly assigned 1:1 from 202 centers in abiraterone and enzalutamide (n = 28 each; 21.1%) in the
North and Latin America, Europe, and Asia; 1,146 patients placebo plus ADT group (Data Supplement Table A3). At
received at least one dose of the study drug (Fig 1). this interim OS analysis, data were immature, with
Baseline demographics were well balanced between 84 deaths (enzalutamide plus ADT, n = 39; placebo plus ADT,
treatment groups (Table 1); 727 patients (63.2%) had high- n = 45); median duration of OS was NR in either treatment
volume disease, and 205 (17.9%) received prior docetaxel group (HR, 0.81; 95% CI, 0.53 to 1.25; P = .3361; Table 2;
chemotherapy. Use of concomitant antiandrogens as Data Supplement Fig A2). Enzalutamide plus ADT also
prostate cancer therapy during the study was reported by significantly reduced the risk of a first symptomatic skeletal

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

Enrollment

Assessed for eligibility

(N = 1,432)

Screen failures
(n = 282)

Randomly assigned 1:1*

(n = 1,150)

Allocation

Allocated to enzalutamide plus ADT, ie, ITT population (n = 574) Allocated to placebo plus ADT, ie, ITT population (n = 576)
Received study drug, ie, safety population (n = 572) Received study drug, ie, safety population (n = 574)
Did not receive study drug (n = 2) Did not receive study drug (n = 2)

Follow-up

Ongoing (n = 437) Ongoing (n = 332)

Discontinued study drug (n = 135) Discontinued study drug (n = 242)
Adverse event (n = 28; 4.9%) Adverse event (n = 21; 3.6%)
Death (n = 9; 1.6%) Death (n = 7; 1.2%)
Progressive disease† (n = 65; 11.3%) Progressive disease† (n = 171; 29.7%)
Radiographic progression (n = 49; 8.5%) Radiographic progression (n = 125; 21.7%)
Clinical progression (n = 38; 6.6%) Clinical progression (n = 75; 13.0%)
Prostate-specific antigen progression (n = 29; 5.1%) Prostate-specific antigen progression (n = 105; 18.2%)
Protocol deviation (n = 2; 0.3%) Protocol deviation (n = 1; 0.2%)
Withdrawal by subject (n = 25; 4.4%) Withdrawal by subject (n = 30; 5.2%)
Lost to follow-up (n = 0) Lost to follow-up (n = 1; 0.2%)
Other (n = 6; 1.0%) Other (n = 11; 1.9%)

FIG 1. CONSORT diagram. (*) Randomization 1:1 was stratified by volume of disease (low v high) and prior docetaxel therapy for prostate cancer (no
cycles, one to five cycles, or six cycles); high volume of disease was defined as presence of metastases involving the viscera, or in the absence of visceral
lesions, four or more bone lesions, one or more of which must have been in a bony structure beyond the vertebral column and pelvic bone, per
CHAARTED (ClinicalTrials.gov identifier: NCT00309985) criteria.6 (†) Progressive disease types are not mutually exclusive; the same patient may be
reported in multiple categories. ADT, androgen deprivation therapy; ITT, intent-to-treat.

event (Table 2; Fig 3) and castration resistance (Table 2; and pain severity versus placebo plus ADT (Table 2; Data
Data Supplement Fig A3). Supplement Fig A5).
Mean Functional Assessment of Cancer Therapy–Prostate
total score, as a global indicator of QoL, was high at baseline Safety
for both treatment groups (Table 1) and remained high over Median treatment duration was 12.8 months (range,
time (Data Supplement Fig A4). Enzalutamide plus ADT did 0.2 to 26.6 months) in the enzalutamide plus ADT group
not significantly affect time to deterioration in urinary and 11.6 months (range, 0.2 to 24.6 months) in the
symptoms or QoL compared with placebo plus ADT placebo plus ADT group. Grade 3 or greater AEs, serious
(Table 2). Although the analysis of time to pain progression, AEs, and AEs leading to treatment discontinuation were
with progression defined as a 30% or greater increase from reported in similar proportions of patients in both treat-
baseline in average BPI-SF pain severity score, was not ment groups (Table 3). There were no unexpected AEs; of
delayed (Table 2), prespecified sensitivity analyses from the the 14 AEs (2.4%) leading to death in the enzalutamide
PRO SAP, using a clinically significant 2-point or greater plus ADT group and 10 (1.7%) in the placebo plus ADT
increase from baseline in average BPI-SF score as the group, none were assessed by the investigator to be re-
progression threshold, demonstrated that enzalutamide lated to treatment in the enzalutamide plus ADT group,
plus ADT delayed time to pain progression for worst pain whereas one event (general physical health deterioration)

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 Armstrong et al

TABLE 1. Baseline Demographics

Enzalutamide Plus ADT Placebo Plus ADT
Characteristic (n = 574) (n = 576)
Age (years)
Median 70.0 70.0
Range 46-92 42-92
Age category, years
, 65 148 (25.8) 152 (26.4)
65-74 256 (44.6) 255 (44.3)
$ 75 170 (29.6) 169 (29.3)
a
Race
White 466 (81.2) 460 (79.9)
Asian 75 (13.1) 80 (13.9)
Black or African American 8 (1.4) 8 (1.4)
American Indian or Alaska Native 0 0
Native Hawaiian or other Pacific Islander 0 0
Other 2 (0.3) 3 (0.5)
Missing 23 (4.0) 25 (4.3)
Geographic region
Europe 341 (59.4) 344 (59.7)
Asia-Pacific 104 (18.1) 113 (19.6)
North America 86 (15.0) 77 (13.4)
South America 32 (5.6) 30 (5.2)
Other 11 (1.9) 12 (2.1)
ECOG performance status score on day 1
0 448 (78.0) 443 (76.9)
1 125 (21.8) 133 (23.1)
Total Gleason score at initial diagnosis
,8 171 (29.8) 187 (32.5)
$8 386 (67.2) 373 (64.8)
Confirmed metastases at screeningb
Yes 536 (93.4) 531 (92.2)
No 34 (5.9) 45 (7.8)
Unknown 4 (0.7) 0
Localization of confirmed metastases at screeningb
Bone only 268 (46.7) 245 (42.5)
Soft tissue only 51 (8.9) 45 (7.8)
Bone and soft tissue 217 (37.8) 241 (41.8)
Distant metastasis at initial diagnosis
M1 402 (70.0) 365 (63.4)
M0 83 (14.5) 86 (14.9)
MX/unknown 88 (15.3) 125 (21.7)
Disease volume
Highc 354 (61.7) 373 (64.8)
Low 220 (38.3) 203 (35.2)
(continued on following page)

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

TABLE 1. Baseline Demographics (continued)

Enzalutamide Plus ADT Placebo Plus ADT
Characteristic (n = 574) (n = 576)
Prior local therapy
Radical prostatectomy 72 (12.5) 89 (15.5)
Radiation therapy 73 (12.7) 72 (12.5)
No. of cycles of prior docetaxel chemotherapy
0 471 (82.1) 474 (82.3)
1-5 14 (2.4) 11 (1.9)
6 89 (15.5) 91 (15.8)
d
Previous use of ADT
None 39 (6.8) 61 (10.6)
# 3 months 414 (72.1) 394 (68.4)
. 3 months 121 (21.1) 120 (20.8)
Unknowne 0 1 (0.2)
f
Median duration of prior ADT, months (range) 1.6 (0.03-55.3) 1.6 (0.03-198.8)
Previous use of antiandrogeng 205 (35.8) 229 (39.9)
g
Median PSA, ng/mL (range) 5.4 (0-4,823.5) 5.1 (0-19,000.0)
h
Modified QLQ-PR25 urinary symptoms score, mean (SD) 35.2 (25.3) 35.8 (25.4)
FACT-P total score, mean (SD)i 113.9 (19.8) 112.7 (19.0)
BPI-SF item 3 (worst pain), mean (SD)j 1.8 (2.4) 1.8 (2.3)
BPI-SF pain severity score, mean (SD)j 1.4 (1.8) 1.4 (1.7)

NOTE. Data are No. (%) unless otherwise indicated.

Abbreviations: ADT, androgen deprivation therapy; BPI-SF, Brief Pain Inventory–Short Form; ECOG, Eastern Cooperative Oncology Group;
FACT-P, Functional Assessment of Cancer Therapy–Prostate; MX, distant metastasis cannot be assessed (not evaluated by any modality); M0, no
distant metastasis; M1, distant metastasis; PSA, prostate-specific antigen; QLQ-PR25, Quality of Life Prostate-Specific questionnaire; SD,
standard deviation.
a
By country regulations, race is not collected in France.
b
Assessed by independent central review after investigator assessment at study entry.
c
Defined by CHAARTED criteria6 as presence of metastases involving the viscera, or, in the absence of visceral lesions, four or more bone
lesions, one or more of which must be in a bony structure beyond the vertebral column and pelvic bone; some study sites incorrectly reported
disease volume information for some patients at the time of randomization, which was corrected during medical review on study entry, resulting in
a difference of approximately 20 patients with either high or low disease volume between the treatment arms.
d
Includes the time since bilateral orchiectomy for patients who had prior bilateral orchiectomy.
e
The patient had prior ADT; however, the duration of ADT use was unknown.
f
Intent-to-treat patients who had received prior ADT (enzalutamide plus ADT, n = 535; placebo plus ADT, n = 514).
g
Safety-analysis-set patients (enzalutamide plus ADT, n = 572; placebo plus ADT, n = 574).
h
Intent-to-treat patients who had a baseline modified QLQ-PR25 urinary symptoms score (enzalutamide plus ADT, n = 539; placebo plus ADT,
n = 546). Only items Q31-Q33 from the urinary symptoms subscale were assessed. All items and scale scores of the QLQ-PR25 are linearly
transformed to a 0 to 100 scale. A higher score in the urinary symptoms subscale indicates more symptoms.27
i
Intent-to-treat patients who had a baseline Functional Assessment of Cancer Therapy–Prostate total score (enzalutamide plus ADT, n = 550;
placebo plus ADT, n = 553). The Functional Assessment of Cancer Therapy–Prostate total score ranges from 0 to 156, with the higher scores
indicating more favorable quality of life.26
j
Intent-to-treat patients who had baseline average Brief Pain Inventory–Short Form worst pain and pain severity scores (enzalutamide plus
ADT, n = 542; placebo plus ADT, n = 552). The Brief Pain Inventory–Short Form average score ranges from 0 to 10, with higher scores indicating
worse pain.

was assessed by the investigator to be related in the radiographic disease progression or death by 61% com-
placebo plus ADT group. pared with placebo plus ADT (HR, 0.39; P , .001). Sig-
nificant improvements with enzalutamide plus ADT were
also observed in secondary efficacy end points. OS data are
DISCUSSION immature and will be analyzed when 342 deaths have
In this phase III trial involving men with mHSPC, adding occurred. Preliminary safety analysis showed an accept-
enzalutamide to ADT significantly reduced the risk of able safety profile that seems consistent with that in

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 Armstrong et al

TABLE 2. Primary and Secondary End Points

Enzalutamide
Plus ADT Placebo Plus ADT
End Point (n = 574) (n = 576) HR (95% CI) P
Primary end point
Median rPFS, months NR 19.0 0.39 (0.30 to 0.50) , .001
Radiographic progression 79 (13.8) 188 (32.6)
Prespecified sensitivity analysis (using PCWG2)a NR 19.4 0.39 (0.30 to 0.50) , .001
Death within 24 weeks of treatment discontinuation in 12 (2.1) 13 (2.3)
the absence of radiographic progression
Prespecified sensitivity analysis (all deaths)b NR 19.0 0.39 (0.30 to 0.50) , .001
Key secondary end points
Median time to PSA progression (months) NR NR 0.19 (0.13 to 0.26) , .001
Median time to initiation of new antineoplastic therapy (months) 30.2 NR 0.28 (0.20 to 0.40) , .001
PSA undetectable (, 0.2 ng/mL) ratec 348 (68.1) 89 (17.6) , .001
Objective response rated 147 (83.1) 116 (63.7) , .001
Complete response 65 (36.7) 42 (23.1)
Partial response 82 (46.3) 74 (40.7)
Stable disease 17 (9.6) 43 (23.6)
Progressive disease 7 (4.0) 9 (4.9)
NE/NA 6 (3.4) 14 (7.7)
Median time to deterioration of urinary symptoms (months)e NR 16.8 0.88 (0.72 to 1.08) .2162
Median OS (months) NR NR 0.81 (0.53 to 1.25) .3361
Other secondary end points
Median time to first SSE, months NR NR 0.52 (0.33 to 0.80) .0026
Median time to castration resistance, months NR 13.8 0.28 (0.22 to 0.36) , .001
Median time to deterioration of QoL (months)f 11.3 11.1 0.96 (0.81 to 1.14) .6548
Median time to pain progression (months)g 8.3 8.3 0.92 (0.78 to 1.07) .2715
Prespecified sensitivity analyses of time to pain progression from the PRO SAP
Median time to worst pain (item 3) (months)h 14.1 11.1 0.82 (0.69 to 0.98) .0322
h
Median time to pain severity (months) 19.4 16.8 0.79 (0.65 to 0.97) .0209

NOTE. All data are No. (%) unless otherwise specified.

Abbreviations: ADT, androgen deprivation therapy; HR, hazard ratio; NA, not applicable; NE, not evaluable; NR, not reached; OS, overall
survival; PCWG2, Prostate Cancer Working Group 2; PRO, patient-reported outcome; PSA, prostate-specific antigen; QoL, quality of life; rPFS,
radiographic progression-free survival; SAP, statistical analysis plan; SSE, symptomatic skeletal event.
a
Radiographic progression was documented by central review according to Prostate Cancer Working Group 2 criteria for bone assessment.25
b
All deaths (in the absence of evidence of radiographic progression), regardless of timing, were included.
c
This analysis was conducted using intent-to-treat patients who had detectable PSA values at baseline (enzalutamide plus ADT, n = 511;
placebo plus ADT, n = 506).
d
Objective response is defined as patients achieving a complete or partial response in their soft tissue disease using the Response Evaluation
Criteria in Solid Tumors (version 1.1).28 Patients with no postbaseline assessment at any visit are reported in the NE category. This analysis was
conducted using intent-to-treat patients who had measurable soft tissue disease at baseline (enzalutamide plus ADT, n = 177; placebo plus ADT,
n = 182).
e
A deterioration in urinary symptoms is defined as an increase in the urinary symptoms subscale score by $ 50% of the standard deviation
observed in the urinary symptoms subscale score at baseline (ie, Q31-Q33).
f
A deterioration of QoL is defined as a decrease of $ 10 points in the total Functional Assessment of Cancer Therapy–Prostate score from
baseline.
g
Pain progression is defined an increase of $ 30% from baseline in the average Brief Pain Inventory–Short Form pain severity score.
h
Pain progression is defined as an increase of $ 2 points from baseline in the average Brief Pain Inventory–Short Form score.

previously reported clinical trials involving patients with prompted the DSMB to recommend crossing patients
CRPC,17,18 with maintenance of QoL at the high level re- treated with placebo plus ADT over to enzalutamide
ported at baseline. These efficacy and safety results plus ADT.

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

A
100
90
Enzalutamide + ADT
80
70
rPFS* (%)

60 Placebo + ADT
50
40
Median, months (95% CI)
30
Enzalutamide + ADT NR (NR to NR)
20 Placebo + ADT 19.0 (16.6 to 22.2)
10 HR 0.39 (0.30 to 0.50)
P < .001

0 3 6 9 12 15 18 21 24 27 30 33
Months
No. at risk
Enzalutamide + ADT 574 516 493 370 256 144 62 23 4 1 0 0
Placebo + ADT 576 511 445 314 191 106 39 10 0 0 0 0

B
†
Subgroup Enzalutamide + ADT Placebo + ADT HR (95% CI)
No. of patients (E) No. of patients (E)

All patients 574 (91) 576 (201) 0.39 (0.30 to 0.50)

Age < 65 years 148 (21) 152 (58) 0.29 (0.17 to 0.47)
Age ≥ 65 years 426 (70) 424 (143) 0.44 (0.33 to 0.58)
Geographic region – Europe 341 (55) 344 (122) 0.42 (0.31 to 0.58)
Geographic region – North America 86 (14) 77 (29) 0.30 (0.16 to 0.57)
Geographic region – rest of the world 147 (22) 155 (50) 0.40 (0.24 to 0.66)
ECOG status 0 at baseline 448 (67) 443 (146) 0.38 (0.29 to 0.51)
ECOG status 1 at baseline 125 (24) 133 (55) 0.43 (0.27 to 0.70)
Gleason score at initial diagnosis < 8 171 (21) 187 (47) 0.42 (0.25 to 0.70)
Gleason score at initial diagnosis ≥ 8 386 (65) 373 (151) 0.36 (0.27 to 0.48)
Disease localization at baseline – bone only 268 (35) 245 (82) 0.33 (0.22 to 0.49)
Disease localization at baseline – soft tissue only 51 (5) 45 (12) 0.42 (0.15 to 1.20)
Disease localization at baseline – bone and soft tissue 217 (50) 241 (104) 0.42 (0.30 to 0.60)
Baseline PSA value at or below overall median 293 (41) 305 (96) 0.38 (0.26 to 0.54)
Baseline PSA value above overall median 279 (50) 269 (104) 0.41 (0.30 to 0.58)
Low volume of disease 220 (14) 203 (47) 0.25 (0.14 to 0.46)
High volume of disease 354 (77) 373 (154) 0.43 (0.33 to 0.57)
No prior docetaxel therapy 471 (70) 474 (166) 0.37 (0.28 to 0.49)
Prior docetaxel therapy 103 (21) 102 (35) 0.52 (0.30 to 0.89)
Previous use of ADT or orchiectomy 535 (88) 515 (179) 0.41 (0.32 to 0.53)
No previous use of ADT or orchiectomy 39 (3) 61 (22) 0.19 (0.06 to 0.62)

0.0 0.5 1.0 1.5 2.0

Favors Favors
Enzalutamide + ADT Placebo + ADT

FIG 2. Kaplan-Meier estimate of (A) radiographic progression-free survival (rPFS) and (B) forest plot of rPFS for prespecified subgroups (intent-to-treat
population). The dashed line at the 50th percentile indicates the median. Crosses indicate censored data. (*) For patients with no documented progression
event, rPFS was censored on the date of the last radiologic assessment performed before the cutoff date. (†) 95% CIs provided are not adjusted for the
number of subgroups summarized. ADT, androgen deprivation therapy; E, No. of events; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio;
NR, not reached; PSA, prostate-specific antigen.

Importantly, the significant reduction in the risk of radio- prespecified subgroups, including men with or without prior
graphic disease progression or death with enzalutamide docetaxel chemotherapy and those with a low or high
plus ADT in this study (P , .001) was observed in all volume of metastatic disease. These data support the

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 Armstrong et al

A
100
Enzalutamide + ADT
90 FIG 3. Kaplan-Meier esti-
mates of time to (A)
80
prostate-specific antigen

Progression* (%)
70 (PSA) progression, (B)
Free of PSA 60 initiation of new antineo-
Placebo + ADT
50 plastic therapy, and (C)
first symptomatic skeletal
40
Median, months (95% CI) event (intent-to-treat pop-
30 Enzalutamide + ADT NR (NR to NR) ulation). The dashed
20 Placebo + ADT NR (16.6 to NR) line at the 50th percentile
HR 0.19 (0.13 to 0.26)
10 indicates the median.
P < .001
Crosses indicate censored
0 3 6 9 12 15 18 21 24 27 30 33 data. (*) In patients with
no PSA progression, time
Time (months)
to PSA progression was
No. at risk:
Enzalutamide + ADT 574 530 495 371 247 134 58 22 4 0 0 0 censored on the date of
Placebo + ADT 576 469 387 257 153 76 25 4 0 0 0 0 the last PSA sample taken.
Patients without PSA pro-
B gression before two or
100 more consecutive missed
PSA assessments were
Without New Antineoplastic

90
Enzalutamide + ADT
censored on the date of
80
last PSA assessment be-
70 Placebo + ADT fore the assessments
Therapy† (%)

60 missed. (†) In patients

50 with no new antineoplastic
therapy initiated for pros-
40
Median, months (95% CI) tate cancer after random-
30 ization, time to start of new
Enzalutamide + ADT 30.2 (NR to NR)
20 Placebo + ADT NR (21.1 to NR) antineoplastic therapy was
HR 0.28 (0.20 to 0.40) censored on the last visit
10
P < .001
date or the date of ran-
0 3 6 9 12 15 18 21 24 27 30 33 domization, whichever oc-
curred last. The median for
Time (months)
the enzalutamide plus an-
No. at risk:
Enzalutamide + ADT 574 559 548 438 299 174 83 28 7 1 1 0
drogen deprivation therapy
Placebo + ADT 576 552 515 383 252 140 53 13 0 0 0 0 (ADT) group was not a reli-
able estimate because it
C resulted from an event ob-
100 served in the only remaining
Enzalutamide + ADT
patient at risk at approxi-
Free of Symptomatic Skeletal

90
Placebo + ADT mately 30 months, leading
80
to the vertical drop at the end
70 of the Kaplan-Meier curve.
Event‡ (%)

60 The hazard ratio (HR; 95%

50 CI) is a more accurate de-
piction of the differences
40
Median, months (95% CI) between treatment arms. (‡)
30 In patients with no symp-
Enzalutamide + ADT NR (NR to NR)
20 Placebo + ADT NR (NR to NR) tomatic skeletal event by the
HR 0.52 (0.33 to 0.80) time of the data cutoff point,
10
P = .0026
time to symptomatic skeletal
0 3 6 9 12 15 18 21 24 27 30 33
event was censored on the
last visit date or the date of
Time (months) randomization, whichever
No. at risk:
Enzalutamide + ADT 574 558 549 448 303 181 91 33 11 2 1 0 occurred last. HR, hazard
Placebo + ADT 576 552 526 408 280 173 75 19 3 1 0 0
ratio; NR, not reached.

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

TABLE 3. Summary of AEs

Event Enzalutamide Plus ADT (n = 572) Placebo Plus ADT (n = 574)
AEs leading to withdrawal of treatment 41 (7.2) 30 (5.2)
Drug-related serious AEs 22 (3.8) 16 (2.8)
AEs leading to death 14 (2.4) 10 (1.7)

All Grades Grade ‡ 3 All Grades Grade ‡ 3

AEs 487 (85.1) 139 (24.3) 493 (85.9) 147 (25.6)
Serious AEs 104 (18.2) 84 (14.7) 112 (19.5) 90 (15.7)
Most common AEs, occurring in $ 5% of patients*
Hot flash 155 (27.1) 2 (0.3) 128 (22.3) 0
Fatigue 112 (19.6) 5 (0.9) 88 (15.3) 6 (1.0)
Arthralgia 70 (12.2) 2 (0.3) 61 (10.6) 4 (0.7)
Back pain 43 (7.5) 5 (0.9) 62 (10.8) 3 (0.5)
Increased weight 35 (6.1) 2 (0.3) 44 (7.7) 1 (0.2)
Hypertension 46 (8.0) 19 (3.3) 32 (5.6) 10 (1.7)
Diarrhea 34 (5.9) 0 33 (5.7) 1 (0.2)
Edema, peripheral 29 (5.1) 1 (0.2) 38 (6.6) 1 (0.2)
Nausea 37 (6.5) 1 (0.2) 29 (5.1) 0
Asthenia 31 (5.4) 6 (1.0) 28 (4.9) 3 (0.5)
Constipation 28 (4.9) 0 31 (5.4) 0
Musculoskeletal pain 36 (6.3) 1 (0.2) 23 (4.0) 1 (0.2)
Dizziness 29 (5.1) 0 20 (3.5) 0
AEs of special interest†
Convulsion 2 (0.3) 2 (0.3) 2 (0.3) 2 (0.3)
Hypertension 49 (8.6) 19 (3.3) 36 (6.3) 12 (2.1)
Neutrophil count decreased 5 (0.9) 2 (0.3) 4 (0.7) 2 (0.3)
Cognitive/memory impairment 26 (4.5) 4 (0.7) 12 (2.1) 0
Ischemic heart disease 10 (1.7) 3 (0.5) 8 (1.4) 6 (1.0)
Other selected cardiovascular events 13 (2.3) 6 (1.0) 9 (1.6) 5 (0.9)
Posterior reversible encephalopathy syndrome 0 0 0 0
Fatigue 138 (24.1) 10 (1.7) 112 (19.5) 9 (1.6)
Fall 21 (3.7) 2 (0.3) 15 (2.6) 1 (0.2)
Fractures 37 (6.5) 6 (1.0) 24 (4.2) 6 (1.0)
Loss of consciousness 9 (1.6) 6 (1.0) 1 (0.2) 1 (0.2)
Thrombocytopenia 3 (0.5) 0 3 (0.5) 0
Musculoskeletal events 151 (26.4) 9 (1.6) 159 (27.7) 12 (2.1)
Severe cutaneous adverse reactions 0 0 1 (0.2) 0
Angioedema 7 (1.2) 1 (0.2) 1 (0.2) 0
Rash 15 (2.6) 0 9 (1.6) 0
Second primary malignancies 11 (1.9) 9 (1.6) 11 (1.9) 7 (1.2)

NOTE. All data are No. (%). AEs were recorded in the electronic case report form and graded based on the National Cancer Institute’s Common
Terminology Criteria for Adverse Events (version 4.03) by the study investigator.
Abbreviations: ADT, androgen deprivation therapy; AE, adverse event.
*AEs reported in at least 5% of the patients in either treatment group, listed in descending order by preferred term. None of the most common
AEs was grade 5.
†AEs of special interest were based on prespecified combinations of preferred terms (Medical Dictionary for Regulatory Activities, version 21.0)
related to the AE of special interest; for example, the combination of preferred terms used to define fatigue as an AE of special interest was fatigue
and asthenia. Two of the AEs of special interest in the enzalutamide plus ADT group were grade 5 (ischemic heart disease, n = 1; other selected
cardiovascular events, n = 1).

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Armstrong et al

consideration of enzalutamide in addition to ADT for men OS in patients with metastatic CRPC34,35 and the direct
with mHSPC, including patients with prior docetaxel impact of additional metastatic progression in this setting
treatment and regardless of disease volume. Although OS on patient management. Furthermore, rPFS requires
data remain immature, these findings have clear clinical shorter follow-up periods and fewer patients compared with
implications for the current management of these patients. OS as a result of the higher event rate, accelerating trial
PROs from assessments of daily living have also been completion.36 It is also in the interest of patients to unblind
shown to predict survival in prostate cancer.29 In this trials earlier, on the basis of robust rPFS evidence, espe-
population of men with mHSPC, we observed maintenance cially when supported by strong secondary end points, to
of high QoL over time, similar to that observed in the pop- allow crossover to active treatment. Therefore, ARCHES
ulation with nonmetastatic castration-resistant disease.30 was accelerated, with rPFS analysis conducted after only
Baseline average BPI-SF scores were low overall, with 262 events, despite an immature OS analysis. At the time of
almost half of patients reporting scores of zero. Conse- manuscript submission, a phase III study investigating the
quently, no significant difference between treatment addition of enzalutamide versus a first-generation non-
groups in risk of pain progression, defined as a 30% or steroidal antiandrogen, such as bicalutamide, to ADT, with
greater increase in average BPI-SF pain severity score, or without docetaxel chemotherapy, in men with mHSPC37
was observed. However, when using a more clinically is currently ongoing and will provide additional data on the
meaningful definition of pain progression ($ 2-point clinical benefits of enzalutamide plus ADT, including the
threshold)31 during the prespecified sensitivity analyses impact on OS.
from the PRO SAP, enzalutamide plus ADT showed Several therapies have recently been shown to be effective in
a delay in pain progression versus placebo plus ADT. men with mHSPC; therefore, ADT alone may no longer be an
Ultimately, no significant difference between treatment appropriate control arm in this patient population. However,
groups in risk of deterioration of urinary symptoms or QoL docetaxel plus ADT only became part of the global SOC for
was observed, suggesting there was no negative impact on mHSPC in 2016, after patients were already enrolling in
PROs due to the addition of enzalutamide to ADT. Ad- ARCHES,12 and thus, docetaxel could not have been con-
ditional analyses of the PROs are ongoing and are also sidered as part of the comparator arm in the current study.
planned as part of the long-term follow-up. Furthermore, patients with high-volume disease who had
Currently, ARCHES is the first trial to demonstrate clinically completed prior docetaxel were eligible for trial entry by
meaningful benefits of potent AR inhibition with a second- study design, and for those with low-volume disease,
generation nonsteroidal antiandrogen (enzalutamide) in the benefit of early treatment with docetaxel combined
combination with ADT, including a subgroup of men with with ADT has not been established. 13,38,39
mHSPC after docetaxel chemotherapy. Whereas some pre- In conclusion, in comparison with placebo, the addition of
vious studies focused on patients with high risk and entirely enzalutamide to ADT for men with mHSPC provided clin-
excluded patients with previous chemotherapy,6-8,10,11 the ically meaningful improvements across key efficacy end
specific inclusion of patients with prior docetaxel chemo- points while maintaining the high level of QoL reported at
therapy in ARCHES provides unique insight into this im- baseline. Enzalutamide was generally well tolerated, with
portant patient subgroup with unmet clinical needs. a preliminary safety analysis seeming to be consistent with
Both rPFS and metastasis-free survival are accepted by the the safety profile of enzalutamide in previous clinical trials
US Food and Drug Administration as primary efficacy end in CRPC. Enzalutamide plus ADT should therefore be
points in metastatic CRPC and nonmetastatic CRPC, considered as a treatment option for men with mHSPC,
respectively.32,33 However, although rPFS has not yet been including those with low-volume disease or who had re-
established as a surrogate for OS in mHSPC, it is an ac- ceived prior docetaxel. Additional studies are necessary to
ceptable regulatory end point, and reducing the risk of clarify whether combination or sequential approaches with
radiographic progression or death is of clinical importance, AR-targeted therapies or chemotherapy are favored for
given the strong positive correlation reported for rPFS and initial management.

7
AFFILIATIONS Hospital Clinic of Barcelona, Barcelona, Spain
8
1
Duke Cancer Institute Center for Prostate and Urologic Cancers, Hertzen Moscow Cancer Research Institute, Moscow, Russia
9
Durham, NC Osaka City University Graduate School of Medicine, Osaka, Japan
10
2
The University of Chicago, Chicago, IL Carolina Urologic Research Center, Myrtle Beach, SC
11
3
Yale Cancer Center, New Haven, CT Pfizer, San Diego, CA
12
4
The University of Kansas Medical Center, Kansas City, KS Astellas Pharma, Northbrook, IL
13
5
Lille University, Lille, France Astellas Pharma, Leiden, the Netherlands
14
6
Monash Health, Melbourne, Victoria, Australia Eberhard Karls University of Tübingen, Tübingen, Germany

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

CORRESPONDING AUTHOR ACKNOWLEDGMENT

Andrew J. Armstrong, MD, ScM, Duke University Medical Center, Box The senior academic authors and employees of the study sponsors were
103861, Durham, NC 27710; e-mail: [email protected]. responsible for the study design. Data analyses were performed by the
study sponsors and provided to all authors. A professional medical writer,
funded by the sponsors, assisted in the preparation of the manuscript. All
PRIOR PRESENTATION authors had full access to the data, were involved in drafting the
Presented in part at the ASCO 2019 Genitourinary Cancers Symposium, manuscript, and made the decision to submit it for publication. The
San Francisco, CA, February 14 to 16, 2019; and European Association authors assume responsibility for the accuracy and completeness of the
of Urology 2019 Annual Congress, Barcelona, Spain, March 15 to data and for the adherence of the trial to the protocol. All of the authors
19, 2019. and participating institutions have agreements with the sponsors
regarding data confidentiality. We thank the patients who volunteered to
SUPPORT participate in this trial and the investigators and trial staff who cared for
Supported by Astellas Pharma and Pfizer. them; and Stephanie Rippon, MBio, and Lauren Smith from Complete
HealthVizion, for medical writing and editing assistance, funded by the
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST sponsor companies.
AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if DATA SHARING
applicable) are available with this article at DOI https://doi.org/10.1200/ Access to anonymized, individual, participant-level data collected during
JCO.19.00799. the trial, in addition to supporting clinical documentation, is planned for
trials conducted with approved product indications and formulations, as
AUTHOR CONTRIBUTIONS well as compounds terminated during development. Conditions and
exceptions are described under the Sponsor Specific Details for Astellas
Conception and design: Andrew J. Armstrong, Benoit Baron
on www.clinicalstudydatarequest.com. Study-related supporting
Provision of study materials or patients: Andrew J. Armstrong, Russell Z.
documentation is redacted and provided if available, such as the protocol
Szmulewitz, Daniel P. Petrylak, Jeffrey Holzbeierlein, Arnauld Villers,
and amendments, statistical analysis plan, and clinical study report.
Arun Azad, Antonio Alcaraz, Boris Alekseev, Taro Iguchi, Neal D. Shore,
Access to participant-level data is offered to researchers after publication
Lucy Chen, Arnulf Stenzl
of the primary manuscript (if applicable) and is available as long as
Collection and assembly of data: Andrew J. Armstrong, Russell Z. Astellas has legal authority to provide the data. Researchers must submit
Szmulewitz, Arnauld Villers, Arun Azad, Antonio Alcaraz, Boris Alekseev, a proposal to conduct a scientifically relevant analysis of the study data.
Lucy Chen, Arnulf Stenzl The research proposal is reviewed by an Independent Research Panel. If
Data analysis and interpretation: Andrew J. Armstrong, Russell Z. the proposal is approved, access to the study data is provided in a secure
Szmulewitz, Daniel P. Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, data-sharing environment after receipt of a signed Data-Sharing
Arun Azad, Antonio Alcaraz, Boris Alekseev, Taro Iguchi, Neal D. Shore, Agreement.
Brad Rosbrook, Jennifer Sugg, Benoit Baron, Lucy Chen, Arnulf Stenzl
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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n n n

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 Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men with Metastatic Hormone-Sensitive Prostate
Cancer
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held
unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about
ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Andrew J. Armstrong Boris Alexeev

Honoraria: Sanofi, Dendreon, Janssen Oncology Consulting or Advisory Role: AstraZeneca, Astellas Pharma, Bayer, Bristol-
Consulting or Advisory Role: Bayer, Sanofi, Dendreon, Medivation, Janssen Myers Squibb, Ferring, Janssen, Merck, Sanofi, Pfizer
Biotech, Pfizer, Astellas Scientific and Medical Affairs, Clovis Oncology, Speakers’ Bureau: Janssen, Sanofi, Ferring, Astellas Pharma, Pfizer,
AstraZeneca AstraZeneca, Bayer, Merck, Bristol-Myers Squibb
Speakers’ Bureau: Dendreon, Sanofi, Bayer Research Funding: AstraZeneca, Merck, Sanofi, Bayer, Astellas Pharma,
Research Funding: Dendreon (Inst), Sanofi (Inst), Bayer (Inst), Pfizer (Inst), Janssen, Bristol-Myers Squibb, Bavarian Nordic, Pfizer, Icon Clinical Research
Novartis (Inst), Janssen Oncology (Inst), Medivation (Inst), Astellas Pharma Travel, Accommodations, Expenses: AstraZeneca, Astellas, Bayer, BMS,
(Inst), Gilead Sciences (Inst), Genentech (Inst), Active Biotech (Inst), Bristol- Janssen, MSD, Pfizer, Sanofi
Myers Squibb (Inst)
Patents, Royalties, Other Intellectual Property: Circulating tumor cell novel Taro Iguchi
capture technology (Inst) Consulting or Advisory Role: Astellas Pharma, Bayer Yakuhin, Janssen
Travel, Accommodations, Expenses: Dendreon, Janssen Biotech, Bayer, Pharmaceutical
Astellas Scientific and Medical Affairs Speakers’ Bureau: Astellas Pharma, Bayer Yakuhin, Janssen Pharmaceutical,
Sanofi
Russell Z. Szmulewitz
Research Funding: Astellas Pharma, Bayer Yakuhin
Honoraria: Astellas Pharma
Consulting or Advisory Role: AstraZeneca, AbbVie, Exelixis, Merck, Amgen, Neal D. Shore
Janssen Oncology, Sanofi, Astellas Pharma, Pfizer Consulting or Advisory Role: Bayer, Janssen Scientific Affairs, Dendreon,
Research Funding: AbbVie, Astellas Pharma, Incyte, Macrogenics, Janssen Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Genentech,
Oncology Myovant Sciences
Patents, Royalties, Other Intellectual Property: Patent licensed by University of Speakers’ Bureau: Janssen, Bayer, Dendreon
Chicago of which I am co-inventor to Corcept Therapeutics for combination AR/
GR inhibition in prostate cancer Brad Rosbrook
Travel, Accommodations, Expenses: Corcept Therapeutics Employment: Pfizer
Daniel P. Petrylak Stock and Other Ownership Interests: Pfizer
Stock and Other Ownership Interests: Bellicum Pharmaceuticals, Tyme
Consulting or Advisory Role: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, Jennifer Sugg
AstraZeneca, Lilly, Ada Cap, Amgen, Boehringer Ingelheim, Bristol-Myers Employment: Astellas Pharma
Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, Stock and Other Ownership Interests: AstraZeneca
Urogen Pharma
Benoit Baron
Research Funding: Progenics (Inst), Sanofi (Inst), Endocyte (Inst), Genentech
Employment: Astellas Pharma (during conduct of the study)
(Inst), Merck (Inst), Astellas Medivation (Inst), Novartis (Inst), AstraZeneca (Inst),
Consulting or Advisory Role: Astellas Pharma
Bayer (Inst), Lilly (Inst), Innocrin Pharma (Inst), MedImmune (Inst), Pfizer (Inst),
Travel, Accommodations, Expenses: Astellas Pharma
Roche (Inst), Seattle Genetics (Inst), Clovis Oncology (Inst), Ada Cap (Inst),
Bristol-Myers Squibb (Inst)
Lucy Chen
Expert Testimony: Celgene, Sanofi
Employment: Astellas Pharma
Jeffrey Holzbeierlein Honoraria: Abbvie (I), Reflexion Medical (I)
Research Funding: Astellas Pharma (Inst), MDxHealth (Inst) Consulting or Advisory Role: AbbVie (I), Reflexion Medical (I)
Travel, Accommodations, Expenses: AbbVie (I), Reflexion Medical (I)
Arnauld Villers
Consulting or Advisory Role: Astellas Pharma
Arnulf Stenzl
Research Funding: Astellas Pharma (Inst), Ipsen (Inst) Consulting or Advisory Role: Ipsen Pharma, Roche, Janssen, Alere, Bristol-
Travel, Accommodations, Expenses: Astellas Pharma, Janssen-Cilag
Myers-Squibb, Stebabiotech
Arun Azad Research Funding: Karl Storz AG, Astellas Pharma, AstraZeneca, Medivation,
Honoraria: Janssen, Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer, Bayer, Janssen
Telix Pharmaceuticals Patents, Royalties, Other Intellectual Property: Patent A290/99: Implantable
Consulting or Advisory Role: Astellas Pharma, Novartis, Janssen, Sanofi, incontinence device; AT00/0001: C-Trap, implantable device to treat urinary
AstraZeneca, Pfizer, Bristol-Myers Squibb, Tolmar, Telix Pharmaceuticals incontinence; 2018/6579: Gene-expression signature for subtype and
Speakers’ Bureau: Astellas Pharma, Novartis, Amgen, Bayer prognostic prediction of renal cell carcinoma
Research Funding: Astellas Pharma, Merck Serono (Inst) Expert Testimony: GBA photodynamic therapy of prostate cancer
Travel, Accommodations, Expenses: Astellas Pharma, Sanofi, Merck Serono Travel, Accommodations, Expenses: Janssen, Ipsen Pharma, Sanofi Aventis,
CureVac, Ferring
Antonio Alcaraz
Travel, Accommodations, Expenses: Astellas, Olympus, Ipsen, Janssen, Bayer No other potential conflicts of interest were reported.

Journal of Clinical Oncology

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 Armstrong et al

APPENDIX

Radiographic
progression-free
survival

N
P < .05? Stop

 = 0.04 Y  = 0.01

Time to prostate-specific
Overall survival
antigen progression

 = 0.05*
N
P < .01? Stop

Y
Time to initiation of
new antineoplastic
therapy

N
P < .01? Stop

Prostate-specific antigen
undetectable rate

N
P < .01? Stop

Objective response rate

N
P < .01? Stop

Time to deterioration
in urinary symptoms

Y N
P < .01? Stop

FIG A1. Multiplicity adjustment strategy. (*) Overall survival will be

tested at 0.05 only if all the other five secondary end points analyses
are statistically significant at 0.01, otherwise it will be tested at 0.04.
N, no; Y, yes.

© 2019 by American Society of Clinical Oncology Volume 37, Issue 32

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