EMBARK: A Phase 3 Randomized Study of

Enzalutamide or Placebo Plus Leuprolide Acetate

and Enzalutamide Monotherapy in High-Risk
Biochemically Recurrent Prostate Cancer
Neal D. Shore,1 Murilo de Almeida Luz,2 Ugo De Giorgi,3 Martin Gleave,4 Geoffrey T. Gotto,5
Gabriel P. Haas,6 Miguel Ramirez-Backhaus,7 Antti Rannikko,8 Jamal Tarazi,9 Swetha Sridharan,10
Jennifer Sugg,6 Yiyun Tang,11 Ronald F. Tutrone, Jr.,12 Balaji Venugopal,13 Arnauld Villers,14 Henry
H. Woo,15 Fabian Zohren,16 Stephen J. Freedland17
1
Carolina Urologic Research Center/GenesisCare US, Myrtle Beach, SC, USA; 2Erasto Gaertner Hospital, Curitiba,
Brazil; 3IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy; 4University of British
Columbia, Vancouver, BC, Canada; 5University of Calgary, Calgary, AB, Canada; 6Astellas Pharma Inc., Northbrook,
IL, USA; 7Servicio de Urología, Fundación Instituto Valenciano de Oncología, Valencia, Spain; 8University of Helsinki
and Helsinki University Hospital, Helsinki, Finland; 9Pfizer Inc., Collegeville, PA, USA; 10Calvary Mater, Newcastle,
NSW, Australia; 11Pfizer Inc., San Francisco, CA, USA; 12Chesapeake Urology Research Associates, Towson, MD,
USA; 13Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK; 14University of Lille,
Department of Urology, Claude Huriez Hospital, CHU LILLE, Lille, France; 15Sydney Adventist Hospital, Sydney,
NSW, Australia; 16Pfizer Inc., Cambridge, MA, USA; 17Samuel Oschin Comprehensive Cancer Institute,
Cedars-Sinai Medical Center, Los Angeles, CA, USA
 aPLS

Disclosures and
acknowledgements

• Disclosures: Neal D. Shore reports grant support and consulting fees from AbbVie, Amgen,
Astellas Pharma Inc., AstraZeneca, Bayer, Clovis Oncology, Dendreon Pharmaceuticals LLC,
Ferring Pharmaceuticals, GenesisCare, Janssen Oncology, Merck, Myovant Sciences, Pfizer Inc.,
Sanofi-Genzyme, and Tolmar Pharmaceuticals, Inc.
• Funding: This study was sponsored by Astellas Pharma Inc. and Pfizer Inc.
• Acknowledgements: The authors thank all the patients, their families, and the investigators and
investigational site members involved in this study. Medical writing and editorial support were
provided by Julie B. Stimmel, PhD, CMPP, Sinead Stewart, and Rosie Henderson, of Onyx
(a Prime Global Agency), funded by Pfizer, Inc. and Astellas Pharma Inc., the co-developers
of enzalutamide.
 Introduction

• Within 10 years following definitive therapy, between 20–50% of patients experience disease
recurrence characterized by rising PSA levels.1-3

• Limited level 1 clinical data exists for the treatment of patients with BCR.

• Patients with high-risk BCR are at increased risk of prostate cancer-specific mortality. 3-5

• Evidence from phase 3 clinical trials demonstrates that treatment intensification with ARSI, such as
enzalutamide, consistently improves patient outcomes across the prostate cancer continuum. 6-10

The objective of EMBARK was to evaluate enzalutamide in combination with leuprolide acetate
and enzalutamide monotherapy earlier in the prostate cancer disease course.

1. Kupelian PA, et al. Cancer. 2002;95:2302–7. 2. Kupelian PA et al. Urology. 2006;68;593–8. 3. Freedland SJ et al. JAMA. 2005;294:433–9. 4. Freedland SJ, et al. J Clin Oncol. 2007; 25:1765–71. 5. Markowski MC, et al. Clin Genitourin Cancer.
2019;17:470–1. 6. Scher HI, et al. N Engl J Med. 2012;367:1187–97. 7. Beer TM, et al. N Engl J Med. 2014;371:424–33. 8. Hussain M, et al. N Engl J Med. 2018;378:2465–74. 9. Armstrong AJ, et al. J Clin Oncol. 2019;37:2974–86. 10. Davis ID, et al. N Engl
J Med. 2019;381:121–31. ARSI, androgen receptor signaling inhibitor; BCR, biochemical recurrence; PSA, prostate-specific antigen.
 aPLS

EMBARK study design

Enzalutamide (160 mg oral qd) Primary endpointb:

Patient population:
+ leuprolide acetate
• Screening PSA ≥1 ng/mL after RP (22.5 mg IM/q12w) Week 37 MFS by BICR, enzalutamide +
and at least 2 ng/mL above the nadir Suspend leuprolide acetate vs. leuprolide
n = 355
for primary EBRT Blinded treatment at acetate alone
• PSADT ≤9 mo Yes week 37
Monitor PSA

PSA <0.2 ng/mLa

• No metastases on bone scan or Key secondary endpointsb,c:
(reinitiate if
CT/MRI per central read Placebo + leuprolide acetate PSA rises) • MFS by BICR, enzalutamide
• Testosterone ≥150 ng/dL R (22.5 mg IM/q12w) monotherapy vs. leuprolide
• Prior hormonal therapy ≥9 mo prior 1:1:1 n = 358 acetate alone
to R (≤36 mo OR ≤6 mo for rising Blinded
N = 1068 • Time to PSA progression
PSA)
No • Time to first use of new
Stratification factors: Remain on
treatment antineoplastic therapy
• Screening PSA (≤10 ng/mL vs. Enzalutamide monotherapy • OSc
>10 ng/mL) (160 mg oral qd)
n = 355 Other secondary endpoints:
• PSADT (≤3 mo vs. >3 to ≤9 mo)
Unblinded • Safety
• Prior hormonal therapy (yes vs. no)

a
Study treatment was suspended once if PSA was <0.2 ng/mL at week 37 and restarted when PSA was ≥5.0 ng/mL (without prior RP) and ≥2 ng/mL (prior RP). bIntent-to-treat population. cPrimary endpoint and key secondary endpoints for enzalutamide
combination and enzalutamide monotherapy are alpha-protected. cP-value to determine significance for OS of combination and monotherapy treatment comparisons was dependent on outcomes of primary endpoint and key secondary endpoints.
BICR, blinded independent central review; CT, computed tomography; d, day; EBRT, external beam radiotherapy; IM, intramuscular; MFS, metastasis-free survival; mo, month; MRI, magnetic resonance imaging; OS, overall survival; PSA, prostate-specific
antigen; PSADT, PSA doubling time; q, every; R, randomization; RP, radical prostatectomy; w, weeks.
 Demographics
Enzalutamide combination Leuprolide acetate Enzalutamide monotherapy
Characteristic (n = 355) (n = 358) (n = 355)
Age, median (range), yr 69 (51–87) 70 (50–92) 69 (49–93)
Race, n (%)a
White 293 (82.5) 301 (84.1) 295 (83.1)
Asian 26 (7.3) 26 (7.3) 26 (7.3)
Black 16 (4.5) 16 (4.5) 15 (4.2)
Otherb 10 (2.8) 10 (2.8) 5 (1.4)
PSADT, n (%)c
≤3 mo 69 (19.4) 80 (22.3) 76 (21.4)
>3 to ≤9 mo 285 (80.2) 277 (77.4) 278 (78.3)
PSADT, median, mo 4.6 5.0 5.0
Serum PSA, median, ng/mL 5.0 5.5 5.3
≤10, n (%) 278 (78.3) 273 (76.3) 272 (76.6)
>10, n (%) 77 (21.7) 83 (23.2) 82 (23.1)
Prior hormonal therapy, n (%) 107 (30.1) 113 (31.6) 112 (31.5)
RP alone, n (%) 90 (25.4) 75 (20.9) 99 (27.9)
RT alone, n (%) 86 (24.2) 104 (29.1) 90 (25.4)
RP and RT, n (%) 179 (50.4) 179 (50.0) 166 (46.8)
a
Not reported included: enzalutamide combination, n = 10 (2.8%); leuprolide acetate, n = 5 (1.4%); enzalutamide monotherapy, n = 14 (3.9%). bIncludes patients who identified as multiple races (enzalutamide combination, n = 5; leuprolide acetate, n = 9;
enzalutamide monotherapy, n = 5), American Indian or Alaskan Native (enzalutamide combination, n = 4; leuprolide acetate, n = 1; enzalutamide monotherapy, n = 0), Native Hawaiian or other Pacific Islander (enzalutamide combination, n = 1; leuprolide
acetate and enzalutamide monotherapy, n = 0). cMissing included n = 1 (0.3%) for each treatment group. RT, radiation therapy; yr, year.
 Primary endpoint — MFS for enzalutamide
combination vs. leuprolide acetate
3-yr rate
92.9% 5-yr rate
83.5% 87.3%
100 71.4% Enzalutamide Leuprolide
combination acetate
(n = 355) (n = 358)
80 Median follow-up, mo 60.7 60.6
Enzalutamide combination Events, n (%) 45 (13) 92 (26)
Leuprolide acetate Per BICR, median MFS NR (NR)
NR
60
MFS (%)

(95% CI), mo (85.1–NR)

40 Stratified HR (95% CI):

0.42 (0.31–0.61); P<0.0001a
20

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
MFS (mo)
Patients at risk
Enzalutamide 355 331 324 318 304 292 281 265 251 234 180 116 60 24 6 0 0
combination
Leuprolide acetate 358 335 321 303 280 259 238 221 203 183 138 88 32 15 6 1 0

A consistent treatment effect was seen for investigator-assessed MFS: HR (95% CI): 0.47 (0.37–0.67); P<0.0001
Data cutoff: January 31, 2023. aHR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring enzalutamide
combination. The two-sided P-value is based on a stratified log-rank test by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS. CI, confidence interval; HR, hazard ratio; IWRS, interactive web response system; NR, not reached.
 Subgroup analysis of MFS for enzalutamide
combination vs. leuprolide acetate
Enzalutamide Leuprolide
combination acetate
Subgroup Events, n /patients, n MFS HR (95% CI)
All patients 45/355 92/358 0.42 (0.30–0.61)
PSADT ≤3 mo 14/69 30/80 0.46 (0.24–0.88)
>3 to ≤6 mo 18/187 35/142 0.33 (0.19–0.59)
>6 to ≤9 mo 13/98 27/135 0.63 (0.32–1.22)
Baseline age ≤65 years 11/81 28/91 0.40 (0.20–0.81)
≥65 years 34/274 64/267 0.44 (0.29–0.67)
Geographic region North America 22/144 32/137 0.62 (0.36–1.06)
Europe 14/130 33/128 0.35 (0.19–0.66)
ROW 9/81 27/93 0.32 (0.15–0.68)
Baseline PSA ≤10 ng/mL 31/278 64/273 0.42 (0.27–0.64)
>10 ng/mL 14/77 28/83 0.45 (0.24–0.85)
Prior hormonal therapy Yes 19/107 34/113 0.48 (0.28–0.85)
No 26/248 58/245 0.39 (0.25–0.62)
Prior RP Yes 26/269 61/254 0.36 (0.23–0.58)
No 19/86 31/104 0.57 (0.32–1.00)
0.0 0.5 1.0 1.5 2.0
Favors enzalutamide combination Favors leuprolide acetate
Data cutoff: January 31, 2023. The HR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring
enzalutamide.
 Key secondary endpoint — MFS for
enzalutamide monotherapy vs.
leuprolide acetate

100 Enzalutamide Leuprolide

monotherapy acetate
(n = 355) (n = 358)

80 Median follow-up, mo 60.7 60.6

Enzalutamide monotherapy Events, n (%) 63 (18) 92 (26)
Leuprolide acetate Per BICR, median MFS NR (NR) NR
60
MFS (%)

(95% CI), mo (85.1–NR)

40 Stratified HR (95% CI):

0.63 (0.46–0.87); P=0.0049a
20

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
MFS (mo)
Patients at risk
Enzalutamide 355 342 328 309 287 273 260 247 228 209 171 108 52 26 5 0 0
monotherapy
Leuprolide acetate 358 335 321 303 280 259 238 221 203 183 138 88 32 15 6 1 0

A consistent treatment effect was seen for investigator-assessed MFS: HR (95% CI): 0.56 (0.40–0.78); P=0.0006

Data cutoff: January 31, 2023. aThe HR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring
enzalutamide. The two-sided P-value is based on a stratified log-rank test by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS.
 Key secondary endpoint — Time to PSA
progression for enzalutamide combination
vs. leuprolide acetate

100 Enzalutamide Leuprolide

combination acetate
(n = 355) (n = 358)
PSA progression free (%)

80 Events, n (%) 8 (2) 93 (26)

Enzalutamide combination Median time to PSA NR (NR) NR (NR)
Leuprolide acetate progression (95% CI),
60 mo

40 Stratified HR (95% CI):

0.07 (0.03–0.14); P<0.0001a
20

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Time to PSA progression (mo)
Patients at risk
Enzalutamide 355 337 326 319 302 286 270 260 247 230 175 119 75 37 12 0
combination
Leuprolide acetate 358 341 314 293 268 253 223 201 182 168 128 83 42 20 7 3

Data cutoff: January 31, 2023. aThe HR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring
enzalutamide. The two-sided P-value is based on a stratified log-rank test by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS.
 Key secondary endpoint — Time to first use of
new antineoplastic therapy for enzalutamide
combination vs. leuprolide acetate

100 Enzalutamide Leuprolide

combination acetate
Antineoplastic therapy free (%)

(n = 355) (n = 358)
80 Events, n (%) 58 (16) 140 (39)
Enzalutamide combination Median time to first use
NR (NR) 76.2
Leuprolide acetate of new antineoplastic (71.3–NR)
60 therapy (95% CI), mo

40 Stratified HR (95% CI):

0.36 (0.26–0.49); P<0.0001a
20

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time to first use of new antineoplastic therapy (mo)
Patients at risk
Enzalutamide 355 342 335 328 318 302 292 284 273 255 195 135 87 43 16 3 0
combination
Leuprolide acetate 358 342 332 322 304 281 262 240 218 202 149 100 56 25 9 3 0

Data cutoff: January 31, 2023. aThe HR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring
enzalutamide. The two-sided P-value is based on a stratified log-rank test by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS.
 Key secondary endpoint — Interim OS for
enzalutamide combination vs. leuprolide
acetate

100 Enzalutamide Leuprolide

combination acetate
(n = 355) (n = 358)
80 Events, n (%) 33 (9) 55 (15)
Enzalutamide combination Median time to death
Leuprolide acetate (95% CI), mo NR (NR) NR (NR)
60
OS (%)

40 Stratified HR (95% CI):

0.59 (0.38–0.90) P=0.0142a
20 (Pre-specified efficacy boundary, P<0.0001)

0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
OS (mo)
Patients at risk
Enzalutamide 355 350 346 337 335 331 322 316 307 292 232 163 101 53 20 4 0
combination
Leuprolide acetate 358 351 346 343 341 329 321 312 301 287 224 157 99 49 20 6 0

Final analysis at 271 deaths across all treatment groups.

Data cutoff: January 31, 2023. aThe HR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring
enzalutamide. The two-sided P-value is based on a stratified log-rank test by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS.
 Key secondary endpoint — Interim OS of
enzalutamide monotherapy vs. leuprolide
acetate

100 Enzalutamide Leuprolide

monotherapy acetate
(n = 355) (n = 358)
80 Events, n (%) 42 (12) 55 (15)
Enzalutamide monotherapy Median time to death NR
Leuprolide acetate (95% CI), mo NR (NR) (85.1–NR)
60
OS (%)

40 Stratified HR (95% CI):

0.77 (0.51–1.15);
20
nominal P=0.1963a
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Overall survival (mo)
Patients at risk
Enzalutamide 355 353 349 344 340 333 324 312 298 289 227 155 97 50 15 3 0
monotherapy
Leuprolide acetate 358 351 346 343 341 329 321 312 301 287 224 157 99 49 20 6 0

Final analysis at 271 deaths across all treatment groups.

Data cutoff: January 31, 2023. aThe HR was based on a Cox regression model with treatment as the only covariate stratified by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS; relative to leuprolide acetate <1 favoring
enzalutamide. The two-sided P-value is based on a stratified log-rank test by screening PSA, PSADT, and prior hormonal therapy as reported in the IWRS.
 Secondary endpoint — Undetectable PSA

Patients with PSA <0.2 ng/mL at week 36 Median duration of treatment suspensiona

100 25
90.0
90 85.9
20.2
80 20
70 67.8 16.8

Duration (mo)
Patients (%)

60 15
50 11.1
40 10
30
20 5
10
0 0
Enzalutamide
Enzalutamide Leuprolide
Leuprolide Enzalutamide
Enzalutamide Enzalutamide
Enzalutamide Leuprolide
Leuprolide Enzalutamide
Enzalutamide
combination acetate monotherapy combination acetate monotherapy
combination acetate monotherapy combination acetate monotherapy

Data cutoff: January 31, 2023. aLast date of suspension without treatment. .
 Effect of treatment on serum testosterone

Treatment
850 Treatment
suspended
Enzalutamide monotherapy (11.1 mo)
750 suspended
Mean testosterone (95% CI)

650

550

450
Leuprolide acetate (16.8 mo)
350

250 Enzalutamide combination (20.2

150 mo)

50
0
–50

–150

BL Wk Wk 6 12 18 24 30 36 42 48 54 60 66 72 78 84
25 37 Time from treatment suspension at week 37 (mo)
Enzalutamide combination 351 328 294 281 273 268 250 251 234 231 217 191 142 97 68 33 12
Leuprolide acetate 354 329 304 286 281 253 238 222 213 192 188 154 107 74 40 22 8
Enzalutamide monotherapy 354 333 314 303 298 279 265 243 233 219 203 182 126 92 60 35 9
 Safety profile

Enzalutamide combination Leuprolide acetate Enzalutamide monotherapy

(n = 353) (n = 354) (n = 354)
Event, n (%)a All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3
Any AE 343 (97.2) 164 (46.5) 345 (97.5) 151 (42.7) 347 (98.0) 177 (50.0)
Treatment-related AE 305 (86.4) 62 (17.6) 283 (79.9) 31 (8.8) 312 (88.1) 57 (16.1)
Serious AE 123 (34.8) 110 (31.2) 112 (31.6) 100 (28.2) 131 (37.0) 116 (32.8)
Treatment-related serious AE 26 (7.4) 22 (6.2) 8 (2.3) 7 (2.0) 17 (4.8) 17 (4.8)
AE leading to dose reduction 25 (7.1) 11 (3.1) 16 (4.5) 5 (1.4) 56 (15.8) 14 (4.0)
AE leading to permanent
73 (20.7) 31 (8.8) 36 (10.2) 19 (5.4) 63 (17.8) 34 (9.6)
discontinuation
AE leading to death – 6 (1.7)b – 3 (0.8)b – 8 (2.3)b

• Median treatment duration excluding treatment suspension was 32.4 mo (range, 0.1–83.4 mo) for enzalutamide combination,
35.4 mo (range, 0.7–85.7 mo) for leuprolide acetate, and 45.9 mo (0.4–88.9 mo) for enzalutamide monotherapy.
• The most common AE leading to study drug discontinuation was fatigue (enzalutamide combination, 3.4% [n = 12]; leuprolide
acetate, 1.1% [n = 4]; enzalutamide monotherapy, 2.3% [n = 8]).

Data cutoff: January 31, 2023. aPercentages may not total 100 because of rounding. Shown are AE that occurred from the time of first dose of study treatment through 30 days after permanent discontinuation. AE were graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events version 4.03. bGrade 5 AE; none were considered treatment-related. AE, adverse event.
 Most common TEAEs

Enzalutamide combination Leuprolide acetate Enzalutamide monotherapy

(n = 353) (n = 354) (n = 354)
Most common TEAEs (>15% of
All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3
patients), n (%)a
Hot flash 243 (68.8) 2 (0.6) 203 (57.3) 3 (0.8) 77 (21.8) 1 (0.3)
Fatigue 151 (42.8) 12 (3.4) 116 (32.8) 5 (1.4) 165 (46.6) 14 (4.0)
Arthralgia 97 (27.5) 5 (1.4) 75 (21.2) 1 (0.3) 81 (22.9) 1 (0.3)
Hypertension 82 (23.2) 2 (0.6) 69 (19.5) 0 67 (18.9) 0
Fall 74 (21.0) 3 (0.8) 51 (14.4) 2 (0.6) 56 (15.8) 5 (1.4)
Back pain 60 (17.0) 1 (0.3) 54 (15.3) 0 62 (17.5) 1 (0.3)
Nausea 42 (11.9) 0 29 (8.2) 0 54 (15.3) 1 (0.3)
Gynecomastia 29 (8.2) 0 32 (9.0) 0 159 (44.9) 1 (0.3)
Nipple pain 11 (3.1) 0 4 (1.1) 0 54 (15.3) 0

• The most common AEs (>15% of patients) for all treatment cohorts were hot flash, fatigue; plus gynecomastia in the enzalutamide
monotherapy cohort; most were grade <3.

Data cutoff: January 31, 2023. aPercentages may not total 100 because of rounding. Shown are AEs that occurred from the time of first dose of study treatment through 30 days after permanent discontinuation. AEs were graded according to the National
Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. TEAE, treatment-emergent AE.
 Selected TEAEs of special interest

Enzalutamide combination Leuprolide acetate Enzalutamide monotherapy

(n = 353) (n = 354) (n = 354)
TEAEs of special interest, n (%)a All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3
Fatigueb 178 (50.4)c 14 (4.0) 134 (37.9)c 6 (1.7) 191 (54.0)c 17 (4.8)
Musculoskeletal eventsd 163 (46.2)c 13 (3.7) 148 (41.8)c 4 (1.1) 158 (44.6)c 6 (1.7)
Hypertension 89 (25.2)c 27 (7.6) 74 (20.9) 21 (5.9) 77 (21.8)c 20 (5.6)
Fall 74 (21.0) 4 (1.1) 51 (14.4) 4 (1.1) 56 (15.8) 7 (2.0)
Fracturee 65 (18.4) 14 (4.0) 48 (13.6) 9 (2.5) 39 (11.0) 7 (2.0)
Cognitive and memory impairment 53 (15.0)c 2 (0.6) 23 (6.5) 2 (0.6) 50 (14.1)c 0
Loss of consciousnessf 20 (5.7) 17 (4.8) 12 (3.4) 6 (1.7) 12 (3.4) 8 (2.3)
Ischemic heart disease 19 (5.4) 14 (4.0) 20 (5.6) 11 (3.1) 32 (9.0) 21 (5.9)
Other selected CV eventsg 18 (5.1) 13 (3.7) 17 (4.8) 10 (2.8) 13 (3.7) 8 (2.3)
Convulsion (seizure) 4 (1.1) 2 (0.6) 0 0 3 (0.8) 2 (0.6)

• The most common AEs of special interest for all treatment cohorts (≥10% of patients) were fatigue, fall, fracture, hypertension, and
musculoskeletal events.
Data cutoff: January 31, 2023. aPercentages may not total 100 because of rounding. Shown are AEs that occurred from the time of first dose of study treatment through 30 days after permanent discontinuation. AEs were graded according to the
National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Bolded TEAEs are grouped AEs. bFatigue events included asthenia. cThe most common (≥10% of patients) TEAEs. dMusculoskeletal events included back pain,
arthralgia, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal stiffness, muscular weakness, and muscle spasms. eFractures excluded tooth fracture and fracture of the penis. f Loss of consciousness included syncope and presyncope. gOther
selected CV events included hemorrhagic central nervous system vascular conditions, ischemic central nervous system vascular conditions, and cardiac failure. CV, cardiovascular.
 aPLS

EMBARK: Conclusions

• In patients with high-risk BCR, compared with leuprolide acetate, enzalutamide

combination demonstrated a statistically significant and clinically meaningful
improvement in MFS (HR 0.42; 95% CI, 0.30–0.61; P<0.0001).
− A consistent treatment effect in pre-specified subgroups
− Significant reductions in time to PSA progression and time to first new antineoplastic therapy
− A trend toward improved survival in interim analysis (HR 0.59; 95% CI, 0.38–0.90; P=0.0142);
study ongoing for final analysis
• Enzalutamide monotherapy also demonstrated statistically significant and
clinically improvements in MFS (HR 0.63; 95% CI 0.46–0.87); P=0.0049.
• No new safety signals observed to date with enzalutamide treatment

Enzalutamide in combination with ADT, if approved in this setting, has the potential
to become a new standard of care for patients with high-risk BCR.
.
 EMBARK was a global, multicenter study
with 244 sites across 17 countries
• The first patient was randomized on January 26, 2015; the last patient started on treatment August 1, 2018.
• The authors thank the patients, their families, all other investigators, and all investigational site members
involved in this study.
• Australia
• Austria
• Brazil
• Canada
• Denmark
• Finland
• France
• Italy
• Korea, Republic of
• Netherlands
• Poland
• Slovakia
• Spain
• Sweden
• Taiwan
• United Kingdom
• United States
Back-up slides
 aPLS

Patient disposition

1068 underwent randomization

355 were allocated to enzalutamide combination 358 were allocated to leuprolide acetate 355 were allocated to enzalutamide monotherapy

2 underwent randomization, but were not treated 4 underwent randomization, but were not treated 1 underwent randomization, but was not treated

353 received enzalutamide combination and were 354 received leuprolide acetate and were included in 354 received enzalutamide monotherapy and were
included in the safety analysis the safety analysis included in the safety analysis

201 discontinued treatment

• 36 had an adverse event
• 32 withdrew consent 157 discontinued treatment
146 discontinued treatment • 63 had an adverse event
• 73 had an adverse event • 66 had radiographic progression
• 25 withdrew consent
• 26 had radiographic progression • 41 had other reasons
• 37 had radiographic progression
• 17 had other reasons • 20 had PSA progression
• 26 had other reasons
• 2 had PSA progression • 2 had castration resistance
• 5 had PSA progression
• 2 had protocol deviation • 2 had protocol deviation
• 1 had protocol deviation
• 1 was lost due to follow-up
• 1 due to site closure

207 continued to receive treatment 153 continued to receive treatment

• 114 with treatment reinitiation 197 continued to receive treatment
• 168 with treatment reinitiation • 171 with treatment reinitiation
• 34 with treatment suspension, but no reinitiation • 14 with treatment suspension, but no reinitiation
• 25 without treatment suspension • 13 with treatment suspension, but no reinitiation
• 5 without treatment suspension • 13 without treatment suspension
 Hierarchical statistical testing for
secondary endpoints
Enzalutamide combination: MFS
• P-value to determine significance α1 = 0.05

for OS of combination and Significant

monotherapy treatment
comparisons was dependent on Enzalutamide combination: Time to PSA progression Enzalutamide monotherapy: MFS
α2 = 0.02 α3 = 0.03
outcomes of primary endpoint
(MFS) and key secondary Significant
Significant

endpoints Enzalutamide monotherapy: Time to PSA progression

Enzalutamide combination: Time to antineoplastic α3 = 0.03
– time to PSA progression therapy α2 = 0.02
Significant
– time to first new antineoplastic Significant
therapy Enzalutamide monotherapy: Time to antineoplastic
therapy α3 = 0.03

Significant
Enzalutamide combination: OS
α4 = (α2+α3)*

Significant

Enzalutamide monotherapy: OS
α4