History of Changes for Study: NCT02677896

Version	Submitted Date	Changes
1	February 5, 2016	None (earliest Version on record)
2	April 4, 2016	Recruitment Status, Study Status and Contacts/Locations
3	May 13, 2016	Recruitment Status, Study Status and Contacts/Locations
4	June 17, 2016	Contacts/Locations and Study Status
5	July 25, 2016	Recruitment Status, Study Status, Contacts/Locations and Eligibility
6	September 14, 2016	Contacts/Locations and Study Status
7	March 17, 2017	Study Status and Contacts/Locations
8	May 4, 2017	Contacts/Locations and Study Status
9	August 15, 2017	Study Status, Contacts/Locations and Oversight
10	December 7, 2017	Contacts/Locations and Study Status
11	January 26, 2018	Recruitment Status, Contacts/Locations, Study Status, Study Design, Eligibility and Study Identification
12	March 29, 2018	Study Status and Contacts/Locations
13	April 5, 2018	Contacts/Locations and Study Status
14	May 7, 2018	Contacts/Locations and Study Status
15	July 10, 2018	Study Status and Contacts/Locations
16	August 27, 2018	Study Status and Contacts/Locations
17	November 26, 2018	IPDSharing, Study Status and Sponsor/Collaborators
18	January 30, 2019	Study Status, Eligibility, Outcome Measures and Study Description
19	February 5, 2019	Contacts/Locations and Study Status
20	April 25, 2019	Study Status
21	August 9, 2019	Study Status
22	October 1, 2019	Study Status and IPDSharing
23	January 8, 2020	Outcome Measures, Study Status, Arms and Interventions, More Information, Study Description, Document Section, Adverse Events, Baseline Characteristics and Participant Flow
24	February 10, 2020	Outcome Measures, Study Status, Baseline Characteristics, Adverse Events
25	April 1, 2020	Study Status and Contacts/Locations
26	April 8, 2020	References and Study Status
27	April 23, 2020	Contacts/Locations and Study Status
28	May 29, 2020	Study Status
29	July 1, 2020	Study Status
30	October 26, 2020	Study Status
31	November 27, 2020	Study Status
32	January 16, 2021	Study Status
33	March 9, 2021	Study Status
34	April 8, 2021	Study Status
35	June 18, 2021	Study Status
36	August 18, 2021	Study Status
37	September 3, 2021	Study Status
38	October 19, 2021	Oversight and Study Status
39	December 9, 2021	Study Status
40	January 1, 2022	Study Status
41	January 25, 2022	Study Status
42	February 23, 2022	Study Status
43	April 1, 2022	Outcome Measures, Adverse Events, Participant Flow, Arms and Interventions, Baseline Characteristics, Study Status and References
44	May 11, 2022	Study Status
45	June 23, 2022	Study Status
46	July 29, 2022	Study Status
47	August 18, 2022	Study Status
48	September 19, 2022	Study Status
49	October 25, 2022	Study Status
50	November 16, 2022	Study Status
51	December 23, 2022	Study Status
52	January 17, 2023	Study Status
53	February 22, 2023	Study Status
54	March 15, 2023	Study Status
55	June 18, 2023	Study Status
56	July 19, 2023	Study Status
57	August 21, 2023	Study Status
58	September 29, 2023	Study Status
59	October 25, 2023	Study Status
60	November 17, 2023	Study Status
61	December 19, 2023	Study Status
62	January 18, 2024	Study Status
63	February 19, 2024	Study Status
64	March 15, 2024	Study Status
65	April 18, 2024	Study Status
66	May 22, 2024	Study Status

Record Verification:

February 2024

Overall Status:

Active, not recruiting

Study Start:

March 9, 2016

Primary Completion:

October 14, 2018 [Actual]

Study Completion:

July 31, 2024 [Anticipated]

First Submitted:

February 5, 2016

First Submitted that
Met QC Criteria:

February 5, 2016

First Posted:

February 9, 2016 [Estimate]

Results First Submitted:

January 8, 2020

Results First Submitted that
Met QC Criteria:

January 8, 2020

Results First Posted:

January 21, 2020 [Actual]

Certification/Extension
First Submitted:

October 1, 2019

Certification/Extension
First Submitted that
Met QC Criteria:

October 1, 2019

Certification/Extension
First Posted:

October 9, 2019 [Actual]

Last Update Submitted that
Met QC Criteria:

February 19, 2024

Last Update Posted:

February 21, 2024 [Actual]

Arms

Assigned Interventions

Experimental: Enzalutamide + Androgen Deprivation Therapy (ADT)

Participants received 160 mg enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.

Drug: Enzalutamide

Oral

Other Names:

Xtandi

Placebo Comparator: Placebo + Androgen Deprivation Therapy (ADT)

Participants received matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.

Drug: Placebo

Oral

Experimental: Placebo followed by Enzalutamide

Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.

Drug: Enzalutamide

Oral

Other Names:

Xtandi

Primary Outcome Measures:

Radiographic Progression-Free Survival (rPFS) Based on Independent Central Review (ICR) of Bone Scan According to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria
[ Time Frame: From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline or week 13 according to PCWG2 criteria, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.

rPFS Based on ICR of Bone Scan According to Protocol Assessment Criteria
[ Time Frame: From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months. ]

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline for week 13 or the best response on treatment for week 25 or later assessments, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.

Secondary Outcome Measures:

Overall Survival (OS)
[ Time Frame: From date of randomization to OS final analysis (28 May 2021); Maximum treatment duration was 58.6 months ]

OS was defined as the time from randomization to death due to any cause. In participants still alive at the date of the analysis cutoff point, OS was censored on the last date the participant was known to be alive. OS was analyzed using Kaplan-Meier estimates.

Time to Prostate Specific Antigen (PSA) Progression
[ Time Frame: From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

Time to PSA progression was calculated as the time from the date of randomization to the first observation of PSA progression. A PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir, which was confirmed by a second consecutive value at least 3 weeks later. In participants with no PSA progression, time to PSA progression was censored on the date of the last PSA sample taken (or last value prior to 2 or more consecutive missed PSA assessments).

Time to Start of New Antineoplastic Therapy
[ Time Frame: From date of randomization to data cut-off date (28 May 2021); Maximum treatment duration was 58.6 months ]

In participants with a new antineoplastic therapy initiated for prostate cancer after randomization, time to start of a new antineoplastic therapy was defined as the time interval from randomization to the date of the first dose administration of the first antineoplastic therapy. In participants with no new antineoplastic therapy initiated for prostate cancer after randomization, time to start of new antineoplastic therapy was censored on the last visit date or the date of randomization, whichever occurred last. Time to start of new antineoplastic therapy was analyzed using Kaplan-Meier estimates.

PSA Undetectable Rate
[ Time Frame: Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

The PSA undetectable rate was defined as the percentage of participants with undetectable (< 0.2 ng/mL) PSA values at any time during study treatment, of those participants with detectable (≥ 0.2 ng/mL) PSA values at baseline.

Objective Response Rate (ORR)
[ Time Frame: Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

The ORR was calculated as the percentage of participants who achieved a completed response (CR) or a partial response (PR) (unconfirmed responses) in their soft tissue disease using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by ICR.

Time to Deterioration in Urinary Symptoms
[ Time Frame: From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

In participants with deterioration, the time to deterioration was calculated as the time interval between randomization and the first deterioration in urinary symptoms at any postbaseline visit. A deterioration in urinary symptoms was defined as an increase in the Quality of Life Prostate-specific Questionnaire (QLQ-PR25) modified urinary symptoms. Subscale score by ≥ 50% of the standard deviation observed in the QLQ-PR25 modified urinary symptoms subscale score at baseline. Modified urinary symptoms subscale score consisted of 3-items (Q31 - Q33) from the QLQ-PR25, each scored from 1 (not at all) to 4 (very much). The total modified urinary symptoms subscale score ranges from 0-100, with higher scores represents a higher level of symptomatology/problems. In participants without deterioration in urinary symptoms, the time to deterioration in urinary symptoms was censored on the date the last urinary symptoms QLQ-PR25 score was calculable.

Time to First Symptomatic Skeletal Event (SSE)
[ Time Frame: From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

Time to first SSE was calculated as the time from randomization to the occurrence of the first SSE prior to the data analysis cut-off date. An SSE was defined as radiation to bone, surgery to bone, clinically apparent pathological bone fracture, or spinal cord compression. In participants with no SSE by the time of the data cut-off point, time to SSE was censored on the last visit date or the date of randomization, whichever occurred last.

Time to Castration Resistance
[ Time Frame: From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

Time to castration resistance was calculated as the time from randomization to the first castration-resistant event. A castration resistance event was defined as any of the following in the presence of castrate levels of testosterone (< 50 ng/dL): radiographic disease progression, PSA progression or SSE, whichever occurred first. In participants with no documented castration resistance event, the time to castration resistance was censored on the latest date from: the date of last radiologic assessment, the last PSA sample taken prior to the start of any new prostate cancer therapy and prior to 2 or more consecutive missed PSA assessments (if applicable), and the last visit date performed.

Time to Deterioration of Quality of Life (QoL) in Functional Assessment of Cancer Therapy-Prostate (FACT-P)
[ Time Frame: From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

Time to deterioration of QoL was calculated as the time interval from the date of randomization to the first date a decline from baseline of 10 points or more in the FACT-P total score was recorded. The FACT-P consists of 27 core items that assess participant function in 4 domains and 12 prostate cancer-related items grouped into 5 subscales as follows: physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing and prostate cancer subscale. Each item is rated on a 0 to 4 Likert-type scale. The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0 to 156), where high score represent better quality of life. In participants without FACT-P progression, the time to deterioration of QoL was censored on the date of the last FACT-P total score was calculable.

10.

Time to Pain Progression Based on Brief Pain Inventory-Short Form (BPI-SF)
[ Time Frame: From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months ]

Time to pain progression was defined as time from randomization to the first pain progression event. Pain progression was defined as an increase of ≥ 30% from baseline in the average BPI-SF pain severity score. BPI-SF contains 9 questions with rating scales from 0 (no pain/no interference) to 10 (worst pain/interferes completely). Total score was calculated as the average of each question. Higher scores represent a higher level of pain or interference. In participants with no pain progression event, time to pain progression was censored on the last visit date where BPI-SF was collected.

Minimum Age:

18 Years

Maximum Age:

Sex:

Male

Gender Based:

Accepts Healthy Volunteers:

Criteria:

Inclusion Criteria:

Subject is considered an adult according to local regulation at the time of signing informed consent.
Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell histology.
Subject has metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan (for soft tissue). Subjects whose disease spread is limited to regional pelvic lymph nodes are not eligible.
Once randomized at day 1, subject must maintain ADT with an LHRH agonist or antagonist during study treatment or have a history of bilateral orchiectomy (i.e., medical or surgical castration).
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Inclusion Criteria for Open-Label Extension:

Subject received randomized double-blind treatment in ARCHES
Subject has not met any of the discontinuation criteria in the main ARCHES protocol
Subject is willing to maintain ADT with LHRH agonist or antagonist or has had a bilateral orchiectomy.
Subject is able to swallow enzalutamide capsules whole and to comply with study requirements throughout the study
Subject and subject's female partner agree to follow contraception and sperm donation requirements in main protocol

Exclusion Criteria:

Subject has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer (the following exceptions are permitted):
- Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
- Subject may have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to day 1;
- Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of day 1 and no evidence of disease progression during or after the completion of docetaxel therapy;
- Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1 if subject was treated with docetaxel, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
- Prior ADT given for < 39 months in duration and > 9 months before randomization as neoadjuvant/adjuvant therapy.
Subject had a major surgery within 4 weeks prior to day 1.
Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks prior to day 1.
Subject received treatment with estrogens, cyprotoerone acetate or androgens within 4 weeks prior to day 1.
Subject received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to day 1, intended for the treatment of prostate cancer.
Subject received treatment with herbal medications that have known hormonal antiprostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior to day 1.
Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or enzalutamide for the treatment of prostate cancer or participation in a clinical study of an investigational agent that inhibits the AR or androgen synthesis (e.g., TAK-700, ARN-509, ODM-201).
Subject has known or suspected brain metastasis or active leptomeningeal disease.
Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or hemoglobin < 10 g/dL (6.2 mmol/L).
Subject has total bilirubin (TBL) ≥ 1.5 x the upper limit of normal (ULN) (except subjects with documented Gilbert's disease), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 x the ULN .
Subject has creatinine > 2 mg/dL (177 μmol/L).
Subject has albumin < 3.0 g/dL (30 g/L).
Subject has a history of seizure or any condition that may predispose to seizure.
Subject has history of loss of consciousness or transient ischemic attack within 12 months prior to day 1.
Subject has clinically significant cardiovascular disease.
Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless administered at stable dose or to treat diagnosed osteoporosis

Exclusion Criteria for Open-Label Extension:

Subject has taken commercially available enzalutamide (Xtandi).
Subject's disease has progressed radiographically during the double-blind period of the study and treatment with study drug was stopped prior to study-wide unblinding. (Note: Subjects who progressed radiographically while in the double-blind portion of the study and continued treatment per protocol are allowed to participate in the open label extension.)
After study-wide unblinding, subject has started any new investigational agent or anti-neoplastic therapy intended to treat prostate cancer
Subject has any clinically significant disorder or condition including excessive alcohol or drug abuse, or secondary malignancy, which may interfere with study participation
Subject has current or previously treated brain metastasis or active leptomeningeal disease
Subject has a history of seizure or any condition that may increase the risk of seizure

Study Officials:

Medical Director
Study Director
Astellas Pharma Global Development, Inc.

Locations:

United States, Alabama

Site US10016
Homewood, Alabama, United States, 35209

United States, Alaska

Site US10007
Anchorage, Alaska, United States, 99503

United States, Arizona

Site US10008
Tucson, Arizona, United States, 85741

United States, California

Site US10034
Fountain Valley, California, United States, 92708

Site US10056
La Jolla, California, United States, 92093

Site US10026
Santa Rosa, California, United States, 95403

United States, Colorado

Site US10035
Aurora, Colorado, United States, 80045

Site US10050
Denver, Colorado, United States, 80220

United States, Florida

Site US10048
Saint Petersburg, Florida, United States, 33710

United States, Georgia

Site US10054
Thomasville, Georgia, United States, 31792

United States, Illinois

Site US10015
Chicago, Illinois, United States, 60637

Site US10043
Springfield, Illinois, United States, 62703

United States, Indiana

Site US10045
Jeffersonville, Indiana, United States, 47130

United States, Iowa

Site US10020
West Des Moines, Iowa, United States, 50266

United States, Kansas

Site US10055
Kansas City, Kansas, United States, 66160-7233

United States, Maryland

Site US10017
Towson, Maryland, United States, 21204

United States, Nebraska

Site US10036
Omaha, Nebraska, United States, 68114

United States, New Jersey

Site US10018
Lawrenceville, New Jersey, United States, 08648

United States, New York

Site US10025
Newburgh, New York, United States, 12550

Site US10029
Syracuse, New York, United States, 13210

United States, North Carolina

Site US10068
Charlotte, North Carolina, United States, 28207

Site US10009
Concord, North Carolina, United States, 28025

Site US10014
Durham, North Carolina, United States, 27710

Site US10060
Greenville, North Carolina, United States, 27834

United States, Ohio

Site US10044
Middleburg Heights, Ohio, United States, 44130

United States, Pennsylvania

Site US10011
Lancaster, Pennsylvania, United States, 17604

United States, South Carolina

Site US10012
Myrtle Beach, South Carolina, United States, 29572

United States, Tennessee

Site US10059
Nashville, Tennessee, United States, 37208

United States, Texas

Site US10046
Dallas, Texas, United States, 75231

Site US10004
Dallas, Texas, United States, 75390-9110

United States, Virginia

Site US10040
Virginia Beach, Virginia, United States, 23462

United States, Washington

Site US10002
Burien, Washington, United States, 98166

Site US10013
Seattle, Washington, United States, 98101

Site US10028
Wenatchee, Washington, United States, 98801

Argentina

Site AR54010
Buenos Aires, Argentina, C1180AAX

Argentina, Santa Fe

Site AR54002
Rosario, Santa Fe, Argentina, S2000DSV

Argentina, Tucuman

Site AR54007
San Miguel de Tucuman, Tucuman, Argentina, 4000

Australia, New South Wales

Site AU61016
Camperdown, New South Wales, Australia, 2050

Site AU61007
St Leonards, New South Wales, Australia, 2065

Site AU61006
Sydney, New South Wales, Australia

Site AU61009
Tweed Heads, New South Wales, Australia, 2485

Site AU61013
Waratah, New South Wales, Australia, 2298

Australia, South Australia

Site AU61001
Woodville South, South Australia, Australia, 5011

Australia, Victoria

Site AU61004
Ballarat, Victoria, Australia

Site AU61015
Clayton, Victoria, Australia

Site AU61017
Parkville, Victoria, Australia

Site AU61008
St. Albans, Victoria, Australia

Belgium

Site BE32008
Liege, Belgium

Site BE32007
Yvoir, Belgium

Belgium, Hainaut

Site BE32001
Mons, Hainaut, Belgium

Belgium, Oost-Vlaanderen

Site BE32012
Gent, Oost-Vlaanderen, Belgium

Belgium, West-Vlaanderen

Site BE32005
Kortrijk, West-Vlaanderen, Belgium

Canada, Alberta

Site CA15016
Edmonton, Alberta, Canada, T6G 1Z2

Canada, British Columbia

Site CA15024
Abbotsford, British Columbia, Canada, V2S 3N6

Site CA15003
Kelowna, British Columbia, Canada, V1W 4V5

Site CA15022
Kelowna, British Columbia, Canada, V1Y 5L3

Canada, Ontario

Site CA15010
Brampton, Ontario, Canada, L6T 4S5

Site CA15021
Kingston, Ontario, Canada, K7L 2V7

Site CA15013
Oakville, Ontario, Canada, L6H 3P1

Site CA15020
Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Site CA15023
Granby, Quebec, Canada, J2G 8Z9

Site CA15004
Montreal, Quebec, Canada, H3T1E2

Chile

Site CL56003
Santiago, Chile

Chile, IX Region

Site CL56002
Temuco, IX Region, Chile

Chile, RM

Site CL56001
Santiago, RM, Chile

Chile, Santiago

Site CL56007
Providencia, Santiago, Chile

Chile, Valparaiso

Site CL56005
Viña Del Mar, Valparaiso, Chile

Chile, Viña Del Mar

Site CL56004
Reñaca, Viña Del Mar, Chile

Denmark

Site DK45003
Herlev, Denmark

Site DK45001
Odense C, Denmark

Denmark, Hovestaden

Site DK45002
Copenhagen, Hovestaden, Denmark

Denmark, Midtjylland

Site DK45005
Aarhus, Midtjylland, Denmark

Site DK45008
Holstebro, Midtjylland, Denmark

Denmark, Nordjylland

Site DK45004
Aalborg, Nordjylland, Denmark

Finland

Site FI35805
Oulu, Finland

Site FI35806
Pietarsaari, Finland

Site FI35807
Turku, Finland

Finland, Etelä-Suomen Lääni

Site FI35802
Helsinki, Etelä-Suomen Lääni, Finland

Finland, Länsi-Suomen Lääni

Site FI35804
Pori, Länsi-Suomen Lääni, Finland

Site FI35803
Seinäjoki, Länsi-Suomen Lääni, Finland

Finland, Oulun Laani

Site FI35801
Tampere, Oulun Laani, Finland

France

Site FR33006
Bordeaux, France

Site FR33014
Caen Cedex 05, France, 14076

Site FR33005
La Roche sur Yon, France

Site FR33015
Le Mans Cedex 2, France

Site FR33012
Lille Cedex, France

Site FR33007
Lyon Cedex 3, France

Site FR33011
Nimes, France

Site FR33001
Pierre Benite, France

Site FR33009
Quimper, France

Site FR33013
Saint Mande, France

France, Maine-et-Loire

Site FR33010
Angers, Maine-et-Loire, France

France, Val-de-Marne

Site FR33003
Creteil, Val-de-Marne, France, 94010

Germany

Site DE49005
Bonn, Germany, 53111

Site DE49014
Hamburg, Germany, 20246

Site DE49013
Heidelberg, Germany, 69120

Germany, Baden-Württemberg

Site DE49002
Freiburg, Baden-Württemberg, Germany

Site DE49004
Nürtingen, Baden-Württemberg, Germany

Israel

Site IL97210
Beer-Sheva, Israel

Site IL97202
Haifa, Israel

Site IL97205
Haifa, Israel

Site IL97206
Jerusalem, Israel

Israel, HaMerkaz

Site IL97201
Kfar-Saba, HaMerkaz, Israel

Site IL97211
Zerifin, HaMerkaz, Israel

Italy

Site IT39009
Candiolo, Italy, 10060

Italy, Emilia-Romagna

Site IT39005
Meldola, Emilia-Romagna, Italy

Italy, Lombardia

Site IT39004
Cremona, Lombardia, Italy

Site IT39003
Milano, Lombardia, Italy

Site IT39012
Milano, Lombardia, Italy

Italy, Piemonte

Site IT39007
Novara, Piemonte, Italy

Italy, Toscana

Site IT39008
Pisa, Toscana, Italy

Italy, Trentino-Alto Adige

Site IT39011
Trento, Trentino-Alto Adige, Italy, 38100

Italy, Veneto

Site IT39006
Padova, Veneto, Italy

Japan

Site JP81002
Chiba, Japan

Site JP81014
Fukuoka, Japan

Site JP81015
Fukuoka, Japan

Site JP81008
Kyoto, Japan

Site JP81018
Nagasaki, Japan

Site JP81020
Niigata, Japan

Site JP81019
Yamagata, Japan

Japan, Chiba

Site JP81003
Sakura, Chiba, Japan

Japan, Gunma

Site JP81001
Maebashi, Gunma, Japan

Japan, Kagawa

Site JP81013
Kita-gun, Kagawa, Japan

Japan, Kanagawa

Site JP81007
Yokohama, Kanagawa, Japan

Japan, Miyagi

Site JP81016
Sendai, Miyagi, Japan

Japan, Osaka

Site JP81010
Abeno-ku, Osaka, Japan

Site JP81011
Chuo-ku, Osaka, Japan

Site JP81012
Osakasayama, Osaka, Japan

Japan, Tokyo

Site JP81006
Bunkyo-ku, Tokyo, Japan

Site JP81004
Koto-ku, Tokyo, Japan

Site JP81005
Shinjuku-ku, Tokyo, Japan

Japan, Yamaguchi

Site JP81017
Ube, Yamaguchi, Japan

Korea, Republic of

Site KR82007
Busan, Korea, Republic of

Site KR82004
Incheon, Korea, Republic of

Site KR82001
Seoul, Korea, Republic of

Site KR82002
Seoul, Korea, Republic of

Site KR82003
Seoul, Korea, Republic of

Korea, Republic of, Gyeonggi-do

Site KR82008
Seongnam-si, Gyeonggi-do, Korea, Republic of

Netherlands, Friesland

Site NL31002
Sneek, Friesland, Netherlands

Netherlands, Gelderland

Site NL31003
Nijmegen, Gelderland, Netherlands

Site NL31007
Nijmegen, Gelderland, Netherlands

Netherlands, Noord-Brabant

Site NL31005
Eindhoven, Noord-Brabant, Netherlands

Netherlands, Noord-Holland

Site NL31010
Alkmaar, Noord-Holland, Netherlands

Site NL31008
Amsterdam, Noord-Holland, Netherlands

Netherlands, Overijssel

Site NL31009
Zwolle, Overijssel, Netherlands

Netherlands, Zuid-Holland

Site NL31006
Rotterdam, Zuid-Holland, Netherlands

New Zealand

Site NZ64004
Hamilton, New Zealand

New Zealand, Bay Of Plenty

Site NZ64003
Tauranga, Bay Of Plenty, New Zealand

New Zealand, Northland

Site NZ64008
Kensington, Northland, New Zealand

New Zealand, South Island

Site NZ64002
Dunedin, South Island, New Zealand

New Zealand, Tasman District

Site NZ64005
Nelson, Tasman District, New Zealand

Poland

Site PL48001
Myslowice, Poland

Poland, Dolnoslaskie

Site PL48003
Wroclaw, Dolnoslaskie, Poland

Poland, Malopolskie

Site PL48007
Krakow, Malopolskie, Poland

Poland, Mazowieckie

Site PL48011
Warszawa, Mazowieckie, Poland

Poland, Pomerania

Site PL48005
Gdańsk, Pomerania, Poland

Poland, Pomorskie

Site PL48010
Slupsk, Pomorskie, Poland

Romania

Site RO40007
Brasov, Romania

Site RO40003
Bucharest, Romania

Site RO40006
Bucharest, Romania

Romania, Cluj

Site RO40008
Cluj-Napoca, Cluj, Romania

Site RO40009
Cluj-Napoca, Cluj, Romania

Site RO40002
Floresti, Cluj, Romania

Romania, Timis

Site RO40011
Timisoara, Timis, Romania

Russian Federation

Site RU70013
Ivanovo, Russian Federation

Site RU70001
Moscow, Russian Federation

Site RU70003
Moscow, Russian Federation

Site RU70014
Moscow, Russian Federation

Site RU70006
Omsk, Russian Federation

Site RU70005
Penza, Russian Federation

Site RU70007
St. Petersburg, Russian Federation

Site RU70008
St. Petersburg, Russian Federation

Site RU70009
St. Petersburg, Russian Federation

Site RU70012
St. Petersburg, Russian Federation

Site RU70016
St. Petersburg, Russian Federation

Slovakia

Site SK42110
Bratislava, Slovakia

Site SK42109
Kosice, Slovakia

Site SK42102
Michalovce, Slovakia

Site SK42103
Nitra, Slovakia

Site SK42101
Poprad, Slovakia

Site SK42107
Trencin, Slovakia

Site SK42106
Žilina, Slovakia, 012 07

Spain

Site ES34001
Avila, Spain

Site ES34007
Barcelona, Spain

Site ES34004
Madrid, Spain

Site ES34019
Madrid, Spain

Spain, A Coruña

Site ES34011
Salamanca, A Coruña, Spain

Spain, Asturias

Site ES34020
Oviedo, Asturias, Spain

Spain, Barcelona

Site ES34010
Sabadell, Barcelona, Spain

Spain, Cataluña

Site ES34012
Barcelona, Cataluña, Spain

Site ES34014
Barcelona, Cataluña, Spain

Spain, Comunidad Valenciana

Site ES34013
Valencia, Comunidad Valenciana, Spain

Spain, Navarra

Site ES34006
Pamplona, Navarra, Spain

Sweden, Orebro Län

Site SE46002
Örebro, Orebro Län, Sweden

Sweden, Skåne Län

Site SE46001
Malmö, Skåne Län, Sweden

Sweden, Sodermanlands Lan

Site SE46006
Stockholm, Sodermanlands Lan, Sweden

Sweden, Vasternorrlands Lan

Site SE46004
Sundsvall, Vasternorrlands Lan, Sweden

Sweden, Vastra Gotalands Lan

Site SE46007
Goteborg, Vastra Gotalands Lan, Sweden

Taiwan

Site TW88601
Kaohsiung, Taiwan, 112

Site TW88606
Taichung, Taiwan, 40705

Site TW88605
Taipei, Taiwan

Site TW88607
Taoyuan, Taiwan, 333

United Kingdom, Manchester

Site GB44002
Withington, Manchester, United Kingdom

Plan to Share IPD:

Yes
Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

Supporting Information:

Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)

Time Frame:

Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.

Access Criteria:

Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

URL: https://www.clinicalstudydatarequest.com/

Outcome Measures

1. Primary Outcome:

Title

Radiographic Progression-Free Survival (rPFS) Based on Independent Central Review (ICR) of Bone Scan According to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria

Description

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline or week 13 according to PCWG2 criteria, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.

Time Frame

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT population is defined as all participants who were randomized in this study.


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	19.4(16.59 to NA)^[1]

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	rPFS Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.39
	Confidence Interval	(2-sided) 95% 0.30 to 0.50
	Estimation Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.

2. Primary Outcome:

Title

rPFS Based on ICR of Bone Scan According to Protocol Assessment Criteria

Description

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline for week 13 or the best response on treatment for week 25 or later assessments, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.

Time Frame

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months.

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	19.0(16.59 to 22.24)

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	rPFS Treatment Comparision
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not specified]
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox proportional hazards model
	Estimated Value	0.39
	Confidence Interval	(2-sided) 95% 0.30 to 0.50
	Estimation Comments	[Not specified]

3. Secondary Outcome:

Title

Overall Survival (OS)

Description

OS was defined as the time from randomization to death due to any cause. In participants still alive at the date of the analysis cutoff point, OS was censored on the last date the participant was known to be alive. OS was analyzed using Kaplan-Meier estimates.

Time Frame

From date of randomization to OS final analysis (28 May 2021); Maximum treatment duration was 58.6 months

Outcome Measure Data

Analysis Population Description

ITT population


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	NA(49.74 to NA)^[1]

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not specified]
	Method	Log Rank
	Comments	P-value from stratified log-rank test.


Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-sided) 95% 0.53 to 0.81
	Estimation Comments	Significance level is 0.04. Hazard ratio and 95 % CI are estimated by cox proportional hazards model.

4. Secondary Outcome:

Title

Time to Prostate Specific Antigen (PSA) Progression

Description

Time to PSA progression was calculated as the time from the date of randomization to the first observation of PSA progression. A PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir, which was confirmed by a second consecutive value at least 3 weeks later. In participants with no PSA progression, time to PSA progression was censored on the date of the last PSA sample taken (or last value prior to 2 or more consecutive missed PSA assessments).

Time Frame

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	NA(16.59 to NA)^[1]

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to PSA Progression Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.19
	Confidence Interval	(2-sided) 95% 0.13 to 0.26
	Estimation Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.

5. Secondary Outcome:

Title

Time to Start of New Antineoplastic Therapy

Description

In participants with a new antineoplastic therapy initiated for prostate cancer after randomization, time to start of a new antineoplastic therapy was defined as the time interval from randomization to the date of the first dose administration of the first antineoplastic therapy. In participants with no new antineoplastic therapy initiated for prostate cancer after randomization, time to start of new antineoplastic therapy was censored on the last visit date or the date of randomization, whichever occurred last. Time to start of new antineoplastic therapy was analyzed using Kaplan-Meier estimates.

Time Frame

From date of randomization to data cut-off date (28 May 2021); Maximum treatment duration was 58.6 months

Outcome Measure Data

Analysis Population Description

ITT Population


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	40.5(26.25 to NA)^[1]

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.38
	Confidence Interval	(2-sided) 95% 0.31 to 0.48
	Estimation Comments	Hazard ratio and 95 % CI are estimated by cox proportional hazards model.

6. Secondary Outcome:

Title

PSA Undetectable Rate

Description

The PSA undetectable rate was defined as the percentage of participants with undetectable (< 0.2 ng/mL) PSA values at any time during study treatment, of those participants with detectable (≥ 0.2 ng/mL) PSA values at baseline.

Time Frame

Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT with detectable PSA at baseline


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	511	506
Number (95% Confidence Interval) Unit of Measure: percentage of participants	68.1(63.9 to 72.1)	17.6(14.4 to 21.2)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	PSA Undetectable Rate Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in rate
	Estimated Value	50.5
	Confidence Interval	(2-sided) 95% 45.3 to 55.7
	Estimation Comments	[Not specified]

7. Secondary Outcome:

Title

Objective Response Rate (ORR)

Description

The ORR was calculated as the percentage of participants who achieved a completed response (CR) or a partial response (PR) (unconfirmed responses) in their soft tissue disease using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by ICR.

Time Frame

Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT participants with measurable disease at baseline


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	177	182
Number (95% Confidence Interval) Unit of Measure: percentage of participants	83.1(76.7 to 88.3)	63.7(56.3 to 70.7)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	ORR Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Difference in rate
	Estimated Value	19.3
	Confidence Interval	(2-sided) 95% 10.4 to 28.2
	Estimation Comments	[Not specified]

8. Secondary Outcome:

Title

Time to Deterioration in Urinary Symptoms

Description

In participants with deterioration, the time to deterioration was calculated as the time interval between randomization and the first deterioration in urinary symptoms at any postbaseline visit. A deterioration in urinary symptoms was defined as an increase in the Quality of Life Prostate-specific Questionnaire (QLQ-PR25) modified urinary symptoms. Subscale score by ≥ 50% of the standard deviation observed in the QLQ-PR25 modified urinary symptoms subscale score at baseline. Modified urinary symptoms subscale score consisted of 3-items (Q31 - Q33) from the QLQ-PR25, each scored from 1 (not at all) to 4 (very much). The total modified urinary symptoms subscale score ranges from 0-100, with higher scores represents a higher level of symptomatology/problems. In participants without deterioration in urinary symptoms, the time to deterioration in urinary symptoms was censored on the date the last urinary symptoms QLQ-PR25 score was calculable.

Time Frame

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(19.35 to NA)^[1]	16.8(14.06 to NA)^[1]

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Deterioration of Urinary Symptoms Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.2162
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.88
	Confidence Interval	(2-sided) 95% 0.72 to 1.08
	Estimation Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.

9. Secondary Outcome:

Title

Time to First Symptomatic Skeletal Event (SSE)

Description

Time to first SSE was calculated as the time from randomization to the occurrence of the first SSE prior to the data analysis cut-off date. An SSE was defined as radiation to bone, surgery to bone, clinically apparent pathological bone fracture, or spinal cord compression. In participants with no SSE by the time of the data cut-off point, time to SSE was censored on the last visit date or the date of randomization, whichever occurred last.

Time Frame

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	NA(NA to NA)^[1]

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to SSE Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.0026
	Comments	[Not specified]
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.52
	Confidence Interval	(2-sided) 95% 0.33 to 0.80
	Estimation Comments	[Not specified]

10. Secondary Outcome:

Title

Time to Castration Resistance

Description

Time to castration resistance was calculated as the time from randomization to the first castration-resistant event. A castration resistance event was defined as any of the following in the presence of castrate levels of testosterone (< 50 ng/dL): radiographic disease progression, PSA progression or SSE, whichever occurred first. In participants with no documented castration resistance event, the time to castration resistance was censored on the latest date from: the date of last radiologic assessment, the last PSA sample taken prior to the start of any new prostate cancer therapy and prior to 2 or more consecutive missed PSA assessments (if applicable), and the last visit date performed.

Time Frame

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	NA(NA to NA)^[1]	13.9(11.40 to 17.18)

[1]	NA Explanation: Not reached. Data was not reached due to low number of events.

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Castration Resistance Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not specified]
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.28
	Confidence Interval	(2-sided) 95% 0.22 to 0.36
	Estimation Comments	[Not specified]

11. Secondary Outcome:

Title

Time to Deterioration of Quality of Life (QoL) in Functional Assessment of Cancer Therapy-Prostate (FACT-P)

Description

Time to deterioration of QoL was calculated as the time interval from the date of randomization to the first date a decline from baseline of 10 points or more in the FACT-P total score was recorded. The FACT-P consists of 27 core items that assess participant function in 4 domains and 12 prostate cancer-related items grouped into 5 subscales as follows: physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing and prostate cancer subscale. Each item is rated on a 0 to 4 Likert-type scale. The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0 to 156), where high score represent better quality of life. In participants without FACT-P progression, the time to deterioration of QoL was censored on the date of the last FACT-P total score was calculable.

Time Frame

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	11.3(11.04 to 13.83)	11.1(8.48 to 13.83)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Deterioration of QoL in FACT-P Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.6548
	Comments	[Not specified]
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.96
	Confidence Interval	(2-sided) 95% 0.81 to 1.14
	Estimation Comments	[Not specified]

12. Secondary Outcome:

Title

Time to Pain Progression Based on Brief Pain Inventory-Short Form (BPI-SF)

Description

Time to pain progression was defined as time from randomization to the first pain progression event. Pain progression was defined as an increase of ≥ 30% from baseline in the average BPI-SF pain severity score. BPI-SF contains 9 questions with rating scales from 0 (no pain/no interference) to 10 (worst pain/interferes completely). Total score was calculated as the average of each question. Higher scores represent a higher level of pain or interference. In participants with no pain progression event, time to pain progression was censored on the last visit date where BPI-SF was collected.

Time Frame

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT


Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval) Unit of Measure: months	8.3(8.25 to 10.91)	8.3(5.65 to 8.38)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Pain Progression Based on BPI-SF Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.2715
	Comments	[Not specified]
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.92
	Confidence Interval	(2-sided) 95% 0.78 to 1.07
	Estimation Comments	[Not specified]

Time Frame

From first dose of study drug up to 30 days after last dose of study or prior to initiation of new therapy for prostate cancer, whichever occurred first. Maximum duration of treatment to the data cut-off date of 28 May 2021 was 58.6 months

Adverse Event Reporting Description

Safety Analysis Set (SAF) consisted of all randomized participants who received at least one dose of study drug.

Arm/Group Title

Enzalutamide + Androgen Deprivation Therapy (ADT)

Placebo + Androgen Deprivation Therapy

Placebo Cross-over Enzalutamide

Arm/Group Description

Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.

Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. This arm represents only double blind period.

All-Cause Mortality

Enzalutamide + Androgen Deprivation Therapy (ADT)

Placebo + Androgen Deprivation Therapy

Placebo Cross-over Enzalutamide

Affected / At Risk (%)

# Events

Affected / At Risk (%)

# Events

Affected / At Risk (%)

# Events

Total

154 / 572 (26.92%)

189 / 574 (32.93%)

14 / 180 (7.78%)

Serious Adverse Events

Enzalutamide + Androgen Deprivation Therapy (ADT)

Placebo + Androgen Deprivation Therapy

Placebo Cross-over Enzalutamide

Affected / At Risk (%)

# Events

Affected / At Risk (%)

# Events

Affected / At Risk (%)

# Events

Total

197 / 572 (34.44%)

128 / 574 (22.3%)

36 / 180 (20%)

Blood and lymphatic system disorders

Anaemia ^{† A}

5 / 572 (0.87%)

2 / 574 (0.35%)

1 / 180 (0.56%)

Blood loss anaemia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Febrile neutropenia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Immune thrombocytopenia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Iron deficiency anaemia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Lymphadenopathy ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Pancytopenia ^{† A}

3 / 572 (0.52%)

1 / 574 (0.17%)

0 / 180 (0%)

Cardiac disorders

Acute coronary syndrome ^{† A}

2 / 572 (0.35%)

2 / 574 (0.35%)

0 / 180 (0%)

Acute myocardial infarction ^{† A}

3 / 572 (0.52%)

1 / 574 (0.17%)

2 / 180 (1.11%)

Angina pectoris ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Angina unstable ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Aortic valve incompetence ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Arteriosclerosis coronary artery ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Atrial fibrillation ^{† A}

8 / 572 (1.4%)

7 / 574 (1.22%)

1 / 180 (0.56%)

Atrial flutter ^{† A}

1 / 572 (0.17%)

2 / 574 (0.35%)

0 / 180 (0%)

Atrioventricular block ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Atrioventricular block complete ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Atrioventricular block second degree ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Bradycardia ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Cardiac arrest ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Cardiac failure ^{† A}

3 / 572 (0.52%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Cardiac failure chronic ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cardio-respiratory arrest ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Cardiopulmonary failure ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Coronary artery disease ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

1 / 180 (0.56%)

Coronary artery stenosis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Myocardial infarction ^{† A}

3 / 572 (0.52%)

2 / 574 (0.35%)

2 / 180 (1.11%)

Myocardial ischaemia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Sinus node dysfunction ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Supraventricular tachycardia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Trifascicular block ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Ventricular fibrillation ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Ear and labyrinth disorders

Deafness ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Deafness neurosensory ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Endocrine disorders

Goitre ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hyperparathyroidism ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Eye disorders

Cataract ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Eye haemorrhage ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Retinal detachment ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Ulcerative keratitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Gastrointestinal disorders

Abdominal pain ^{† A}

3 / 572 (0.52%)

2 / 574 (0.35%)

0 / 180 (0%)

Colitis ischaemic ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Constipation ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Diarrhoea ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Diverticulum intestinal haemorrhagic ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Duodenal ulcer haemorrhage ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Duodenal ulcer perforation ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Duodenitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Dyspepsia ^{† A}

1 / 572 (0.17%)

2 / 574 (0.35%)

1 / 180 (0.56%)

Dysphagia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Epiploic appendagitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Gastritis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Gastritis erosive ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Gastrointestinal haemorrhage ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Impaired gastric emptying ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Incarcerated inguinal hernia ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Inguinal hernia ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Large intestinal obstruction ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Large intestine perforation ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Large intestine polyp ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Nausea ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Pneumoperitoneum ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Proctalgia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Retroperitoneal fibrosis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Retroperitoneal haematoma ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Small intestinal obstruction ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Subileus ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Upper gastrointestinal haemorrhage ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

1 / 180 (0.56%)

General disorders

Asthenia ^{† A}

1 / 572 (0.17%)

2 / 574 (0.35%)

0 / 180 (0%)

Chills ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Death ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Drowning ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Euthanasia ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Fatigue ^{† A}

3 / 572 (0.52%)

0 / 574 (0%)

0 / 180 (0%)

General physical health deterioration ^{† A}

3 / 572 (0.52%)

2 / 574 (0.35%)

0 / 180 (0%)

Implant site dehiscence ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Malaise ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Pyrexia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Sudden cardiac death ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Sudden death ^{† A}

0 / 572 (0%)

2 / 574 (0.35%)

0 / 180 (0%)

Hepatobiliary disorders

Cholecystitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cholecystitis acute ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Cholelithiasis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hepatic function abnormal ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

3 / 180 (1.67%)

Jaundice cholestatic ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Infections and infestations

Anorectal infection ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Appendicitis ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Bronchitis ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Bronchopulmonary aspergillosis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

COVID-19 ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

2 / 180 (1.11%)

COVID-19 pneumonia ^{† A}

3 / 572 (0.52%)

0 / 574 (0%)

1 / 180 (0.56%)

Cellulitis ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Cholecystitis infective ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Cystitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Device related infection ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Diverticulitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Endocarditis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Erysipelas ^{† A}

1 / 572 (0.17%)

2 / 574 (0.35%)

1 / 180 (0.56%)

Escherichia pyelonephritis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Escherichia urinary tract infection ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Gangrene ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Gastroenteritis ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Genital abscess ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Groin abscess ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Infected lymphocele ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Infection ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Influenza ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Osteomyelitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Otitis media chronic ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Pneumonia ^{† A}

5 / 572 (0.87%)

5 / 574 (0.87%)

1 / 180 (0.56%)

Pyelonephritis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Sepsis ^{† A}

4 / 572 (0.7%)

3 / 574 (0.52%)

2 / 180 (1.11%)

Septic shock ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Spinal cord infection ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Subcutaneous abscess ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Systemic candida ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Urinary tract infection ^{† A}

1 / 572 (0.17%)

2 / 574 (0.35%)

0 / 180 (0%)

Urinary tract infection bacterial ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Urinary tract infection staphylococcal ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Urosepsis ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Injury, poisoning and procedural complications

Accidental overdose ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Bone fissure ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Brain contusion ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cervical vertebral fracture ^{† A}

0 / 572 (0%)

2 / 574 (0.35%)

0 / 180 (0%)

Clavicle fracture ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Comminuted fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Concussion ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Coronary artery restenosis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Craniocerebral injury ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Fall ^{† A}

8 / 572 (1.4%)

4 / 574 (0.7%)

1 / 180 (0.56%)

Femoral neck fracture ^{† A}

2 / 572 (0.35%)

3 / 574 (0.52%)

0 / 180 (0%)

Femur fracture ^{† A}

4 / 572 (0.7%)

1 / 574 (0.17%)

0 / 180 (0%)

Fracture displacement ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Head injury ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hip fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Humerus fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Infusion related reaction ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Jaw fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Limb injury ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Lumbar vertebral fracture ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Multiple fractures ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Overdose ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Patella fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Peripheral artery restenosis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Radius fracture ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Rib fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Road traffic accident ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Scapula fracture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Skull fractured base ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Spinal compression fracture ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Stenosis of vesicourethral anastomosis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Subdural haematoma ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Thermal burn ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Thoracic vertebral fracture ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Ulna fracture ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Urinary retention postoperative ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Urinary tract stoma complication ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Wound ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Wound haemorrhage ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Wrong dose ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Investigations

Alanine aminotransferase increased ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Antineutrophil cytoplasmic antibody increased ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Aspartate aminotransferase increased ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Blood alkaline phosphatase increased ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Blood bilirubin increased ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Blood creatinine increased ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Blood testosterone increased ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Intraocular pressure increased ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Liver function test abnormal ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Transaminases increased ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Metabolism and nutrition disorders

Adult failure to thrive ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cachexia ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Dehydration ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Hypercalcaemia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hypoglycaemia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Musculoskeletal and connective tissue disorders

Arthralgia ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Arthritis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Back pain ^{† A}

3 / 572 (0.52%)

2 / 574 (0.35%)

1 / 180 (0.56%)

Bone pain ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Compartment syndrome ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Flank pain ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Groin pain ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Muscle spasms ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Muscular weakness ^{† A}

1 / 572 (0.17%)

2 / 574 (0.35%)

0 / 180 (0%)

Musculoskeletal chest pain ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Neck pain ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Osteoarthritis ^{† A}

3 / 572 (0.52%)

2 / 574 (0.35%)

0 / 180 (0%)

Osteonecrosis of jaw ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Osteoporotic fracture ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Pain in extremity ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Pathological fracture ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Spinal osteoarthritis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Adenocarcinoma ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Adenocarcinoma gastric ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

B-cell lymphoma ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Basal cell carcinoma ^{† A}

4 / 572 (0.7%)

5 / 574 (0.87%)

1 / 180 (0.56%)

Benign pancreatic neoplasm ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Bladder cancer ^{† A}

3 / 572 (0.52%)

0 / 574 (0%)

0 / 180 (0%)

Bone cancer ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Bowen's disease ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Bronchial carcinoma ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Cancer pain ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Colon cancer ^{† A}

2 / 572 (0.35%)

3 / 574 (0.52%)

1 / 180 (0.56%)

Colorectal adenocarcinoma ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Diffuse large B-cell lymphoma ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Gastric cancer ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Laryngeal squamous cell carcinoma ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Lung adenocarcinoma ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Lung adenocarcinoma stage 0 ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Lung adenocarcinoma stage I ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Lung neoplasm malignant ^{† A}

3 / 572 (0.52%)

1 / 574 (0.17%)

0 / 180 (0%)

Malignant melanoma ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

1 / 180 (0.56%)

Malignant melanoma in situ ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Malignant neoplasm progression ^{† A}

11 / 572 (1.92%)

3 / 574 (0.52%)

2 / 180 (1.11%)

Meningioma ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Metastases to adrenals ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Metastases to central nervous system ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Metastases to liver ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

1 / 180 (0.56%)

Monoclonal gammopathy ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Neuroendocrine carcinoma ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Non-small cell lung cancer ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Oesophageal squamous cell carcinoma ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Paraproteinaemia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Penile cancer ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Plasmacytoma ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Squamous cell carcinoma ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Squamous cell carcinoma of head and neck ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Squamous cell carcinoma of lung ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Squamous cell carcinoma of skin ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Transitional cell carcinoma ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Tumour pain ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Nervous system disorders

Altered state of consciousness ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Aphasia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Brain stem haemorrhage ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Carotid arteriosclerosis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cerebellar infarction ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cerebral haemorrhage ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Cerebral infarction ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Cerebral ischaemia ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Cerebrovascular accident ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Cervicobrachial syndrome ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Cognitive disorder ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Dementia ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Dementia Alzheimer's type ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Dizziness ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Facial paralysis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Guillain-Barre syndrome ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Headache ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Hemianopia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hypoglycaemic seizure ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Ischaemic stroke ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Lethargy ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Loss of consciousness ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Lumbar radiculopathy ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Memory impairment ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Monoparesis ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Paraparesis ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Seizure ^{† A}

3 / 572 (0.52%)

2 / 574 (0.35%)

0 / 180 (0%)

Spinal cord compression ^{† A}

3 / 572 (0.52%)

7 / 574 (1.22%)

1 / 180 (0.56%)

Subarachnoid haemorrhage ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Syncope ^{† A}

5 / 572 (0.87%)

0 / 574 (0%)

0 / 180 (0%)

Thalamus haemorrhage ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Toxic encephalopathy ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Transient global amnesia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Transient ischaemic attack ^{† A}

4 / 572 (0.7%)

2 / 574 (0.35%)

0 / 180 (0%)

Product Issues

Device occlusion ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Psychiatric disorders

Completed suicide ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Confusional state ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Delirium ^{† A}

2 / 572 (0.35%)

2 / 574 (0.35%)

1 / 180 (0.56%)

Renal and urinary disorders

Acute kidney injury ^{† A}

6 / 572 (1.05%)

3 / 574 (0.52%)

1 / 180 (0.56%)

Bladder mass ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Bladder perforation ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Calculus bladder ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Dysuria ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Haematuria ^{† A}

8 / 572 (1.4%)

2 / 574 (0.35%)

1 / 180 (0.56%)

Hydronephrosis ^{† A}

4 / 572 (0.7%)

3 / 574 (0.52%)

1 / 180 (0.56%)

Nephrolithiasis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Renal colic ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Renal failure ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Renal impairment ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Ureterolithiasis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Urethral obstruction ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Urethral stenosis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Urinary bladder haemorrhage ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Urinary incontinence ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Urinary retention ^{† A}

7 / 572 (1.22%)

4 / 574 (0.7%)

2 / 180 (1.11%)

Urinary tract obstruction ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

1 / 180 (0.56%)

Reproductive system and breast disorders

Benign prostatic hyperplasia ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Pelvic pain ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Chronic obstructive pulmonary disease ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Diaphragmatic paralysis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Dyspnoea ^{† A}

0 / 572 (0%)

2 / 574 (0.35%)

0 / 180 (0%)

Eosinophilic pneumonia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Epistaxis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hypoxia ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Interstitial lung disease ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Pneumonia aspiration ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Pneumonitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Pneumothorax ^{† A}

3 / 572 (0.52%)

0 / 574 (0%)

1 / 180 (0.56%)

Pulmonary embolism ^{† A}

5 / 572 (0.87%)

3 / 574 (0.52%)

1 / 180 (0.56%)

Pulmonary haemorrhage ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Respiratory distress ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Respiratory failure ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Surgical and medical procedures

Bone lesion excision ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Vascular disorders

Aortic aneurysm ^{† A}

2 / 572 (0.35%)

1 / 574 (0.17%)

0 / 180 (0%)

Aortic dissection ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

0 / 180 (0%)

Aortic dissection rupture ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Circulatory collapse ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

1 / 180 (0.56%)

Deep vein thrombosis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

1 / 180 (0.56%)

Embolism ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Essential hypertension ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Granulomatosis with polyangiitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Haematoma ^{† A}

2 / 572 (0.35%)

0 / 574 (0%)

1 / 180 (0.56%)

Hypertensive crisis ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Hypotension ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Hypovolaemic shock ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Lymphoedema ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Peripheral arterial occlusive disease ^{† A}

0 / 572 (0%)

0 / 574 (0%)

1 / 180 (0.56%)

Peripheral embolism ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Peripheral ischaemia ^{† A}

1 / 572 (0.17%)

1 / 574 (0.17%)

0 / 180 (0%)

Phlebitis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Thrombosis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

Vena cava thrombosis ^{† A}

0 / 572 (0%)

1 / 574 (0.17%)

0 / 180 (0%)

Venous thrombosis ^{† A}

1 / 572 (0.17%)

0 / 574 (0%)

0 / 180 (0%)

†Indicates events were collected by systematic assessment.
ATerm from vocabulary, MedDRA v23.0

Other (Not Including Serious) Adverse Events

Frequency Threshold for Reporting Other Adverse Events

Enzalutamide + Androgen Deprivation Therapy (ADT)

Placebo + Androgen Deprivation Therapy

Placebo Cross-over Enzalutamide

Affected / At Risk (%)

# Events

Affected / At Risk (%)

# Events

Affected / At Risk (%)

# Events

Total

443 / 572 (77.45%)

396 / 574 (68.99%)

110 / 180 (61.11%)

Blood and lymphatic system disorders

Anaemia ^{† A}

38 / 572 (6.64%)

28 / 574 (4.88%)

4 / 180 (2.22%)

Gastrointestinal disorders

Constipation ^{† A}

52 / 572 (9.09%)

34 / 574 (5.92%)

8 / 180 (4.44%)

Diarrhoea ^{† A}

48 / 572 (8.39%)

34 / 574 (5.92%)

6 / 180 (3.33%)

Nausea ^{† A}

51 / 572 (8.92%)

34 / 574 (5.92%)

12 / 180 (6.67%)

General disorders

Asthenia ^{† A}

49 / 572 (8.57%)

28 / 574 (4.88%)

4 / 180 (2.22%)

Fatigue ^{† A}

141 / 572 (24.65%)

180

92 / 574 (16.03%)

103

39 / 180 (21.67%)

Oedema peripheral ^{† A}

46 / 572 (8.04%)

40 / 574 (6.97%)

7 / 180 (3.89%)

Infections and infestations

Nasopharyngitis ^{† A}

48 / 572 (8.39%)

33 / 574 (5.75%)

13 / 180 (7.22%)

Injury, poisoning and procedural complications

Fall ^{† A}

52 / 572 (9.09%)

16 / 574 (2.79%)

12 / 180 (6.67%)

Investigations

Weight increased ^{† A}

46 / 572 (8.04%)

45 / 574 (7.84%)

2 / 180 (1.11%)

Metabolism and nutrition disorders

Decreased appetite ^{† A}

39 / 572 (6.82%)

18 / 574 (3.14%)

12 / 180 (6.67%)

Musculoskeletal and connective tissue disorders

Arthralgia ^{† A}

104 / 572 (18.18%)

136

65 / 574 (11.32%)

11 / 180 (6.11%)

Back pain ^{† A}

74 / 572 (12.94%)

67 / 574 (11.67%)

19 / 180 (10.56%)

Bone pain ^{† A}

34 / 572 (5.94%)

31 / 574 (5.4%)

2 / 180 (1.11%)

Musculoskeletal pain ^{† A}

50 / 572 (8.74%)

26 / 574 (4.53%)

7 / 180 (3.89%)

Pain in extremity ^{† A}

37 / 572 (6.47%)

27 / 574 (4.7%)

7 / 180 (3.89%)

Nervous system disorders

Dizziness ^{† A}

44 / 572 (7.69%)

22 / 574 (3.83%)

7 / 180 (3.89%)

Headache ^{† A}

46 / 572 (8.04%)

22 / 574 (3.83%)

5 / 180 (2.78%)

Psychiatric disorders

Insomnia ^{† A}

29 / 572 (5.07%)

20 / 574 (3.48%)

4 / 180 (2.22%)

Reproductive system and breast disorders

Gynaecomastia ^{† A}

33 / 572 (5.77%)

8 / 574 (1.39%)

3 / 180 (1.67%)

Vascular disorders

Hot flush ^{† A}

171 / 572 (29.9%)

196

131 / 574 (22.82%)

137

15 / 180 (8.33%)

Hypertension ^{† A}

75 / 572 (13.11%)

35 / 574 (6.1%)

13 / 180 (7.22%)

†Indicates events were collected by systematic assessment.
ATerm from vocabulary, MedDRA v23.0

Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

Results Point of Contact:

Name/Official Title:

Clinical Trial Disclosure

Organization:

Astellas Pharma Inc.

Phone:

+81 3-3244-0512

Email:

astellas.resultsdisclosure@astellas.com