UPWARD: A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide

• Sponsor: Astellas Pharma Global Development, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01977651
• Collaborator: Medivation LLC, a wholly owned subsidiary of Pfizer Inc. (Industry)
• Enrollment: 424
• Locations: 76
• Arm: 1
• Actual Duration (Months): 63.5
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objective of this study was to evaluate the incidence of seizures and monitor the safety of enzalutamide treatment in participants with metastatic castration-resistant prostate cancer (mCRPC) known to have risk factor(s) for seizure.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-resistant Prostate Cancer (mCRPC)	Drug: Enzalutamide	Phase 4

Detailed Description

This was a multicenter, single-arm, open-label, postmarketing safety study to evaluate the risk of seizure among patients with mCRPC treated with enzalutamide who were at potential increased risk of seizure.

Participants who met all inclusion and none of the exclusion criteria were enrolled into the study and participated in a 4-month treatment period, during which once daily dosing of enzalutamide (160 mg/day) occurred. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment were allowed to continue in the extension period where participants continued to receive enzalutamide until 1 of the following criteria was met:

1. The participant experienced bone disease progression per Prostate Cancer Working Group 2 (PCWG2) guidelines or soft tissue disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

2. The participant initiated treatment with another anticancer therapy or, in the opinion of the investigator, continued dosing would have led to undue risk to the patient

3. The participant met a discontinuation criterion

4. The sponsor terminated the study

Participants who continued to receive clinical benefit from treatment with enzalutamide and did not meet any discontinuation criteria may have transitioned to an open label roll-over extension study upon approval of the study protocol at the institution where they were receiving treatment.

Participants who did not continue in the extension period or who met a discontinuation criterion were discontinued from enzalutamide therapy and completed a follow-up visit 30 days from the last dose of enzalutamide or prior to the initiation of another anticancer therapy, whichever occurred first.

For participants who continued on treatment after the 12-month extension period, data collection was limited to dosing information, concomitant medications, and all adverse events (AEs) including serious adverse events (SAEs).

Study Design

• Study Type: Interventional
• Actual Enrollment: 424 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Single-arm, Open-label, Postmarketing Safety Study to Evaluate the Risk of Seizure Among Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide Who Are at Potential Increased Risk of Seizure
• Actual Study Start Date: Sep 25, 2013
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Jan 11, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Enzalutamide 160 mg Participants received 160 mg of enzalutamide orally once a day, for 4 months. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment continued in the extension period. The total study drug treatment duration for the extended period depended on individual clinical benefit. If a participant experienced a Grade 3 or higher toxicity that was attributed to enzalutamide and could not be ameliorated by the use of adequate medical intervention, treatment with enzalutamide was allowed to be interrupted for 1 week or until the toxicity grade improved to Grade 2 or lower severity. Subsequently, enzalutamide was restarted at the original dose 160 mg per day or a reduced dose 120 or 80 mg per day in consultation with the medical monitor.

Drug: Enzalutamide; Participants received 4 capsules (40 mg each) of enzalutamide orally once a day, for a total daily dose of 160 mg. Treatment was given with or without food and as close as possible to the same time each day.; Other Names: Xtandi MDV3100

Outcome Measures

Primary Outcome Measures

1. The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC) [Day 1 up to week 17 (end of 4-month treatment period)]

   Percentage of evaluable participants with at least one confirmed seizure as adjudicated by the IAC during the first 4 months of treatment were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject has histologically confirmed metastatic adenocarcinoma of the prostate.

• Subject has ongoing androgen deprivation therapy with a Gonadotropin-releasing hormone (GnRH) analogue (agonist or antagonist) or bilateral orchiectomy (i.e., surgical or medical castration).

• Subject has disease progression by at least one of the following:

1. Prostate-Specific Antigen (PSA) progression defined by a minimum of 2 rising PSA levels with an interval of at least 1 week between each draw;

2. Bone disease progression as defined by Prostate Cancer Working Group 2 guidelines (at least 2 new lesions) on bone scan; or

3. Soft tissue disease progression as defined by RECIST 1.1

• For subjects who have not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue therapy for the duration of the study.

• Subject must have failed at least one course of androgen deprivation therapy (ADT), i.e., treatment with GnRH analogues.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Subject has been evaluated by a local neurologist prior to study entry who has determined the subject has at least one risk factor for seizure including:

1. past history of seizure due to any cause except a single febrile seizure in childhood. Patients with a history of seizures should not have had a seizure within 12 months of Screening and must have had no anticonvulsants for 12 months prior to Screening,

2. history of cerebrovascular accident (CVA) or transient ischemic attack (TIA),

3. history of traumatic brain or head injury with loss of consciousness

4. unexplained loss of consciousness within the last 12 months,

5. presence of a space occupying lesion in the brain including previously treated brain metastasis(es) or primary central nervous system (CNS) tumor,

6. history of arteriovenous malformations of the brain,

7. history of brain infection (i.e., abscess, meningitis, or encephalitis),

8. current use of medication that may lower seizure threshold

9. presence of Alzheimer's disease, meningioma, leptomeningeal disease from prostate cancer.

• Subject is able to swallow the study drug and comply with study requirements.

• Subject agrees not to participate in another interventional study while on treatment.

• Male subject and his female partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period and for 3 months after final study drug administration.

1. Two acceptable forms of birth control include:

2. Condom (barrier method of contraception), AND

3. One of the following acceptable forms of contraception is required:

4. Established use of oral, injected or implanted hormonal methods of contraception.

5. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

6. Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository).

7. Vasectomy or surgical castration at least 6 months prior to Screening.

• Male subject must use a condom, if having sex with a pregnant woman.

• Male subject must not donate sperm starting at Screening and throughout the study period and for at least 3 months after final drug administration.

Exclusion Criteria:

• Subject with a history of exposure to enzalutamide.

• Subject has severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.

• Subject is currently being treated with anti-epileptics.

• Subject has a history of seizure within the past 12 months of Screening as assessed by neurology examination and history.

• Subject with rapidly progressing visceral disease who has not received and is thought to be able to tolerate cytotoxic chemotherapy. (However, subject who has previously received cytotoxic chemotherapy is permitted).

• Subject has clinical signs suggestive of high or imminent risks for pathological fracture, spinal cord compression and/or cauda equina syndrome.

• Subject's absolute neutrophil count is < 1500/microliter (µL), platelet count is < 100,000/µL) or hemoglobin is < 5.6 millimoles(mmol)/liter (L) (9 grams (g)/deciliter (dL) at Screening.

• Subject's total bilirubin is ≥ 1.5 x upper limit of normal (ULN) (except for subjects with documented Gilbert's disease) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is ≥ 2.5x upper limit of normal (ULN) at Screening.

• Subject's estimated creatinine clearance (Cer) is less than 30 milliliter (mL)/minute (min) by the Cockcroft and Gault formula (Creatinine Clearance (mL/min) = (140 - age)(weight (wt) kilogram (kg) / 72 x serum creatinine (milligram (mg)/100 mL) [Cockcroft, 1976] at Screening.

• Subject has uncontrolled hypertension as indicated by a resting systolic blood pressure > 160 millimeter of mercury (mmHg) or diastolic blood pressure > 100 millimeter of mercury (mmHg) at Screening.

• Subject has received an investigational agent within 4 weeks or 5 half lives whichever is longer prior to Day 1.

• Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site US10005	Anchorage	Alaska	United States	99503
2	Site US10024	Detroit	Michigan	United States	48202
3	Site US10026	Bronx	New York	United States	10461
4	Site US10001	New York	New York	United States	10065
5	Site US10014	New York	New York	United States	10065
6	Site US10039	Syracuse	New York	United States	13210
7	Site US10016	Durham	North Carolina	United States	27710
8	Site US10008	Dallas	Texas	United States	75231
9	Site US10025	Seattle	Washington	United States	98109
10	Site AR54001	Berazategui	Buenos Aires	Argentina	B1880BBF
11	Site AR54006	Ciudad Autonoma de BuenosAires	Buenos Aires	Argentina	C1426ANZ
12	Site AR54002	Buenos Aires	Caba	Argentina	C1120AAT
13	Site AR54003	Cordoba		Argentina	5000
14	Site AR54004	Santa Fe		Argentina	S3000FFU
15	Site AR54005	Tucuman		Argentina	4000
16	Site AU61012	Kogarah	New South Wales	Australia	2217
17	Site AU61005	Randwick	New South Wales	Australia	2031
18	Site AU61011	Sydney	New South Wales	Australia	2109
19	Site AU61001	Tweed Heads	New South Wales	Australia	2485
20	Site AU61002	Nambour	Queensland	Australia	4560
21	Site AU61007	Adelaide	South Australia	Australia	5042
22	Site AU61004	Ballarat	Victoria	Australia	3350
23	Site BE32004	Anderlecht		Belgium	1070
24	Site BE32001	Kortrijk		Belgium	8500
25	Site BE32003	Liege		Belgium	B-4000
26	Site CA15005	Abbotsford	British Columbia	Canada	V2S 3N5
27	Site CA15014	Halifax	Nova Scotia	Canada	B3H 2Y9
28	Site CA15004	Brampton	Ontario	Canada	L6T 4S5
29	Site CA15010	Scarborough	Ontario	Canada	M1S 4V5
30	Site CA15001	Quebec City	Quebec	Canada	G1R3S1
31	Site CL56001	Temuco	IX Region	Chile	4810469
32	Site CL56004	Santiago		Chile	8420383
33	Site CL56002	Temuco		Chile	4781156
34	Site CL56003	Vina del Mar		Chile	2540364
35	Site CZ42004	Praha 2		Czechia	12000
36	Site CZ42002	Praha 6		Czechia	16000
37	Site FI35803	Helsinki		Finland	00290
38	Site FI35801	Oulu		Finland	90220
39	Site FI35802	Tampere		Finland	33520
40	Site FR33002	Lyon Cedex 03		France	69437
41	Site FR33004	Rouen Cedex		France	76031
42	Site FR33005	Suresnes		France	92151
43	Site DE49009	Nürtingen	Baden-Württemberg	Germany	72622
44	Site DE49003	Berlin		Germany	12200
45	Site DE49001	Munster		Germany	48149
46	Site HU36002	Sopron	Gyor-Moson Sopron	Hungary	9400
47	Site IL97202	Kfar Saba	HaMerkaz	Israel	44281
48	Site IL97201	Be'er Ya'akov		Israel	70300
49	Site IL97203	Beer-Sheva		Israel	84101
50	Site IL97205	Haifa		Israel	31096
51	Site IL97204	Jerusalem		Israel	91120
52	Site IL97208	Nahariya		Israel	21000
53	Site IL97206	Petah-Tiqva		Israel	49100
54	Site IL97207	Ramat Gan		Israel	52621
55	Site IT39005	Meldola	Emilia-Romagna	Italy	47014
56	Site IT39001	Cremona	Lombardia	Italy	26100
57	Site IT39002	Arezzo		Italy	52100
58	Site IT39003	Roma		Italy	00144
59	Site KR82006	Seongnam-Si	Gyeonggi-do	Korea, Republic of	013620
60	Site KR82007	Seoul		Korea, Republic of	03080
61	Site KR82003	Seoul		Korea, Republic of	135-710
62	Site KR82001	Seoul		Korea, Republic of	135-720
63	Site KR82004	Seoul		Korea, Republic of	137-701
64	Site NZ64001	Hamilton		New Zealand	3204
65	Site SG65002	Singapore		Singapore	119228
66	Site ES34007	Hospitalet de Llobregat	Barcelona	Spain	08908
67	Site ES34005	Sabadell	Barcelona	Spain	08208
68	Site ES34001	Pamplona	Navarra	Spain	31008
69	Site ES34003	Barcelona		Spain	08025
70	Site ES34004	Barcelona		Spain	08035
71	Site ES34006	Madrid		Spain	28050
72	Site SE46001	Goteborg		Sweden	41345
73	Site SE46002	Orebro		Sweden	701 85
74	Site TW88601	Kaohsiung		Taiwan	81362
75	Site TW88603	Taipei City		Taiwan	10048
76	Site GB44002	Sutton	Surrey	United Kingdom	SM2 5PT

Sponsors and Collaborators

• Astellas Pharma Global Development, Inc.
• Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Investigators

• Study Director: Sr. Medical Director, Astellas Pharma Global Development, Inc.

Study Documents (Full-Text)

• Study Protocol - Oct 20, 2016
• Statistical Analysis Plan - Mar 25, 2014

More Information

Additional Information:

• Link to results on the Astellas Clinical Study Results website.

Publications

None provided.

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT01977651
• Other Study ID Numbers: 9785-CL-0403; 2013-003022-92; U1111-1157-0224
• First Posted: Nov 7, 2013
• Last Update Posted: Dec 9, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Astellas Pharma Global Development, Inc.: enzalutamide; Xtandi; seizure; Central Nervous System; MDV3100; metastatic castration-resistant prostate cancer (mCRPC)
• Additional relevant MeSH terms: Prostatic Neoplasms; Seizures

Study Results

Participant Flow

Recruitment Details	Study enrolled male participants with histologically-confirmed metastatic adenocarcinoma of prostate with ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue (agonist or antagonist) or a prior orchiectomy. Participants were evaluated by a neurologist who determined they had at least 1 risk factor for seizure.
Pre-assignment Detail	Participants who met all inclusion and none of the exclusion criteria were enrolled in the study, completing a 4-month treatment period. Participants who benefited from the treatment were allowed to continue in the extension period. A total 424 participants were enrolled and 423 participants received the study drug.

Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	Participants received 160 mg of enzalutamide orally once a day, for 4 months. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment continued in the extension period. The total study drug treatment duration for the extended period depended on individual clinical benefit. If a participant experienced a Grade 3 or higher toxicity that was attributed to enzalutamide and could not be ameliorated by the use of adequate medical intervention, treatment with enzalutamide was allowed to be interrupted for 1 week or until the toxicity grade improved to Grade 2 or lower severity. Subsequently, enzalutamide was restarted at the original dose 160 mg per day or a reduced dose 120 or 80 mg per day in consultation with the medical monitor.
Period Title: 4 Month Treatment Period
STARTED	423
COMPLETED	322
NOT COMPLETED	101
Period Title: 4 Month Treatment Period
STARTED	287
COMPLETED	157
NOT COMPLETED	130
Period Title: 4 Month Treatment Period
STARTED	145
COMPLETED	1
NOT COMPLETED	144

Baseline Characteristics

Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	Participants received 160 mg of enzalutamide orally once a day, for 4 months.
Overall Participants	423
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.2 (9)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	423 100%
Race/Ethnicity, Customized (Count of Participants)
WHITE	381 90.1%
BLACK OR AFRICAN AMERICAN	9 2.1%
ASIAN	25 5.9%
NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	1 0.2%
NO DATA	3 0.7%
OTHER	4 0.9%
Ethnicity (Count of Participants)
NOT HISPANIC OR LATINO	331 78.3%
HISPANIC OR LATINO	89 21%
NO DATA	3 0.7%
Eastern Cooperative Oncology Group (ECOG) At Study Entry (participants) [Number]
Grade 0	188 44.4%
Grade 1	190 44.9%
Grade 2	45 10.6%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC)
Description	Percentage of evaluable participants with at least one confirmed seizure as adjudicated by the IAC during the first 4 months of treatment were reported.
Time Frame	Day 1 up to week 17 (end of 4-month treatment period)

Outcome Measure Data

Analysis Population Description

The seizure risk evaluation set (SRES) consisted of all participants with a confirmed seizure during the 4-month treatment period of the study or who completed at least 3 months (75 percent [%]) of the planned treatment.

Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	Participants received 160 mg of enzalutamide orally once a day, for 4 months.
Measure Participants	366
Number (95% Confidence Interval) [percentage of participants]	1.1 0.3%

Adverse Events

Time Frame	From first dose of study drug up to 30 days after last dose of study drug (approximately 52 months)
Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	Participants received 160 mg of enzalutamide orally once a day, for 4 months. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment continued in the extension period. The total study drug treatment duration for the extended period depended on individual clinical benefit. If a participant experienced a Grade 3 or higher toxicity that was attributed to enzalutamide and could not be ameliorated by the use of adequate medical intervention, treatment with enzalutamide was allowed to be interrupted for 1 week or until the toxicity grade improved to Grade 2 or lower severity. Subsequently, enzalutamide was restarted at the original dose 160 mg per day or a reduced dose 120 or 80 mg per day in consultation with the medical monitor.
All Cause Mortality
	Enzalutamide 160 mg
	Affected / at Risk (%)	# Events
Total	62/423 (14.7%)
Serious Adverse Events
	Enzalutamide 160 mg
	Affected / at Risk (%)	# Events
Total	193/423 (45.6%)
Blood and lymphatic system disorders
Anaemia	9/423 (2.1%)	11
Anaemia of malignant disease	1/423 (0.2%)	1
Aplastic anaemia	1/423 (0.2%)	1
Febrile neutropenia	3/423 (0.7%)	3
Thrombocytopenia	1/423 (0.2%)	1
Cardiac disorders
Acute myocardial infarction	2/423 (0.5%)	2
Angina pectoris	2/423 (0.5%)	2
Atrial fibrillation	4/423 (0.9%)	5
Atrial flutter	1/423 (0.2%)	1
Atrioventricular block complete	1/423 (0.2%)	1
Cardiac arrest	1/423 (0.2%)	1
Cardiac failure	4/423 (0.9%)	5
Cardiac failure chronic	1/423 (0.2%)	2
Cardiac failure congestive	3/423 (0.7%)	4
Cardiogenic shock	1/423 (0.2%)	1
Coronary artery disease	1/423 (0.2%)	1
Mitral valve incompetence	1/423 (0.2%)	1
Myocardial infarction	5/423 (1.2%)	6
Right ventricular failure	1/423 (0.2%)	1
Ventricular tachycardia	1/423 (0.2%)	3
Ear and labyrinth disorders
Hypoacusis	1/423 (0.2%)	1
Vertigo	1/423 (0.2%)	1
Eye disorders
Blindness	1/423 (0.2%)	1
Eye pain	1/423 (0.2%)	1
Vision blurred	1/423 (0.2%)	1
Gastrointestinal disorders
Abdominal pain	6/423 (1.4%)	6
Colonic obstruction	1/423 (0.2%)	1
Constipation	3/423 (0.7%)	3
Diarrhoea	1/423 (0.2%)	2
Duodenal ulcer haemorrhage	1/423 (0.2%)	1
Dysphagia	1/423 (0.2%)	1
Ileus	1/423 (0.2%)	1
Intestinal obstruction	2/423 (0.5%)	3
Lower gastrointestinal haemorrhage	1/423 (0.2%)	2
Nausea	4/423 (0.9%)	5
Proctalgia	1/423 (0.2%)	1
Vomiting	7/423 (1.7%)	8
General disorders
Asthenia	3/423 (0.7%)	4
Chest pain	1/423 (0.2%)	1
Death	1/423 (0.2%)	1
Device leakage	1/423 (0.2%)	1
Drug ineffective	1/423 (0.2%)	1
Fatigue	3/423 (0.7%)	3
Gait disturbance	1/423 (0.2%)	1
General physical health deterioration	10/423 (2.4%)	18
Glassy eyes	1/423 (0.2%)	1
Multi-organ failure	1/423 (0.2%)	1
Pain	5/423 (1.2%)	6
Performance status decreased	1/423 (0.2%)	1
Pyrexia	8/423 (1.9%)	10
Spinal pain	1/423 (0.2%)	1
Sudden cardiac death	1/423 (0.2%)	1
Hepatobiliary disorders
Hepatocellular injury	1/423 (0.2%)	2
Jaundice cholestatic	1/423 (0.2%)	1
Infections and infestations
Anal abscess	1/423 (0.2%)	1
Appendicitis	1/423 (0.2%)	1
Bacteraemia	1/423 (0.2%)	1
Bronchopneumonia	2/423 (0.5%)	3
Candiduria	1/423 (0.2%)	1
Cellulitis	2/423 (0.5%)	2
Clostridium difficile colitis	1/423 (0.2%)	1
Corona virus infection	1/423 (0.2%)	1
Cystitis	1/423 (0.2%)	1
Diverticulitis	1/423 (0.2%)	1
Enterocolitis infectious	1/423 (0.2%)	2
Erysipelas	1/423 (0.2%)	1
Escherichia urinary tract infection	2/423 (0.5%)	2
Localised infection	1/423 (0.2%)	1
Lower respiratory tract infection	1/423 (0.2%)	1
Lung infection	1/423 (0.2%)	2
Pneumonia	13/423 (3.1%)	16
Pyelonephritis	2/423 (0.5%)	2
Pyelonephritis acute	3/423 (0.7%)	3
Respiratory tract infection	1/423 (0.2%)	2
Sepsis	4/423 (0.9%)	4
Spinal cord infection	1/423 (0.2%)	1
Streptococcal urinary tract infection	1/423 (0.2%)	1
Tracheobronchitis	1/423 (0.2%)	1
Urinary tract infection	4/423 (0.9%)	4
Urinary tract infection bacterial	3/423 (0.7%)	3
Urinary tract infection enterococcal	1/423 (0.2%)	1
Urinary tract infection staphylococcal	2/423 (0.5%)	2
Urosepsis	2/423 (0.5%)	2
Injury, poisoning and procedural complications
Ankle fracture	1/423 (0.2%)	1
Cervical vertebral fracture	1/423 (0.2%)	1
Fall	10/423 (2.4%)	10
Femoral neck fracture	2/423 (0.5%)	2
Femur fracture	4/423 (0.9%)	4
Hip fracture	1/423 (0.2%)	1
Humerus fracture	1/423 (0.2%)	1
Lower limb fracture	1/423 (0.2%)	1
Pelvic fracture	1/423 (0.2%)	1
Post procedural haemorrhage	1/423 (0.2%)	1
Procedural pain	1/423 (0.2%)	1
Subdural haematoma	2/423 (0.5%)	4
Subdural haemorrhage	2/423 (0.5%)	2
Upper limb fracture	1/423 (0.2%)	1
Urostomy complication	1/423 (0.2%)	1
Investigations
Alanine aminotransferase increased	1/423 (0.2%)	1
C-reactive protein increased	1/423 (0.2%)	1
Cystoscopy	1/423 (0.2%)	2
Haemoglobin decreased	1/423 (0.2%)	1
Prostatic specific antigen increased	2/423 (0.5%)	2
Metabolism and nutrition disorders
Cachexia	1/423 (0.2%)	1
Decreased appetite	1/423 (0.2%)	1
Dehydration	5/423 (1.2%)	5
Failure to thrive	1/423 (0.2%)	1
Hypercalcaemia	1/423 (0.2%)	1
Hyperkalaemia	1/423 (0.2%)	1
Hypoglycaemia	2/423 (0.5%)	2
Hypokalaemia	1/423 (0.2%)	1
Hyponatraemia	4/423 (0.9%)	4
Hypophagia	1/423 (0.2%)	1
Musculoskeletal and connective tissue disorders
Back pain	6/423 (1.4%)	7
Bone pain	8/423 (1.9%)	8
Flank pain	2/423 (0.5%)	3
Lumbar spinal stenosis	1/423 (0.2%)	1
Muscular weakness	3/423 (0.7%)	3
Musculoskeletal chest pain	1/423 (0.2%)	1
Musculoskeletal pain	1/423 (0.2%)	2
Myalgia	1/423 (0.2%)	1
Pain in extremity	3/423 (0.7%)	4
Pathological fracture	3/423 (0.7%)	3
Pubic pain	1/423 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/423 (0.2%)	1
Benign neoplasm of ureter	1/423 (0.2%)	1
Bladder cancer	1/423 (0.2%)	1
Cholangiocarcinoma	1/423 (0.2%)	1
Lung neoplasm malignant	1/423 (0.2%)	1
Malignant neoplasm progression	34/423 (8%)	39
Metastases to liver	2/423 (0.5%)	2
Metastases to lymph nodes	1/423 (0.2%)	1
Metastases to spine	1/423 (0.2%)	1
Neoplasm malignant	1/423 (0.2%)	1
Rectal cancer	1/423 (0.2%)	1
Skin cancer	1/423 (0.2%)	1
Squamous cell carcinoma	1/423 (0.2%)	1
Nervous system disorders
Altered state of consciousness	1/423 (0.2%)	1
Brain stem stroke	1/423 (0.2%)	1
Carotid artery stenosis	1/423 (0.2%)	2
Central nervous system haemorrhage	1/423 (0.2%)	1
Cerebral artery occlusion	1/423 (0.2%)	1
Cerebral artery stenosis	1/423 (0.2%)	3
Cerebral haemorrhage	2/423 (0.5%)	3
Cerebral infarction	1/423 (0.2%)	1
Cerebrovascular accident	2/423 (0.5%)	2
Cognitive disorder	1/423 (0.2%)	1
Convulsion	8/423 (1.9%)	10
Diplegia	1/423 (0.2%)	1
Dysgeusia	1/423 (0.2%)	1
Epilepsy	1/423 (0.2%)	1
Grand mal convulsion	1/423 (0.2%)	1
Haemorrhage intracranial	1/423 (0.2%)	1
Haemorrhagic stroke	1/423 (0.2%)	2
IIIrd nerve paralysis	1/423 (0.2%)	1
Lethargy	2/423 (0.5%)	2
Loss of consciousness	2/423 (0.5%)	2
Nerve root compression	1/423 (0.2%)	1
Normal pressure hydrocephalus	1/423 (0.2%)	1
Parkinson's disease	1/423 (0.2%)	1
Presyncope	1/423 (0.2%)	1
Somnolence	1/423 (0.2%)	1
Spinal cord compression	7/423 (1.7%)	8
Syncope	5/423 (1.2%)	5
Transient global amnesia	2/423 (0.5%)	3
Transient ischaemic attack	4/423 (0.9%)	4
Psychiatric disorders
Agitation	1/423 (0.2%)	1
Confusional state	10/423 (2.4%)	10
Delirium	2/423 (0.5%)	2
Disorientation	1/423 (0.2%)	1
Fear of falling	1/423 (0.2%)	1
Mental status changes	1/423 (0.2%)	1
Panic attack	1/423 (0.2%)	1
Paranoia	1/423 (0.2%)	1
Renal and urinary disorders
Anuria	1/423 (0.2%)	2
Bladder dilatation	1/423 (0.2%)	1
Dysuria	4/423 (0.9%)	4
Haematuria	8/423 (1.9%)	12
Hydronephrosis	2/423 (0.5%)	2
Nephritic syndrome	1/423 (0.2%)	1
Renal failure	4/423 (0.9%)	4
Renal failure acute	4/423 (0.9%)	5
Urethral stenosis	2/423 (0.5%)	3
Urinary bladder haemorrhage	1/423 (0.2%)	2
Urinary retention	5/423 (1.2%)	7
Urinary tract obstruction	1/423 (0.2%)	1
Reproductive system and breast disorders
Pelvic pain	1/423 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/423 (0.2%)	1
Dyspnoea	5/423 (1.2%)	6
Dyspnoea exertional	1/423 (0.2%)	1
Epistaxis	1/423 (0.2%)	1
Haemoptysis	1/423 (0.2%)	1
Orthopnoea	1/423 (0.2%)	1
Pleural effusion	3/423 (0.7%)	3
Pulmonary congestion	1/423 (0.2%)	1
Pulmonary embolism	4/423 (0.9%)	6
Pulmonary oedema	1/423 (0.2%)	1
Respiratory arrest	1/423 (0.2%)	1
Respiratory disorder	1/423 (0.2%)	1
Surgical and medical procedures
Bladder lesion excision	1/423 (0.2%)	1
Internal fixation of fracture	1/423 (0.2%)	1
Joint arthroplasty	1/423 (0.2%)	1
Vascular disorders
Aortic aneurysm	1/423 (0.2%)	1
Deep vein thrombosis	2/423 (0.5%)	2
Hypertension	2/423 (0.5%)	2
Other (Not Including Serious) Adverse Events
	Enzalutamide 160 mg
	Affected / at Risk (%)	# Events
Total	318/423 (75.2%)
Blood and lymphatic system disorders
Anaemia	53/423 (12.5%)	82
Gastrointestinal disorders
Constipation	46/423 (10.9%)	50
Diarrhoea	43/423 (10.2%)	54
Nausea	55/423 (13%)	65
Vomiting	24/423 (5.7%)	29
General disorders
Asthenia	86/423 (20.3%)	113
Fatigue	92/423 (21.7%)	120
Oedema peripheral	33/423 (7.8%)	39
Pain	23/423 (5.4%)	28
Injury, poisoning and procedural complications
Fall	24/423 (5.7%)	31
Investigations
Weight decreased	26/423 (6.1%)	27
Metabolism and nutrition disorders
Decreased appetite	77/423 (18.2%)	92
Musculoskeletal and connective tissue disorders
Arthralgia	47/423 (11.1%)	56
Back pain	68/423 (16.1%)	82
Musculoskeletal pain	22/423 (5.2%)	24
Pain in extremity	27/423 (6.4%)	33
Nervous system disorders
Headache	25/423 (5.9%)	26
Psychiatric disorders
Insomnia	27/423 (6.4%)	34
Respiratory, thoracic and mediastinal disorders
Dyspnoea	33/423 (7.8%)	37
Vascular disorders
Hot flush	24/423 (5.7%)	26
Hypertension	31/423 (7.3%)	36

Limitations/Caveats

After completing the extension period participants who were assessed to benefit from enzalutamide completed their treatment in another Astellas study, 9785-CL-0123 (NCT02960022).

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Certain Agreements

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

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.