A Study of Apalutamide (JNJ-56021927, ARN-509) Plus Androgen Deprivation Therapy (ADT) Versus ADT in Participants With mHSPC (TITAN)

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ClinicalTrials.gov Identifier: NCT02489318

Recruitment Status : Active, not recruiting

First Posted : July 3, 2015

Results First Posted : January 18, 2022

Last Update Posted : April 25, 2024

View this study on the modernized ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Aragon Pharmaceuticals, Inc.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Prostate Cancer
Interventions	Drug: Apalutamide Drug: Placebo Drug: Androgen Deprivation Therapy (ADT)
Enrollment	1052

Participant Flow

Recruitment Details
Pre-assignment Details	Per protocol, 208 participants randomized to receive placebo+ADT were switched over to receive apalutamide+ADT after interim analysis and unblinding. Randomized treatment disposition has been reported in participant flow. Response/progression that occurred during a non-randomized switch-over to apalutamide+ADT were not counted towards efficacy outcome measures.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Period Title: Randomized
Started	527	525
Completed	527	524
Not Completed	0	1
Reason Not Completed
Withdrawal by Subject	0	1
Period Title: Treated
Started	527	524
Completed	208 ^[1]	0
Not Completed	319	524
Reason Not Completed
Adverse Event	19	62
Death	13	11
Physician Decision	4	6
Protocol Violation	1	2
Withdrawal by Subject	37	36
Other: Progressive Disease	245	138
Other	0	2
Ongoing	0	267
[1] Participants crossed over from placebo to apalutamide after positive results at interim analysis.

Baseline Characteristics

Arm/Group Title		Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT	Total
Arm/Group Description		Participants received matching plac...	Participants received JNJ-56021927 ...	Total of all reporting groups
Arm/Group Description		Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Total of all reporting groups
Overall Number of Baseline Participants		527	525	1052
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	527 participants	525 participants	1052 participants
		67.9 (8.42)	68.9 (8.11)	68.4 (8.28)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	527 participants	525 participants	1052 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	527 100.0%	525 100.0%	1052 100.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	527 participants	525 participants	1052 participants
	American Indian or Alaska Native	11 2.1%	6 1.1%	17 1.6%
	Asian	112 21.3%	119 22.7%	231 22.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	9 1.7%	10 1.9%	19 1.8%
	White	365 69.3%	354 67.4%	719 68.3%
	More than one race	0 0.0%	1 0.2%	1 0.1%
	Unknown or Not Reported	30 5.7%	35 6.7%	65 6.2%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	527 participants	525 participants	1052 participants
ARGENTINA		20	17	37
AUSTRALIA		5	6	11
BRAZIL		38	54	92
CANADA		16	14	30
CHINA		46	48	94
CZECH REPUBLIC		12	19	31
FRANCE		8	8	16
GERMANY		10	7	17
HUNGARY		11	13	24
ISRAEL		8	6	14
ITALY		18	16	34
JAPAN		23	28	51
MEXICO		25	23	48
POLAND		12	7	19
ROMANIA		7	4	11
RUSSIAN FEDERATION		66	65	131
SOUTH KOREA		41	35	76
SPAIN		12	8	20
SWEDEN		8	8	16
TURKEY		22	28	50
UKRAINE		60	42	102
UNITED KINGDOM		16	20	36
UNITED STATES		43	49	92
Race (NIH/OMB) Measure Type: Number Unit of measure: Participants	Number Analyzed	527 participants	525 participants	1052 participants
American Indian or Alaska Native		11	6	17
Asian		112	119	231
Black or African American		9	10	19
More than one race		0	1	1
Not Reported		8	11	19
Other		22	24	46
White		365	354	719

Outcome Measures

1.Primary Outcome


Title	Radiographic Progression-free Survival (rPFS)
Description	rPFS as assessed by the investigator was defined as the duration from ...
Description	rPFS as assessed by the investigator was defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurred first. Radiographic progressive disease was defined as progression of soft tissue lesions measured by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by modified Response evaluation criteria in solid tumors (RECIST) 1.1.
Time Frame	Up to 35 months

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description:	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description:	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Overall Number of Participants Analyzed	527	525
Median (95% Confidence Interval) Unit of Measure: months
	22.08 (18.46 to 32.92)	NA ^[1] (NA to NA)

[1]

Here NA signifies that the median, lower limit and upper limit of confidence interval (CI) were not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Androgen Deprivation Therapy (ADT), Apalutamide + 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	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.484
	Confidence Interval	(2-Sided) 95% 0.391 to 0.600
	Estimation Comments	[Not Specified]

2.Primary Outcome


Title	Overall Survival (OS)
Description	OS was defined as the time from date of randomization to date of death...
Description	OS was defined as the time from date of randomization to date of death from any cause.
Time Frame	Up to 57 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description:	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description:	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Overall Number of Participants Analyzed	527	525
Median (95% Confidence Interval) Unit of Measure: months
	52.17 ^[1] (41.86 to NA)	NA ^[2] (NA to NA)

[1]

Here NA signifies that the upper limit of CI was not estimable due to lesser number of events.

[2]

Here NA signifies that the median, lower limit and upper limit of CI were not estimable due to lesser number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Androgen Deprivation Therapy (ADT), Apalutamide + 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	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.651
	Confidence Interval	(2-Sided) 95% 0.534 to 0.793
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Time to Initiation of Cytotoxic Chemotherapy
Description	Time to initiation of cytotoxic chemotherapy was defined as the time f...
Description	Time to initiation of cytotoxic chemotherapy was defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
Time Frame	Up to 57 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description:	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description:	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Overall Number of Participants Analyzed	527	525
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (NA to NA)	NA ^[1] (NA to NA)

[1]

Here NA signifies that the median, lower limit and upper limit of CI were not estimable due to lesser number of events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.469
	Confidence Interval	(2-Sided) 95% 0.350 to 0.630
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Time to Pain Progression
Description	Time to pain progression was defined as the time from the date of rand...
Description	Time to pain progression was defined as the time from the date of randomization to the date of the first observation of pain progression. Pain progression was defined as an average increase by 2 points from baseline to greater than (>) 4 on the Brief Pain Inventory - Short Form (BPI-SF) worst pain intensity (item 3) with no decrease in opioids confirmed greater than equal to (>=) 3 weeks apart or initiation of chronic opioids, whichever occurred first. BPI-SF is a self-administered questionnaire developed to assess severity of pain and impact of pain on daily functions. Item 3 (worst pain intensity) asks participants to rate worst pain in prior 7-days on a 0-10 numeric rating scale, where "0" indicates "No pain" and "10" indicates "Pain as bad as you can imagine." A lower score is better.
Time Frame	Up to 57 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description:	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description:	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Overall Number of Participants Analyzed	527	525
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (51.32 to NA)	NA ^[2] (NA to NA)

[1]

Here NA signifies that the median and upper limit of CI were not estimable due to lesser number of events.

[2]

Here NA signifies that the median, lower limit and upper limit of CI were not estimable due to lesser number of events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.1966
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.868
	Confidence Interval	(2-Sided) 95% 0.700 to 1.076
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Time to Chronic Opioid Use
Description	Time to chronic opioid use was defined as the time from date of random...
Description	Time to chronic opioid use was defined as the time from date of randomization to the first date of confirmed chronic opioid use. For participants entering the study without receiving opioids, chronic opioid use was defined as administration of opioid analgesics lasting for greater than or equal to (>=) 3 weeks for oral or >=7 days for non-oral formulations. For participants entering the study already receiving opioids, chronic opioid use was defined as a >=30 percent (%) increase in total daily dose of the opioid analgesics lasting for >= 3 weeks for oral or >= 7 days for non-oral formulation.
Time Frame	Up to 57 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description:	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description:	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Overall Number of Participants Analyzed	527	525
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (51.32 to NA)	NA ^[2] (NA to NA)

[1]

Here NA signifies that the median and upper limit of CI was not estimable due to lesser number of events.

[2]

Here NA signifies that the median, lower limit and upper limit of CI were not estimable due to lesser number of events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.1563
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.794
	Confidence Interval	(2-Sided) 95% 0.576 to 1.094
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Time to Skeletal-related Event (SRE)
Description	Time to SRE was defined as the time from the date of randomization to ...
Description	Time to SRE was defined as the time from the date of randomization to the date of the first observation of an SRE. A SRE was defined as the occurrence of either a pathological fracture, or spinal cord compression, or radiation to bone, or surgery to bone.
Time Frame	Up to 57 months

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received.


Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Apalutamide + ADT
Arm/Group Description:	Participants received matching plac...	Participants received JNJ-56021927 ...
Arm/Group Description:	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
Overall Number of Participants Analyzed	527	525
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (51.78 to NA)	NA ^[2] (NA to NA)

[1]

Here NA signifies that the median and upper limit of CI were not estimable due to lesser number of events. .

[2]

Here NA signifies that the median, lower limit and upper limit of CI were not estimable due to lesser number of events.

Statistical Analysis 1

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

Statistical Test of Hypothesis	P-Value	0.3608
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.857
	Confidence Interval	(2-Sided) 95% 0.615 to 1.194
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Up to 57 months
Adverse Event Reporting Description	Safety Analysis set included all participants who received at least 1 dose of randomized study drug. Crossover participants were counted twice (in Placebo + ADT arm and in Placebo + ADT to Apalutamide + ADT arm) for safety analysis. For crossover participants, adverse events after initiation of crossover treatment were summarized separately in Placebo + ADT to Apalutamide + ADT arm. However, adverse events occurred before crossover treatment were summarized in Placebo + ADT arm.

Arm/Group Title	Placebo + Androgen Deprivation Therapy (ADT)	Placebo + ADT to Apalutamide + ADT	Apalutamide + ADT
Arm/Group Description	Participants received matching plac...	After interim analysis and unblindi...	Participants received JNJ-56021927 ...
Arm/Group Description	Participants received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis participants in treatment phase had opportunity to receive Apalutamide +ADT. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.	After interim analysis and unblinding, participants receiving placebo +ADT crossed over to receive 240 mg apalutamide orally qd along with ADT in open-label extension phase.	Participants received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Participants received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
All-Cause Mortality
	Placebo + Androgen Deprivation Therapy (ADT)	Placebo + ADT to Apalutamide + ADT	Apalutamide + ADT
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	35/527 (6.64%)	10/208 (4.81%)	31/524 (5.92%)
Serious Adverse Events Serious Adverse Events
	Placebo + Androgen Deprivation Therapy (ADT)	Placebo + ADT to Apalutamide + ADT	Apalutamide + ADT
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	115/527 (21.82%)	29/208 (13.94%)	153/524 (29.20%)
Blood and lymphatic system disorders
Anaemia ^* 1	6/527 (1.14%)	0/208 (0.00%)	1/524 (0.19%)
Coagulopathy ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Febrile Neutropenia ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Thrombocytopenia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Cardiac disorders
Acute Coronary Syndrome ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Acute Myocardial Infarction ^* 1	0/527 (0.00%)	0/208 (0.00%)	3/524 (0.57%)
Angina Pectoris ^* 1	2/527 (0.38%)	0/208 (0.00%)	3/524 (0.57%)
Angina Unstable ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Aortic Valve Disease Mixed ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Arteriosclerosis Coronary Artery ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Atrial Fibrillation ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Atrioventricular Block Complete ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Cardiac Amyloidosis ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Cardiac Disorder ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Cardiac Failure ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Cardiac Failure Chronic ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Cardiac Failure Congestive ^* 1	1/527 (0.19%)	0/208 (0.00%)	2/524 (0.38%)
Cor Pulmonale Chronic ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Coronary Artery Disease ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Coronary Artery Occlusion ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Coronary Artery Stenosis ^* 1	0/527 (0.00%)	0/208 (0.00%)	3/524 (0.57%)
Mitral Valve Disease ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Myocardial Infarction ^* 1	0/527 (0.00%)	0/208 (0.00%)	8/524 (1.53%)
Myocardial Ischaemia ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Sinoatrial Block ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Sinus Node Dysfunction ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Supraventricular Extrasystoles ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Supraventricular Tachycardia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Ventricular Fibrillation ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Ear and labyrinth disorders
Vertigo Positional ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Endocrine disorders
Goitre ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hyperparathyroidism ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Eye disorders
Cataract ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Open Angle Glaucoma ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Gastrointestinal disorders
Abdominal Distension ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Abdominal Pain Lower ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Anal Fistula ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Constipation ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Dyschezia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Dysphagia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Gastric Ulcer Perforation ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Gastritis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Gastrointestinal Haemorrhage ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Haemorrhagic Erosive Gastritis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Inguinal Hernia ^* 1	1/527 (0.19%)	0/208 (0.00%)	3/524 (0.57%)
Large Intestinal Ulcer Perforation ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Large Intestine Polyp ^* 1	0/527 (0.00%)	1/208 (0.48%)	1/524 (0.19%)
Nausea ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Proctalgia ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Terminal Ileitis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Umbilical Hernia ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Vomiting ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
General disorders
Asthenia ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Exercise Tolerance Decreased ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Fatigue ^* 1	3/527 (0.57%)	0/208 (0.00%)	0/524 (0.00%)
Gait Disturbance ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
General Physical Health Deterioration ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Non-Cardiac Chest Pain ^* 1	1/527 (0.19%)	2/208 (0.96%)	0/524 (0.00%)
Oedema ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Pain ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Performance Status Decreased ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Peripheral Swelling ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Pyrexia ^* 1	1/527 (0.19%)	0/208 (0.00%)	2/524 (0.38%)
Hepatobiliary disorders
Bile Duct Stone ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Cholangiolitis ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Cholangitis Acute ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Cholecystitis Acute ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Cholelithiasis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hepatic Cirrhosis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hepatic Failure ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Jaundice ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Infections and infestations
Abdominal Abscess ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Abscess Jaw ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Abscess Oral ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Bronchiolitis ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Bronchitis ^* 1	1/527 (0.19%)	1/208 (0.48%)	3/524 (0.57%)
Cellulitis ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Cholecystitis Infective ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Clostridium Difficile Colitis ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Covid-19 ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Erysipelas ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Fournier's Gangrene ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Infected Lymphocele ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Influenza ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Kidney Infection ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Klebsiella Infection ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Localised Infection ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Lower Respiratory Tract Infection ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Muscle Abscess ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Peritonitis ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Pneumonia ^* 1	3/527 (0.57%)	3/208 (1.44%)	10/524 (1.91%)
Pneumonia Bacterial ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Pulmonary Tuberculosis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Pyelonephritis ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Pyelonephritis Acute ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Sepsis ^* 1	2/527 (0.38%)	2/208 (0.96%)	0/524 (0.00%)
Septic Shock ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Sinusitis ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Staphylococcal Infection ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Tuberculosis ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Upper Respiratory Tract Infection ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Urinary Tract Infection ^* 1	2/527 (0.38%)	1/208 (0.48%)	5/524 (0.95%)
Urosepsis ^* 1	1/527 (0.19%)	0/208 (0.00%)	5/524 (0.95%)
Viral Infection ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Viral Upper Respiratory Tract Infection ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Injury, poisoning and procedural complications
Acetabulum Fracture ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Ankle Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Brain Contusion ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Clavicle Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Comminuted Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Fall ^* 1	1/527 (0.19%)	0/208 (0.00%)	3/524 (0.57%)
Femoral Neck Fracture ^* 1	1/527 (0.19%)	0/208 (0.00%)	3/524 (0.57%)
Femur Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Forearm Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hand Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hip Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Incisional Hernia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Ligament Sprain ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Lower Limb Fracture ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Patella Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Radius Fracture ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Rib Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Skull Fracture ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Soft Tissue Injury ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Spinal Compression Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	4/524 (0.76%)
Subarachnoid Haematoma ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Subdural Haematoma ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Subdural Haemorrhage ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Thoracic Vertebral Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Tibia Fracture ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Traumatic Fracture ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Investigations
International Normalised Ratio Increased ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Weight Decreased ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Metabolism and nutrition disorders
Dehydration ^* 1	1/527 (0.19%)	1/208 (0.48%)	0/524 (0.00%)
Diabetes Mellitus ^* 1	0/527 (0.00%)	0/208 (0.00%)	3/524 (0.57%)
Diabetes Mellitus Inadequate Control ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Hypercalcaemia ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hyperglycaemia ^* 1	1/527 (0.19%)	0/208 (0.00%)	2/524 (0.38%)
Hyperkalaemia ^* 1	0/527 (0.00%)	2/208 (0.96%)	0/524 (0.00%)
Hypokalaemia ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Hyponatraemia ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	0/527 (0.00%)	0/208 (0.00%)	4/524 (0.76%)
Arthropathy ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Back Pain ^* 1	6/527 (1.14%)	0/208 (0.00%)	4/524 (0.76%)
Bone Pain ^* 1	2/527 (0.38%)	2/208 (0.96%)	0/524 (0.00%)
Intervertebral Disc Protrusion ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Lumbar Spinal Stenosis ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Muscular Weakness ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Musculoskeletal Pain ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Myalgia ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Osteoarthritis ^* 1	4/527 (0.76%)	1/208 (0.48%)	1/524 (0.19%)
Osteonecrosis ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Pain in Extremity ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Pathological Fracture ^* 1	4/527 (0.76%)	0/208 (0.00%)	2/524 (0.38%)
Rheumatoid Arthritis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Rotator Cuff Syndrome ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of Colon ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Adrenal Neoplasm ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Benign Lung Neoplasm ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Bladder Cancer ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Burkitt's Lymphoma ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Cancer Pain ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Colon Cancer ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Gastric Cancer ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Leiomyosarcoma ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Lung Carcinoma Cell Type Unspecified Stage I ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Lung Neoplasm Malignant ^* 1	1/527 (0.19%)	0/208 (0.00%)	2/524 (0.38%)
Meningioma ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Metastases to Central Nervous System ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Non-Small Cell Lung Cancer ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Respiratory Papilloma ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Squamous Cell Carcinoma ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Nervous system disorders
Cauda Equina Syndrome ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Cerebral Haemorrhage ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Cerebrovascular Accident ^* 1	1/527 (0.19%)	3/208 (1.44%)	4/524 (0.76%)
Cognitive Disorder ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Diplegia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Dizziness ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Haemorrhage Intracranial ^* 1	1/527 (0.19%)	1/208 (0.48%)	1/524 (0.19%)
Hydrocephalus ^* 1	0/527 (0.00%)	1/208 (0.48%)	1/524 (0.19%)
Iiird Nerve Paresis ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Ischaemic Stroke ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Migraine ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Paraplegia ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Presyncope ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Seizure ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Spinal Cord Compression ^* 1	6/527 (1.14%)	0/208 (0.00%)	2/524 (0.38%)
Subarachnoid Haemorrhage ^* 1	0/527 (0.00%)	1/208 (0.48%)	2/524 (0.38%)
Product Issues
Device Malfunction ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Psychiatric disorders
Confusional State ^* 1	1/527 (0.19%)	0/208 (0.00%)	2/524 (0.38%)
Mental Status Changes ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Suicidal Ideation ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Suicide Attempt ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Renal and urinary disorders
Acute Kidney Injury ^* 1	1/527 (0.19%)	0/208 (0.00%)	3/524 (0.57%)
Bladder Perforation ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Bladder Tamponade ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Calculus Bladder ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Calculus Urinary ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Dysuria ^* 1	1/527 (0.19%)	0/208 (0.00%)	3/524 (0.57%)
Haematuria ^* 1	3/527 (0.57%)	1/208 (0.48%)	10/524 (1.91%)
Hydronephrosis ^* 1	4/527 (0.76%)	0/208 (0.00%)	2/524 (0.38%)
Nephrolithiasis ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Renal Disorder ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Renal Failure ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Ureteric Obstruction ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Ureterolithiasis ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Urethral Stenosis ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Urinary Bladder Haematoma ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Urinary Retention ^* 1	9/527 (1.71%)	0/208 (0.00%)	4/524 (0.76%)
Urinary Tract Obstruction ^* 1	0/527 (0.00%)	0/208 (0.00%)	3/524 (0.57%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia ^* 1	2/527 (0.38%)	1/208 (0.48%)	2/524 (0.38%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Acute Respiratory Failure ^* 1	0/527 (0.00%)	0/208 (0.00%)	2/524 (0.38%)
Chronic Obstructive Pulmonary Disease ^* 1	3/527 (0.57%)	1/208 (0.48%)	3/524 (0.57%)
Dyspnoea ^* 1	2/527 (0.38%)	0/208 (0.00%)	0/524 (0.00%)
Haemothorax ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Hydrothorax ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Interstitial Lung Disease ^* 1	0/527 (0.00%)	2/208 (0.96%)	0/524 (0.00%)
Organising Pneumonia ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Paranasal Cyst ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Pleural Effusion ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Pleuritic Pain ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Pneumonia Aspiration ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
Pneumothorax Spontaneous ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Pulmonary Embolism ^* 1	1/527 (0.19%)	0/208 (0.00%)	3/524 (0.57%)
Pulmonary Haemorrhage ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Pulmonary Mass ^* 1	0/527 (0.00%)	1/208 (0.48%)	1/524 (0.19%)
Pulmonary Oedema ^* 1	1/527 (0.19%)	0/208 (0.00%)	0/524 (0.00%)
Respiratory Failure ^* 1	1/527 (0.19%)	2/208 (0.96%)	3/524 (0.57%)
Skin and subcutaneous tissue disorders
Drug Eruption ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Rash ^* 1	0/527 (0.00%)	0/208 (0.00%)	1/524 (0.19%)
Vascular disorders
Deep Vein Thrombosis ^* 1	1/527 (0.19%)	0/208 (0.00%)	1/524 (0.19%)
Hypertension ^* 1	0/527 (0.00%)	1/208 (0.48%)	3/524 (0.57%)
Venous Stenosis ^* 1	0/527 (0.00%)	1/208 (0.48%)	0/524 (0.00%)
1 Term from vocabulary, MedDRA Version 23.0 * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Placebo + Androgen Deprivation Therapy (ADT)	Placebo + ADT to Apalutamide + ADT	Apalutamide + ADT
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	485/527 (92.03%)	153/208 (73.56%)	494/524 (94.27%)
Blood and lymphatic system disorders
Anaemia ^* 1	71/527 (13.47%)	13/208 (6.25%)	68/524 (12.98%)
Leukopenia ^* 1	21/527 (3.98%)	8/208 (3.85%)	29/524 (5.53%)
Neutropenia ^* 1	15/527 (2.85%)	2/208 (0.96%)	16/524 (3.05%)
Thrombocytopenia ^* 1	15/527 (2.85%)	6/208 (2.88%)	12/524 (2.29%)
Endocrine disorders
Hypothyroidism ^* 1	5/527 (0.95%)	5/208 (2.40%)	23/524 (4.39%)
Gastrointestinal disorders
Abdominal Pain ^* 1	22/527 (4.17%)	3/208 (1.44%)	17/524 (3.24%)
Abdominal Pain Upper ^* 1	13/527 (2.47%)	2/208 (0.96%)	17/524 (3.24%)
Constipation ^* 1	57/527 (10.82%)	6/208 (2.88%)	58/524 (11.07%)
Diarrhoea ^* 1	35/527 (6.64%)	11/208 (5.29%)	56/524 (10.69%)
Dyspepsia ^* 1	10/527 (1.90%)	2/208 (0.96%)	12/524 (2.29%)
Nausea ^* 1	44/527 (8.35%)	12/208 (5.77%)	41/524 (7.82%)
Toothache ^* 1	11/527 (2.09%)	1/208 (0.48%)	10/524 (1.91%)
Vomiting ^* 1	23/527 (4.36%)	3/208 (1.44%)	22/524 (4.20%)
General disorders
Asthenia ^* 1	45/527 (8.54%)	8/208 (3.85%)	40/524 (7.63%)
Fatigue ^* 1	87/527 (16.51%)	15/208 (7.21%)	107/524 (20.42%)
Influenza Like Illness ^* 1	17/527 (3.23%)	3/208 (1.44%)	16/524 (3.05%)
Oedema Peripheral ^* 1	41/527 (7.78%)	4/208 (1.92%)	32/524 (6.11%)
Pyrexia ^* 1	16/527 (3.04%)	4/208 (1.92%)	15/524 (2.86%)
Infections and infestations
Bronchitis ^* 1	12/527 (2.28%)	1/208 (0.48%)	18/524 (3.44%)
Conjunctivitis ^* 1	5/527 (0.95%)	2/208 (0.96%)	13/524 (2.48%)
Herpes Zoster ^* 1	11/527 (2.09%)	0/208 (0.00%)	10/524 (1.91%)
Influenza ^* 1	23/527 (4.36%)	5/208 (2.40%)	21/524 (4.01%)
Nasopharyngitis ^* 1	47/527 (8.92%)	6/208 (2.88%)	44/524 (8.40%)
Pneumonia ^* 1	14/527 (2.66%)	4/208 (1.92%)	11/524 (2.10%)
Upper Respiratory Tract Infection ^* 1	29/527 (5.50%)	6/208 (2.88%)	40/524 (7.63%)
Urinary Tract Infection ^* 1	22/527 (4.17%)	4/208 (1.92%)	28/524 (5.34%)
Injury, poisoning and procedural complications
Contusion ^* 1	11/527 (2.09%)	4/208 (1.92%)	11/524 (2.10%)
Fall ^* 1	36/527 (6.83%)	8/208 (3.85%)	47/524 (8.97%)
Rib Fracture ^* 1	14/527 (2.66%)	1/208 (0.48%)	14/524 (2.67%)
Investigations
Alanine Aminotransferase Increased ^* 1	42/527 (7.97%)	4/208 (1.92%)	25/524 (4.77%)
Aspartate Aminotransferase Increased ^* 1	43/527 (8.16%)	5/208 (2.40%)	18/524 (3.44%)
Blood Alkaline Phosphatase Increased ^* 1	32/527 (6.07%)	3/208 (1.44%)	18/524 (3.44%)
Blood Lactate Dehydrogenase Increased ^* 1	17/527 (3.23%)	0/208 (0.00%)	9/524 (1.72%)
Blood Thyroid Stimulating Hormone Increased ^* 1	2/527 (0.38%)	3/208 (1.44%)	16/524 (3.05%)
Weight Decreased ^* 1	29/527 (5.50%)	9/208 (4.33%)	43/524 (8.21%)
Weight Increased ^* 1	92/527 (17.46%)	7/208 (3.37%)	55/524 (10.50%)
Metabolism and nutrition disorders
Decreased Appetite ^* 1	27/527 (5.12%)	11/208 (5.29%)	32/524 (6.11%)
Hypercholesterolaemia ^* 1	8/527 (1.52%)	7/208 (3.37%)	34/524 (6.49%)
Hyperglycaemia ^* 1	11/527 (2.09%)	1/208 (0.48%)	18/524 (3.44%)
Hyperkalaemia ^* 1	27/527 (5.12%)	16/208 (7.69%)	47/524 (8.97%)
Hypertriglyceridaemia ^* 1	13/527 (2.47%)	5/208 (2.40%)	22/524 (4.20%)
Hyponatraemia ^* 1	16/527 (3.04%)	2/208 (0.96%)	7/524 (1.34%)
Vitamin D Deficiency ^* 1	0/527 (0.00%)	0/208 (0.00%)	12/524 (2.29%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	82/527 (15.56%)	15/208 (7.21%)	101/524 (19.27%)
Back Pain ^* 1	108/527 (20.49%)	11/208 (5.29%)	106/524 (20.23%)
Bone Pain ^* 1	53/527 (10.06%)	0/208 (0.00%)	39/524 (7.44%)
Groin Pain ^* 1	7/527 (1.33%)	2/208 (0.96%)	11/524 (2.10%)
Muscle Spasms ^* 1	10/527 (1.90%)	2/208 (0.96%)	21/524 (4.01%)
Muscular Weakness ^* 1	12/527 (2.28%)	2/208 (0.96%)	18/524 (3.44%)
Musculoskeletal Chest Pain ^* 1	15/527 (2.85%)	2/208 (0.96%)	21/524 (4.01%)
Musculoskeletal Pain ^* 1	41/527 (7.78%)	5/208 (2.40%)	39/524 (7.44%)
Myalgia ^* 1	19/527 (3.61%)	2/208 (0.96%)	10/524 (1.91%)
Osteoporosis ^* 1	7/527 (1.33%)	0/208 (0.00%)	16/524 (3.05%)
Pain in Extremity ^* 1	67/527 (12.71%)	8/208 (3.85%)	69/524 (13.17%)
Pathological Fracture ^* 1	5/527 (0.95%)	0/208 (0.00%)	11/524 (2.10%)
Spinal Pain ^* 1	12/527 (2.28%)	3/208 (1.44%)	13/524 (2.48%)
Nervous system disorders
Dizziness ^* 1	35/527 (6.64%)	7/208 (3.37%)	24/524 (4.58%)
Dysgeusia ^* 1	2/527 (0.38%)	2/208 (0.96%)	13/524 (2.48%)
Headache ^* 1	31/527 (5.88%)	12/208 (5.77%)	44/524 (8.40%)
Hypoaesthesia ^* 1	12/527 (2.28%)	1/208 (0.48%)	9/524 (1.72%)
Paraesthesia ^* 1	15/527 (2.85%)	0/208 (0.00%)	11/524 (2.10%)
Psychiatric disorders
Anxiety ^* 1	6/527 (1.14%)	1/208 (0.48%)	11/524 (2.10%)
Insomnia ^* 1	33/527 (6.26%)	5/208 (2.40%)	28/524 (5.34%)
Renal and urinary disorders
Dysuria ^* 1	30/527 (5.69%)	3/208 (1.44%)	35/524 (6.68%)
Haematuria ^* 1	14/527 (2.66%)	3/208 (1.44%)	21/524 (4.01%)
Nocturia ^* 1	15/527 (2.85%)	1/208 (0.48%)	16/524 (3.05%)
Pollakiuria ^* 1	19/527 (3.61%)	5/208 (2.40%)	21/524 (4.01%)
Urinary Incontinence ^* 1	8/527 (1.52%)	0/208 (0.00%)	14/524 (2.67%)
Urinary Retention ^* 1	14/527 (2.66%)	0/208 (0.00%)	13/524 (2.48%)
Reproductive system and breast disorders
Pelvic Pain ^* 1	14/527 (2.66%)	1/208 (0.48%)	10/524 (1.91%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1	33/527 (6.26%)	4/208 (1.92%)	40/524 (7.63%)
Dyspnoea ^* 1	15/527 (2.85%)	6/208 (2.88%)	17/524 (3.24%)
Epistaxis ^* 1	4/527 (0.76%)	2/208 (0.96%)	13/524 (2.48%)
Oropharyngeal Pain ^* 1	7/527 (1.33%)	1/208 (0.48%)	14/524 (2.67%)
Skin and subcutaneous tissue disorders
Alopecia ^* 1	3/527 (0.57%)	1/208 (0.48%)	13/524 (2.48%)
Dry Skin ^* 1	8/527 (1.52%)	2/208 (0.96%)	18/524 (3.44%)
Eczema ^* 1	7/527 (1.33%)	4/208 (1.92%)	12/524 (2.29%)
Erythema ^* 1	2/527 (0.38%)	3/208 (1.44%)	14/524 (2.67%)
Hyperhidrosis ^* 1	10/527 (1.90%)	1/208 (0.48%)	18/524 (3.44%)
Pruritus ^* 1	25/527 (4.74%)	13/208 (6.25%)	58/524 (11.07%)
Rash ^* 1	23/527 (4.36%)	26/208 (12.50%)	106/524 (20.23%)
Rash Maculo-Papular ^* 1	5/527 (0.95%)	6/208 (2.88%)	17/524 (3.24%)
Vascular disorders
Hot Flush ^* 1	87/527 (16.51%)	3/208 (1.44%)	121/524 (23.09%)
Hypertension ^* 1	84/527 (15.94%)	13/208 (6.25%)	100/524 (19.08%)
1 Term from vocabulary, MedDRA Version 23.0 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Executive Medical Director
Organization:	Aragon Pharmaceuticals, Inc.
Phone:	844-434-4210
EMail:	ClinicalTrialDisclosure@its.jnj.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Ozguroglu M, Juarez Soto A, Merseburger AS, Uemura H, Ye D, Given R, Basch E, Miladinovic B, Lopez-Gitlitz A, Chi KN. Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study. J Urol. 2021 Oct;206(4):914-923. doi: 10.1097/JU.0000000000001841. Epub 2021 May 27.

Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juarez A, Merseburger AS, Ozguroglu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021 Jul 10;39(20):2294-2303. doi: 10.1200/JCO.20.03488. Epub 2021 Apr 29.

Uemura H, Koroki Y, Iwaki Y, Imanaka K, Kambara T, Lopez-Gitlitz A, Smith A, Uemura H. Skin rash following Administration of Apalutamide in Japanese patients with Advanced Prostate Cancer: an integrated analysis of the phase 3 SPARTAN and TITAN studies and a phase 1 open-label study. BMC Urol. 2020 Sep 2;20(1):139. doi: 10.1186/s12894-020-00689-0. Erratum In: BMC Urol. 2020 Oct 22;20(1):166.

Agarwal N, McQuarrie K, Bjartell A, Chowdhury S, Pereira de Santana Gomes AJ, Chung BH, Ozguroglu M, Juarez Soto A, Merseburger AS, Uemura H, Ye D, Given R, Cella D, Basch E, Miladinovic B, Dearden L, Deprince K, Naini V, Lopez-Gitlitz A, Chi KN; TITAN investigators. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019 Nov;20(11):1518-1530. doi: 10.1016/S1470-2045(19)30620-5. Epub 2019 Sep 29.

Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juarez Soto A, Merseburger AS, Ozguroglu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. doi: 10.1056/NEJMoa1903307. Epub 2019 May 31.

Layout table for additonal information

Responsible Party:	Aragon Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT02489318
Other Study ID Numbers:	CR107614 2015-000735-32 ( EudraCT Number ) 56021927PCR3002 ( Other Identifier: Janssen Research & Development, LLC )
First Submitted:	July 1, 2015
First Posted:	July 3, 2015
Results First Submitted:	September 6, 2021
Results First Posted:	January 18, 2022
Last Update Posted:	April 25, 2024

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