Trial Outcomes & Findings for Study on Enzalutamide and Flutamide in Patients With Castration Resistant Prostate Cancer (NCT NCT02918968)

Last Updated: 2024-12-09

Results Overview

TTPP1 was defined as the period from the date of randomization to the date of PSA progression in the 1st line AAT period. PSA progression was defined according to the consensus guidelines of prostate cancer clinical trials working group 2 (PCWG2). For participants with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir were documented, which was confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline were documented. Time to event analysis was performed using kaplan-meier (KM) estimates.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

206 participants

Primary outcome timeframe

From date of randomization to the date of PSA progression in the 1st line AAT period (Up to 38 months)

Results posted on

2024-12-09

Participant Flow

Participants with M0 or M1 castration-resistant prostatic neoplasm that relapsed during Combined Androgen Blockade (CAB) therapy with bicalutamide were enrolled in this study.

Randomization was stratified by disease stages (M0/N0, M0/N1 or M1).

Participant milestones

Participant milestones
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of alternative antiandrogen therapy (AAT) until confirmed prostate-specific antigen (PSA) progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
1st Line AAT STARTED	102	104
1st Line AAT Maintained 1st Line AAT Without Progression	25	8
1st Line AAT COMPLETED	73	93
1st Line AAT NOT COMPLETED	29	11
2nd Line AAT STARTED	48	85
2nd Line AAT COMPLETED	23	73
2nd Line AAT NOT COMPLETED	25	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of alternative antiandrogen therapy (AAT) until confirmed prostate-specific antigen (PSA) progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
1st Line AAT Progressive disease	9	4
1st Line AAT Adverse Event	12	3
1st Line AAT Physician Decision	4	2
1st Line AAT Withdrawal by Subject	2	1
1st Line AAT Lost to Follow-up	0	1
1st Line AAT Death	1	0
1st Line AAT Miscellaneous	1	0
2nd Line AAT Progressive disease	21	3
2nd Line AAT Adverse Event	2	5
2nd Line AAT Physician Decision	0	1
2nd Line AAT Withdrawal by Subject	2	2
2nd Line AAT Death	0	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Total n=206 Participants Total of all reporting groups
Age, Continuous	74.4 years STANDARD_DEVIATION 7.6 • n=102 Participants	74.1 years STANDARD_DEVIATION 7.6 • n=104 Participants	74.2 years STANDARD_DEVIATION 7.6 • n=206 Participants
Sex: Female, Male Female	0 Participants n=102 Participants	0 Participants n=104 Participants	0 Participants n=206 Participants
Sex: Female, Male Male	102 Participants n=102 Participants	104 Participants n=104 Participants	206 Participants n=206 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Disease Stages at Randomization M0/N0	24 Participants n=102 Participants	25 Participants n=104 Participants	49 Participants n=206 Participants
Disease Stages at Randomization M0/N1	3 Participants n=102 Participants	4 Participants n=104 Participants	7 Participants n=206 Participants
Disease Stages at Randomization M1	75 Participants n=102 Participants	75 Participants n=104 Participants	150 Participants n=206 Participants

PRIMARY outcome

Timeframe: From date of randomization to the date of PSA progression in the 1st line AAT period (Up to 38 months)

Population: ITT Population

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Time to PSA Progression With 1st Line AAT (TTPP1)	21.39 Months Interval 12.16 to Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.	5.78 Months Interval 4.67 to 8.54

SECONDARY outcome

Timeframe: From date of randomization to the date of PSA progression in 2nd line AAT (Up to 38 months)

Population: ITT population

TTPP2 was defined as the period from day 1 of the 2nd line AAT to the date of PSA progression with the 2nd line AAT. PSA progression was defined according to the consensus guidelines of PCWG2. For participants with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir were documented, which was confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline were documented. Time to event analysis was performed using kaplan-meier estimates.

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Time to PSA Progression With 2nd Line AAT (TTPP2)	NA Months Interval 20.99 to Median was not estimable since KM estimate did not reach to 50%. Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.	21.22 Months Interval 14.78 to Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.

SECONDARY outcome

Timeframe: Baseline and at least 3 weeks after, the lowest PSA decreased by at least 50% or 90% from baseline (Up to 38 months)

Population: ITT population with participants in each disease stage.

PSA response was defined as PSA decreased by at least 50% or 90% from baseline when at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline in the 1st line AAT period after baseline. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N0: (≥ 50% reduction)	75.0 Percentage of participants Interval 53.3 to 90.2	48.0 Percentage of participants Interval 27.8 to 68.7
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N1: (≥ 50% reduction)	66.7 Percentage of participants Interval 9.4 to 99.2	0.0 Percentage of participants Interval 0.0 to 60.2
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M1: (≥ 50% reduction)	72.0 Percentage of participants Interval 60.4 to 81.8	32.0 Percentage of participants Interval 21.7 to 43.8
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT All participants: (≥ 50% reduction)	72.5 Percentage of participants Interval 62.8 to 80.9	34.6 Percentage of participants Interval 25.6 to 44.6
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N0: (≥ 90% reduction)	62.5 Percentage of participants Interval 40.6 to 81.2	8.0 Percentage of participants Interval 1.0 to 26.0
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N1: (≥ 90% reduction)	33.3 Percentage of participants Interval 0.8 to 90.6	0.0 Percentage of participants Interval 0.0 to 60.2
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M1: (≥ 90% reduction)	53.3 Percentage of participants Interval 41.4 to 64.9	20.0 Percentage of participants Interval 11.6 to 30.8
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT All participants: (≥ 90% reduction)	54.9 Percentage of participants Interval 44.7 to 64.8	16.3 Percentage of participants Interval 9.8 to 24.9

SECONDARY outcome

Timeframe: Baseline and week 13

Population: ITT population with participants in each disease stage.

PSA response was defined as the lowest PSA at week 13 decreased by at least 50% or 90% from baseline in the 1st line AAT period. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M1: (≥ 90% reduction)	49.3 Percentage of participants Interval 37.6 to 61.1	18.7 Percentage of participants Interval 10.6 to 29.3
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N0: (≥ 50% reduction)	83.3 Percentage of participants Interval 62.6 to 95.3	40.0 Percentage of participants Interval 21.1 to 61.3
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N1: (≥ 50% reduction)	66.7 Percentage of participants Interval 9.4 to 99.2	0.0 Percentage of participants Interval 0.0 to 60.2
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M1: (≥ 50% reduction)	72.0 Percentage of participants Interval 60.4 to 81.8	33.3 Percentage of participants Interval 22.9 to 45.2
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT All participants: (≥ 50% reduction)	74.5 Percentage of participants Interval 64.9 to 82.6	33.7 Percentage of participants Interval 24.7 to 43.6
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N0: (≥ 90% reduction)	50.0 Percentage of participants Interval 29.1 to 70.9	8.0 Percentage of participants Interval 1.0 to 26.0
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT M0/N1: (≥ 90% reduction)	33.3 Percentage of participants Interval 0.8 to 90.6	0.0 Percentage of participants Interval 0.0 to 60.2
Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT All participants: (≥ 90% reduction)	49.0 Percentage of participants Interval 39.0 to 59.1	15.4 Percentage of participants Interval 9.1 to 23.8

SECONDARY outcome

Timeframe: From date of randomization to the day when the decrease of PSA from baseline by 50% is first identified (Up to 38 months)

Population: ITT population with participants in each disease stage.

Time to PSA decrease by 50% with 1st line AAT was defined as the period from the date of randomization to the day when the decrease of PSA from baseline by 50% is first identified. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Time to PSA Decrease by 50% From Baseline With 1st Line AAT M0/N0	2.79 Months Interval 2.66 to 3.02	3.94 Months Interval 2.79 to Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.
Time to PSA Decrease by 50% From Baseline With 1st Line AAT M0/N1	2.79 Months Interval 2.56 to Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.	NA Months Median was not estimable since KM estimate did not reach to 50%. Lower limit of confidence interval was not estimable since the lower confidence limits for the survivor function lay above 0.5. Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.
Time to PSA Decrease by 50% From Baseline With 1st Line AAT M1	2.79 Months Lower and upper limit of confidence interval were not estimable since a lot of participants had event at same study day.	7.49 Months Interval 3.02 to Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.

SECONDARY outcome

Timeframe: From date of randomization to discontinuation of 1st line AAT (Up to 38 months)

Population: ITT population with participants in each disease stage.

TTF1 was defined as the period from randomization to study drug discontinuation of 1st line AAT for any reason that includes disease progression, onset of adverse events (AEs), participants request, or death. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Time to Treatment Failure of 1st Line AAT (TTF1) M0/N0	17.58 Months Interval 10.15 to 24.11	7.72 Months Interval 4.47 to 15.67
Time to Treatment Failure of 1st Line AAT (TTF1) M0/N1	5.55 Months Interval 4.86 to 10.38	4.73 Months Interval 1.87 to 7.62
Time to Treatment Failure of 1st Line AAT (TTF1) M1	12.02 Months Interval 7.39 to 18.43	3.94 Months Interval 3.65 to 5.55

SECONDARY outcome

Timeframe: From date of randomization to discontinuation of 2nd line AAT (Up to 38 months)

Population: ITT population

TTF2 was defined as the period from randomization to study drug discontinuation of 2nd line AAT for any reason that includes disease progression, onset of AEs, participants request, or death. Time to event analysis was performed using kaplan-meier estimates.

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=102 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Time to Treatment Failure of 2nd Line AAT (TTF2)	23.03 Months Interval 16.79 to Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.	16.59 Months Interval 13.14 to 23.95

SECONDARY outcome

Timeframe: From date of randomization to the time when radiographic disease progression is observed or death of any cause (up to 38 months)

Population: ITT population with M1 diseases stage participants. No data reported for M0/N0 and M0/N1 as there are zero participants with event.

rPFS was defined as the period from randomization to the time when radiographic disease progression is observed or death of any cause during the study period, whichever occurs earlier. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

Outcome measures

Outcome measures
Measure	Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT n=75 Participants Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).	Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT n=104 Participants Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Radiographic Progression-free Survival (rPFS) M1	NA Months Median was not estimable since KM estimate did not reach to 50%. Lower limit of confidence interval was not estimable since the lower confidence limits for the survivor function lay above 0.5. Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.	NA Months Interval 29.08 to Median was not estimable since KM estimate did not reach to 50%. Upper limit of confidence interval was not estimable since the upper confidence limits for the survivor function lay above 0.5.

Adverse Events

Enzalutamide 160mg 1st Line AAT

Serious events: 29 serious events

Other events: 79 other events

Deaths: 1 deaths

Enzalutamide 160mg 2nd Line AAT

Serious events: 18 serious events

Other events: 56 other events

Deaths: 1 deaths

Flutamide 375mg 1st Line AAT

Serious events: 15 serious events

Other events: 65 other events

Deaths: 0 deaths

Flutamide 375mg 2nd Line AAT

Serious events: 4 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosure

Astellas Pharma Inc.

Phone: +81 3-3244-6500 Japanese only

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Enzalutamide 160mg 1st Line AAT n=102 participants at risk Participants received enzalutamide 160mg capsules orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months).	Enzalutamide 160mg 2nd Line AAT n=85 participants at risk Participants received enzalutamide 160mg capsules orally once daily as 2nd line of AAT after confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months).	Flutamide 375mg 1st Line AAT n=104 participants at risk Participants received flutamide 125mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months).	Flutamide 375mg 2nd Line AAT n=48 participants at risk Participants received flutamide 125mg tablets orally thrice daily as 2nd line of AAT after confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months).
Blood and lymphatic system disorders Anaemia	2.9% 3/102 • Number of events 3 • From of date of randomization to end of study (up to 38 months)	1.2% 1/85 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	1.9% 2/104 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	8.3% 4/48 • Number of events 4 • From of date of randomization to end of study (up to 38 months)
Gastrointestinal disorders Constipation	13.7% 14/102 • Number of events 16 • From of date of randomization to end of study (up to 38 months)	2.4% 2/85 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	2.9% 3/104 • Number of events 3 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)
Gastrointestinal disorders Dental caries	0.98% 1/102 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	5.9% 5/85 • Number of events 5 • From of date of randomization to end of study (up to 38 months)	6.7% 7/104 • Number of events 7 • From of date of randomization to end of study (up to 38 months)	2.1% 1/48 • Number of events 1 • From of date of randomization to end of study (up to 38 months)
Gastrointestinal disorders Diarrhoea	6.9% 7/102 • Number of events 7 • From of date of randomization to end of study (up to 38 months)	2.4% 2/85 • Number of events 3 • From of date of randomization to end of study (up to 38 months)	11.5% 12/104 • Number of events 14 • From of date of randomization to end of study (up to 38 months)	12.5% 6/48 • Number of events 6 • From of date of randomization to end of study (up to 38 months)
Gastrointestinal disorders Nausea	6.9% 7/102 • Number of events 8 • From of date of randomization to end of study (up to 38 months)	7.1% 6/85 • Number of events 7 • From of date of randomization to end of study (up to 38 months)	4.8% 5/104 • Number of events 5 • From of date of randomization to end of study (up to 38 months)	4.2% 2/48 • Number of events 2 • From of date of randomization to end of study (up to 38 months)
General disorders Fatigue	14.7% 15/102 • Number of events 17 • From of date of randomization to end of study (up to 38 months)	9.4% 8/85 • Number of events 10 • From of date of randomization to end of study (up to 38 months)	2.9% 3/104 • Number of events 3 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)
General disorders Malaise	14.7% 15/102 • Number of events 16 • From of date of randomization to end of study (up to 38 months)	20.0% 17/85 • Number of events 19 • From of date of randomization to end of study (up to 38 months)	3.8% 4/104 • Number of events 4 • From of date of randomization to end of study (up to 38 months)	4.2% 2/48 • Number of events 2 • From of date of randomization to end of study (up to 38 months)
Hepatobiliary disorders Hepatic function abnormal	2.0% 2/102 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	2.4% 2/85 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	8.7% 9/104 • Number of events 10 • From of date of randomization to end of study (up to 38 months)	4.2% 2/48 • Number of events 2 • From of date of randomization to end of study (up to 38 months)
Infections and infestations Influenza	6.9% 7/102 • Number of events 7 • From of date of randomization to end of study (up to 38 months)	1.2% 1/85 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	1.9% 2/104 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)
Infections and infestations Nasopharyngitis	22.5% 23/102 • Number of events 36 • From of date of randomization to end of study (up to 38 months)	14.1% 12/85 • Number of events 17 • From of date of randomization to end of study (up to 38 months)	16.3% 17/104 • Number of events 33 • From of date of randomization to end of study (up to 38 months)	4.2% 2/48 • Number of events 2 • From of date of randomization to end of study (up to 38 months)
Injury, poisoning and procedural complications Fall	17.6% 18/102 • Number of events 21 • From of date of randomization to end of study (up to 38 months)	11.8% 10/85 • Number of events 10 • From of date of randomization to end of study (up to 38 months)	3.8% 4/104 • Number of events 4 • From of date of randomization to end of study (up to 38 months)	2.1% 1/48 • Number of events 1 • From of date of randomization to end of study (up to 38 months)
Injury, poisoning and procedural complications Spinal compression fracture	5.9% 6/102 • Number of events 6 • From of date of randomization to end of study (up to 38 months)	1.2% 1/85 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	0.00% 0/104 • From of date of randomization to end of study (up to 38 months)	2.1% 1/48 • Number of events 1 • From of date of randomization to end of study (up to 38 months)
Investigations Alanine aminotransferase increased	0.98% 1/102 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	0.00% 0/85 • From of date of randomization to end of study (up to 38 months)	6.7% 7/104 • Number of events 8 • From of date of randomization to end of study (up to 38 months)	2.1% 1/48 • Number of events 1 • From of date of randomization to end of study (up to 38 months)
Investigations Aspartate aminotransferase increased	0.98% 1/102 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	0.00% 0/85 • From of date of randomization to end of study (up to 38 months)	5.8% 6/104 • Number of events 7 • From of date of randomization to end of study (up to 38 months)	4.2% 2/48 • Number of events 2 • From of date of randomization to end of study (up to 38 months)
Metabolism and nutrition disorders Decreased appetite	10.8% 11/102 • Number of events 11 • From of date of randomization to end of study (up to 38 months)	9.4% 8/85 • Number of events 9 • From of date of randomization to end of study (up to 38 months)	3.8% 4/104 • Number of events 5 • From of date of randomization to end of study (up to 38 months)	4.2% 2/48 • Number of events 2 • From of date of randomization to end of study (up to 38 months)
Musculoskeletal and connective tissue disorders Back pain	14.7% 15/102 • Number of events 16 • From of date of randomization to end of study (up to 38 months)	4.7% 4/85 • Number of events 4 • From of date of randomization to end of study (up to 38 months)	5.8% 6/104 • Number of events 6 • From of date of randomization to end of study (up to 38 months)	2.1% 1/48 • Number of events 1 • From of date of randomization to end of study (up to 38 months)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	4.9% 5/102 • Number of events 5 • From of date of randomization to end of study (up to 38 months)	4.7% 4/85 • Number of events 4 • From of date of randomization to end of study (up to 38 months)	3.8% 4/104 • Number of events 4 • From of date of randomization to end of study (up to 38 months)	8.3% 4/48 • Number of events 4 • From of date of randomization to end of study (up to 38 months)
Nervous system disorders Dizziness	5.9% 6/102 • Number of events 6 • From of date of randomization to end of study (up to 38 months)	5.9% 5/85 • Number of events 5 • From of date of randomization to end of study (up to 38 months)	2.9% 3/104 • Number of events 3 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)
Renal and urinary disorders Haematuria	5.9% 6/102 • Number of events 6 • From of date of randomization to end of study (up to 38 months)	2.4% 2/85 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	1.9% 2/104 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)
Vascular disorders Hot flush	3.9% 4/102 • Number of events 4 • From of date of randomization to end of study (up to 38 months)	1.2% 1/85 • Number of events 1 • From of date of randomization to end of study (up to 38 months)	5.8% 6/104 • Number of events 6 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)
Vascular disorders Hypertension	12.7% 13/102 • Number of events 15 • From of date of randomization to end of study (up to 38 months)	5.9% 5/85 • Number of events 6 • From of date of randomization to end of study (up to 38 months)	1.9% 2/104 • Number of events 2 • From of date of randomization to end of study (up to 38 months)	0.00% 0/48 • From of date of randomization to end of study (up to 38 months)