Trial Outcomes & Findings for Study of Enzalutamide (Formerly MDV3100) as a Neoadjuvant Therapy for Patients Undergoing Prostatectomy for Localized Prostate Cancer (NCT NCT01547299)

Last Updated: 2018-10-23

Results Overview

Pathologic complete response rate was defined as percentage of participants with pathologic complete response. Pathologic complete response rate following triplet therapy (enzalutamide in combination with leuprolide and dutasteride) and enzalutamide alone when administered as neoadjuvant therapy for 180 days prior to prostatectomy in participants with localized prostate cancer. Pathologic complete response was defined as the absence of morphologically identifiable carcinoma in the prostatectomy specimen, as assessed by the local and central pathologist.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

52 participants

Primary outcome timeframe

Day 180

Results posted on

2018-10-23

Participant Flow

Participant milestones

Participant milestones
Measure	Enzalutamide + Leuprolide + Dutasteride Participants were administered 160 milligram (mg) of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Overall Study STARTED	25	27
Overall Study COMPLETED	23	25
Overall Study NOT COMPLETED	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Enzalutamide + Leuprolide + Dutasteride Participants were administered 160 milligram (mg) of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Overall Study Withdrawal by Subject	2	2

Baseline Characteristics

Study of Enzalutamide (Formerly MDV3100) as a Neoadjuvant Therapy for Patients Undergoing Prostatectomy for Localized Prostate Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.	Total n=52 Participants Total of all reporting groups
Age, Continuous	60.8 years STANDARD_DEVIATION 6.95 • n=5 Participants	61.4 years STANDARD_DEVIATION 7.65 • n=7 Participants	61.1 years STANDARD_DEVIATION 7.26 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	27 Participants n=7 Participants	52 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a prostatectomy sample evaluated by the local and central pathologist. Here, "N" signifies number of participants evaluable for this specified outcome measure.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Pathologic Complete Response Rate Local pathologist	8.7 percentage of participants Interval 1.1 to 28.0	0.0 percentage of participants Interval 0.0 to 13.7
Pathologic Complete Response Rate Central pathologist	4.3 percentage of participants Interval 0.1 to 21.9	0.0 percentage of participants Interval 0.0 to 13.7

SECONDARY outcome

Timeframe: Day 180

To determine the percentage of participants with positive surgical margins at prostatectomy as assessed by the local and central pathologist. Surgical margin, also known as tumor free margin referred to the visible normal tissue or skin margin that was removed with the surgical excision of a tumor, growth, or malignancy. The margin was described as positive when the pathologist finds cancer cells at the edge of the tissue, suggesting that all of the cancer has not been removed.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Percentage of Participants With Positive Surgical Margins Local pathologist	4.3 percentage of participants Interval 0.1 to 21.9	12.0 percentage of participants Interval 2.5 to 31.2
Percentage of Participants With Positive Surgical Margins Central pathologist	21.7 percentage of participants Interval 7.5 to 43.7	16.0 percentage of participants Interval 4.5 to 36.1

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a prostatectomy sample evaluated by the local pathologist. Here, "N" signifies number of participants evaluable for this specified outcome measure.

To determine the percentage of participants with extracapsular extension at prostatectomy as assessed by the local pathologist. Extracapsular extension was defined as prostate cancer cells when extended into the prostate capsule or outer lining of the prostate gland.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Percentage of Participants With Extracapsular Extension: Local Review	26.1 percentage of participants Interval 10.2 to 48.4	36.0 percentage of participants Interval 18.0 to 57.5

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment with a prostatectomy sample evaluated by the central pathologist. One participant in the Enzalutamide treatment arm was excluded from the analysis because the result reported by the central lab was indeterminate. Here, "N" signifies number of participants evaluable for this outcome measure.

To determine the percentage of participants with extracapsular extension at prostatectomy as assessed by the central pathologist. Extracapsular extension was defined as prostate cancer cells when extended into the prostate capsule or outer lining of the prostate gland.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=24 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Percentage of Participants With Extracapsular Extension: Central Review	56.5 percentage of participants Interval 34.5 to 76.8	70.8 percentage of participants Interval 48.9 to 87.4

SECONDARY outcome

Timeframe: Day 180

To determine the percentage of participants with positive seminal vesicles at prostatectomy as assessed by the local and central pathologist. Seminal vesicles or seminal glands, were defined as a pair of simple tubular glands located within the pelvis. They secrete fluid that partly composes the semen. Seminal vesicles with cancer cells in them were called positive seminal vesicles.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Percentage of Participants With Positive Seminal Vesicles Local pathologist	30.4 percentage of participants Interval 13.2 to 52.9	36.0 percentage of participants Interval 18.0 to 57.5
Percentage of Participants With Positive Seminal Vesicles Central pathologist	30.4 percentage of participants Interval 13.2 to 52.9	36.0 percentage of participants Interval 18.0 to 57.5

SECONDARY outcome

Timeframe: Day 180

To determine the percentage of participants with positive lymph nodes at prostatectomy as assessed by the local and central pathologist. Lymph nodes were small clumps of immune cells that act as filters for the lymphatic system. Lymph nodes with cancer cells in them were called positive lymph nodes.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Percentage of Participants With Positive Lymph Nodes Local pathologist	26.1 percentage of participants Interval 10.2 to 48.4	4.0 percentage of participants Interval 0.1 to 20.4
Percentage of Participants With Positive Lymph Nodes Central pathologist	26.1 percentage of participants Interval 10.2 to 48.4	4.0 percentage of participants Interval 0.1 to 20.4

SECONDARY outcome

Timeframe: Day 195

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a baseline PSA and at least one post baseline PSA. Here, "N" signifies number of participants evaluable for this specified outcome measure.

To determine the effects on PSA as measured by the lowest post baseline PSA value prior to prostatectomy. Prostate-specific antigen (PSA) was a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA nadir was the participant's lowest observed post baseline PSA value.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=24 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Prostate-Specific Antigen (PSA) Nadir	0.04 microgram per liter (mcg/L) Interval 0.01 to 0.53	0.51 microgram per liter (mcg/L) Interval 0.02 to 8.8

SECONDARY outcome

Timeframe: Day 195

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a baseline PSA and at least one post baseline PSA.

To determine the effects on PSA as measured by the time to the lowest post baseline PSA value prior to prostatectomy. Prostate-specific antigen (PSA) was a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA nadir was the participant's lowest observed post baseline PSA value.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Time to Prostate-Specific Antigen (PSA) Nadir	5.09 days Interval 2.79 to 6.44	6.01 days Interval 2.89 to 6.64

SECONDARY outcome

Timeframe: Day 195

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a baseline PSA and at least one post baseline PSA.

To determine the effects on PSA as measured by the percentage of participants with PSA less than (\<) 0.2 nanogram per milliliter (ng/mL), and a 50 percent (%) and 90% decrease in PSA value prior to prostatectomy. Prostate-specific antigen (PSA) was a protein produced by normal, as well as malignant, cells of the prostate gland.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Percentage of Participants With Reduction in Prostate-Specific Antigen (PSA) 90% decrease in PSA	100.0 percentage of participants Interval 86.3 to 100.0	63.0 percentage of participants Interval 42.4 to 80.6
Percentage of Participants With Reduction in Prostate-Specific Antigen (PSA) PSA < 0.2 ng/mL	92.0 percentage of participants Interval 74.0 to 99.0	29.6 percentage of participants Interval 13.8 to 50.2
Percentage of Participants With Reduction in Prostate-Specific Antigen (PSA) 50% decrease in PSA	100.0 percentage of participants Interval 86.3 to 100.0	100.0 percentage of participants Interval 87.2 to 100.0

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a baseline and at least one post baseline score. Here, "N" signifies number of participants evaluable for this specified outcome measure.

EPIC sexual domain was HRQoL instrument that measured the effects of prostate cancer treatment on a participant's sexual function and sexual satisfaction. Sexual domain summary score was measured on a scale ranged from 0 (worst) to 100 (best) with higher scores representing better sexual function and satisfaction. Best change from baseline category in EPIC sexual domain summary score ranged from worsened to improved where worsened indicated decrease of at least 1 minimally important difference, stable indicated changed by less than 1 minimally important difference and improved indicated increase of at least 1 minimally important difference. Minimally important difference was defined as one-half of the standard deviation of baseline score. Number of participants within each category are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With The Expanded Prostate Cancer Index Composite (EPIC) Sexual Domain Summary Score Improved	1 participants	0 participants
Health-Related Quality of Life (HRQoL): Number of Participants With The Expanded Prostate Cancer Index Composite (EPIC) Sexual Domain Summary Score Worsened	11 participants	10 participants
Health-Related Quality of Life (HRQoL): Number of Participants With The Expanded Prostate Cancer Index Composite (EPIC) Sexual Domain Summary Score Stable	4 participants	6 participants

SECONDARY outcome

Timeframe: Day 180

EPIC sexual function subscale was HRQoL instrument that measured the effects of prostate cancer treatment on a participant's sexual function and sexual satisfaction. EPIC sexual function subscale was a component of sexual domain that was evaluated on a distinct set of questions. It was measured on a scale ranged from 0 (worst) to 100 (best) with higher scores representing better sexual function. Best change from baseline category in EPIC sexual function subscale score ranged from worsened to improved where worsened indicated decrease of at least 1 minimally important difference, stable indicated changed by less than 1 minimally important difference and improved indicated increase of at least 1 minimally important difference. Minimally important difference was defined as one-half of the standard deviation of baseline score. Number of participants within each category are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=15 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=17 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Function Subscale Score Worsened	11 participants	12 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Function Subscale Score Stable	4 participants	5 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Function Subscale Score Improved	0 participants	0 participants

SECONDARY outcome

Timeframe: Day 180

EPIC sexual bother subscale was HRQoL instrument that measured the effects of prostate cancer treatment on a participant's sexual function and sexual satisfaction. EPIC sexual bother subscale was a component of sexual domain that was evaluated on a distinct set of questions. It was measured on a scale ranged from 0 (worst) to 100 (best) with higher scores representing less sexual bother and difficulty. Best change from baseline category in EPIC sexual bother subscale score ranged from worsened to improved where worsened indicated decrease of at least 1 minimally important difference, stable indicated changed by less than 1 minimally important difference and improved indicated increase of at least 1 minimally important difference. Minimally important difference was defined as one-half of the standard deviation of baseline score. Number of participants within each category are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Bother Subscale Score Stable	9 participants	7 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Bother Subscale Score Improved	0 participants	4 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Bother Subscale Score Worsened	7 participants	5 participants

SECONDARY outcome

Timeframe: Day 180

EPIC Hormonal Domain was HRQoL instrument that measured the effects of prostate cancer treatment on a participant's hormonal function. It was measured on a scale ranged from 0 (worst) to 100 (best) scale with higher scores representing better hormonal function. Best change from baseline category in EPIC hormonal domain summary score ranged from worsened to improved where worsened indicated decrease of at least 1 minimally important difference, stable indicated changed by less than 1 minimally important difference and improved indicated increase of at least 1 minimally important difference. Minimally important difference was defined as one-half of the standard deviation baseline score. Number of participants within each category are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=18 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Domain Summary Score Worsened	10 participants	10 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Domain Summary Score Stable	3 participants	7 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Domain Summary Score Improved	3 participants	1 participants

SECONDARY outcome

Timeframe: Day 180

EPIC hormonal function subscale score was HRQoL instrument that measured the effects of prostate cancer treatment on a participant's hormonal function. EPIC hormonal function subscale was a component of hormonal domain that was evaluated on a distinct set of questions. It was measured on a scale ranged from 0 (worst) to 100 (best) scale with higher scores representing better hormonal function. Best change from baseline category in EPIC hormonal function subscale score ranged from worsened to improved where worsened indicated decrease of at least 1 minimally important difference, stable indicated changed by less than 1 minimally important difference and improved indicated increase of at least 1 minimally important difference. Minimally important difference was defined as one-half of the standard deviation baseline score. Number of participants within each category are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=18 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Function Subscale Score Worsened	11 participants	11 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Function Subscale Score Stable	2 participants	7 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Function Subscale Score Improved	3 participants	0 participants

SECONDARY outcome

Timeframe: Day 180

EPIC hormonal bother subscale score was HRQoL instrument that measured the effects of prostate cancer treatment on a participant's hormonal function. EPIC hormonal bother subscale was a component of hormonal domain that was evaluated on a distinct set of questions. It was measured on a scale ranged from 0 (worst) to 100 (best) scale with higher scores representing less hormonal bothering. Best change from baseline category in EPIC hormonal bother subscale score ranged from worsened to improved where worsened indicated decrease of at least 1 minimally important difference, stable indicated changed by less than 1 minimally important difference and improved indicated increase of at least 1 minimally important difference. Minimally important difference was defined as one-half of the standard deviation baseline score. Number of participants within each category are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=18 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Bother Subscale Score Worsened	9 participants	6 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Bother Subscale Score Stable	5 participants	11 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Bother Subscale Score Improved	2 participants	1 participants

SECONDARY outcome

Timeframe: Day 180

The Twelve-Item Short Form Version 2 was HRQoL instrument that measured general health and well-being across physical and mental components. The general health domain score contained 1 item scored on a scale of 1 to 5 where 1=excellent to 5=poor health, where higher score indicated worse health status. Best change from baseline category in general health domain score ranged from worsened (decrease of at least 1 minimally important difference), stable (changed by less than 1 minimally important difference), or improved (increase of at least 1 minimally important difference). Minimally important difference was defined as one-half the standard deviation of the score of interest at baseline.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=18 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 General Health Domain Score Stable	9 participants	6 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 General Health Domain Score Worsened	5 participants	5 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 General Health Domain Score Improved	2 participants	7 participants

SECONDARY outcome

Timeframe: Day 180

The Twelve-Item Short Form Version 2 was HRQoL instrument that measured general health and well-being across physical and mental components. The physical functioning domain score contained 2 items each scored on a scale of 1 to 5 where 1=excellent physical functioning to 5=poor physical functioning. Physical functioning domain total score ranged from 1 to 10, where higher scores indicated poor physical functioning. Best change from baseline category in physical functioning domain score ranged from worsened (decrease of at least 1 minimally important difference), stable (changed by less than 1 minimally important difference), or improved (increase of at least 1 minimally important difference). Minimally important difference was defined as one-half the standard deviation of the score of interest at baseline.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=18 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Physical Functioning Domain Score Stable	12 participants	15 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Physical Functioning Domain Score Worsened	3 participants	2 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Physical Functioning Domain Score Improved	1 participants	1 participants

SECONDARY outcome

Timeframe: Day 180

The Twelve-Item Short Form Version 2 was HRQoL instrument that measured general health and well-being across physical and mental components. The mental health domain score had 2 items scored on a scale of 1 to 5, where higher scores indicated worse mental status. The total score ranged from 1 to 10, where higher scores indicated worse mental status. Best change from baseline category in mental component summary ranged from worsened (decrease of at least 1 minimally important difference), stable (changed by less than 1 minimally important difference), or improved (increase of at least 1 minimally important difference). Minimally important difference was defined as one-half the standard deviation of the score of interest at baseline.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=18 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Role-Emotional Domain Score Worsened	3 participants	1 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Role-Emotional Domain Score Improved	4 participants	7 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Role-Emotional Domain Score Stable	9 participants	10 participants

SECONDARY outcome

Timeframe: Day 180

The Twelve-Item Short Form Version 2 was HRQoL instrument that measured general health and well-being across physical and mental components. The mental health domain score had 2 items scored on a scale of 1 to 5 where for 1 item 1=all of the time person felt calm and peaceful to 5=none of the time person felt calm and peaceful. The score ranged from 1 to 5, where higher scores meant worse mental status. For other item 1=all of the time person felt downhearted and blue to 5=none of the time person felt downhearted and blue. The score ranged from 1 to 5, where higher scores meant better mental status. Best change from baseline category in mental component summary ranged from worsened (decrease of at least 1 minimally important difference), stable (changed by less than 1 minimally important difference), or improved (increase of at least 1 minimally important difference). Minimally important difference was defined as one-half the standard deviation of the score of interest at baseline.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=16 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=17 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Mental Component Summary Worsened	4 participants	1 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Mental Component Summary Stable	8 participants	11 participants
Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Mental Component Summary Improved	4 participants	5 participants

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a prostatectomy sample evaluated by the central pathologist. Here, "N" signifies number of participants evaluable for this specified outcome measure.

To determine pharmacodynamic effects as measured by the amount of tissue DHT in prostatectomy specimens following radical prostatectomy.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Pharmacodynamic Effects: Tissue Dihydrotestosterone (DHT)	0.04 picogram per milligram Standard Deviation 0.01 • Interval 0.02 to 0.06	3.34 picogram per milligram Standard Deviation 1.57 • Interval 0.86 to 8.92

SECONDARY outcome

Timeframe: Day 180

To determine pharmacodynamic effects as measured by the amount of tissue testosterone in prostatectomy specimens following radical prostatectomy.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Pharmacodynamic Effects: Tissue Testosterone	0.18 picogram per milligram Standard Deviation 0.13 • Interval 0.04 to 0.54	0.90 picogram per milligram Standard Deviation 0.86 • Interval 0.16 to 4.36

SECONDARY outcome

Timeframe: Day 180

Population: Data for this outcome measure was not collected as assessment of apoptosis was not performed due to limited amounts of tissue samples available.

To determine the effects of triplet therapy and enzalutamide alone on apoptosis in prostatectomy specimens. Apoptosis was a process of biochemical events that lead to characteristic cell changes and death.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 180

Assessment was performed to determine the effects of triplet therapy and enzalutamide alone on mitotic index. Mitotic index was defined as the ratio between the numbers of cells in a population undergoing mitosis to the number of cells in a population not undergoing mitosis in prostatectomy specimens.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=22 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Pharmacodynamic Effects: Assessment of Mitotic Index	0.9 ratio Standard Deviation 1.51	2.6 ratio Standard Deviation 2.81

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a prostatectomy sample evaluated by the local pathologist.

To determine the effects of triplet therapy and enzalutamide alone on androgen receptor signaling in prostatectomy specimens. Androgen receptor (AR) was a type of nuclear receptor that was activated by binding either of the androgenic hormones, testosterone, or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. Androgen receptor (AR) signaling represented the major therapeutic target for treating metastatic prostate cancer. Assessment of androgen receptor signaling was measured by intensity of androgen receptor IHC staining and were graded as 0 (absent), 1 (weak), 2 (moderate) and 3 (strong). Percentage of participants within each grade are reported below.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Pharmacodynamic Effects: Assessment of Androgen Receptor Signaling as Measured by Intensity of Androgen Receptor Immunohistochemical (IHC) Staining 0	0.0 percentage of participants	0.0 percentage of participants
Pharmacodynamic Effects: Assessment of Androgen Receptor Signaling as Measured by Intensity of Androgen Receptor Immunohistochemical (IHC) Staining 1	5.6 percentage of participants	0.0 percentage of participants
Pharmacodynamic Effects: Assessment of Androgen Receptor Signaling as Measured by Intensity of Androgen Receptor Immunohistochemical (IHC) Staining 2	27.8 percentage of participants	5.3 percentage of participants
Pharmacodynamic Effects: Assessment of Androgen Receptor Signaling as Measured by Intensity of Androgen Receptor Immunohistochemical (IHC) Staining 3	66.7 percentage of participants	94.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a baseline serum DHT result. Here, "N" signifies number of participants evaluable for this specified outcome measure.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Serum Dihydrotestosterone (DHT): Baseline	0.34 ng/mL Interval 0.08 to 0.58	0.29 ng/mL Interval 0.16 to 0.85

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with 180 days post baseline serum DHT result. Here, "N" signifies number of participants evaluable for this specified outcome measure.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Serum Dihydrotestosterone (DHT): Day 180	0.01 ng/mL Interval 0.01 to 0.04	0.51 ng/mL Interval 0.1 to 1.1

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a serum DHT result at baseline and 180 days post baseline. Here, "N" signifies number of participants evaluable for this specified outcome measure.

To determine serum hormone effects as measured by change in DHT values from baseline to the completion of therapy.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Change From Baseline in Serum Dihydrotestosterone (DHT) at Day 180	-0.33 ng/mL Interval -0.57 to -0.07	0.25 ng/mL Interval -0.16 to 0.71

SECONDARY outcome

Timeframe: Baseline

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a baseline serum testosterone result. Here, "N" signifies number of participants evaluable for this specified outcome measure.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Serum Testosterone: Baseline	4.10 ng/mL Interval 0.77 to 6.77	3.69 ng/mL Interval 2.0 to 7.91

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a 180 days post baseline serum testosterone result. Here, "N" signifies number of participants evaluable for this specified outcome measure.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Serum Testosterone: Day 180	0.12 ng/mL Interval 0.05 to 0.29	9.76 ng/mL Interval 1.99 to 16.63

SECONDARY outcome

Timeframe: Day 180

Population: All participants randomly assigned to study treatment (intent-to-treat population) with a serum testosterone result at baseline and 180 days post baseline. Here, "N" signifies number of participants evaluable for this specified outcome measure.

To determine serum hormone effects as measured by change in testosterone at baseline and at completion of therapy.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=23 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Change From Baseline in Serum Testosterone at Day 180	-4.00 ng/mL Interval -6.67 to -0.67	5.74 ng/mL Interval -1.94 to 12.29

SECONDARY outcome

Timeframe: From baseline up to 210 days

Population: All participants who received at least 1 partial dose of enzalutamide (safety population).

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

Outcome measures

Outcome measures
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 Participants Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 Participants Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Number of Participants With Adverse Events (AEs) That Led to Dose Interruption, Dose Reduction, and Study Drug Discontinuation Permanent Discontinuation of Enzalutamide	0 participants	0 participants
Number of Participants With Adverse Events (AEs) That Led to Dose Interruption, Dose Reduction, and Study Drug Discontinuation Temporary Interruption of Enzalutamide	3 participants	0 participants
Number of Participants With Adverse Events (AEs) That Led to Dose Interruption, Dose Reduction, and Study Drug Discontinuation Dose Reduction of Enzalutamide	0 participants	0 participants
Number of Participants With Adverse Events (AEs) That Led to Dose Interruption, Dose Reduction, and Study Drug Discontinuation Study Drug Discontinuation	0 participants	0 participants

Adverse Events

Enzalutamide + Leuprolide + Dutasteride

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Enzalutamide

Serious events: 2 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Enzalutamide + Leuprolide + Dutasteride n=25 participants at risk Participants were administered 160 mg of Enzalutamide orally once daily, 22.5 mg of Leuprolide every 3 months through intramuscular injection and 0.5 mg of Dutasteride orally once daily for up to 180 days.	Enzalutamide n=27 participants at risk Participants were administered 160 mg of Enzalutamide orally once daily for up to 180 days.
Injury, poisoning and procedural complications Postoperative ileus	4.0% 1/25 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.	0.00% 0/27 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.
Infections and infestations Pelvic abscess	0.00% 0/25 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.	3.7% 1/27 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.
Infections and infestations Clostridial infection	4.0% 1/25 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.	0.00% 0/27 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.
Vascular disorders Lymphocele	4.0% 1/25 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.	3.7% 1/27 • From baseline to 30 days after the last dose of study drug, up to 210 days. Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 participant and as non-serious in another or 1 participant may have experienced both serious and non-serious event during study. Safety data set included all participants who received at least one partial dose of study drug.

Other adverse events

Additional Information

William Novotny, MD, Sr. Director, Clinical Development

Medivation, Inc.

Phone: 415- 983-3066

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI agrees not to independently publish the results before the publication of the multi-center PI paper. Sponsor shall review and comment 30 days prior to submission or disclosure. If publication or disclosure contains Sponsor Confidential Information, other than study data, PI agrees to remove Confidential Information from publication or disclosure. Sponsor may request that PI delay such publication for an additional 60 days to protect the patentability of any invention described.
Publication restrictions are in place

Restriction type: OTHER