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

Study Overview
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Brief Summary
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The purpose of this study is to determine if enzalutamide is an effective therapy in treating localized prostate cancer prior to prostatectomy.

Official Title
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A Randomized, Open-label, Phase 2 Study Of Mdv3100 As A Neoadjuvant Therapy For Patients Undergoing Prostatectomy For Localized Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Leuprolide
* Drug: Dutasteride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to provide informed consent 18 years of age or older Histologically confirmed adenocarcinoma of the prostate Must be a candidate for radical prostatectomy and considered surgically resectable Exclusion Criteria: Stage T4 prostate cancer by clinical or radiologic evaluation Treatment with an investigational agent within 4 weeks prior to randomization Received therapy for other neoplastic disorders within 5 years Hypogonadism or severe androgen deficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide alone<br>Enzalutamide 160 mg, orally, once daily | Drug: Enzalutamide<br> <br> * Other names: MDV3100;|
| Experimental: Enzalutamide & Leuprolide & Dutasteride<br>Enzalutamide 160 mg, orally, once daily and leuprolide 22.5 mg, intramuscular injection, every 3 months, and dutasteride, 0.5 mg, orally, once daily | Drug: Enzalutamide<br> <br> * Other names: MDV3100;Drug: Leuprolide<br> <br> Drug: Dutasteride<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate | 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. | Day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Positive Surgical Margins | 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. | Day 180 | 
| Percentage of Participants With Extracapsular Extension: Local Review | 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. | Day 180 | 
| Percentage of Participants With Extracapsular Extension: Central Review | 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. | Day 180 | 
| Percentage of Participants With Positive Seminal Vesicles | 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. | Day 180 | 
| Percentage of Participants With Positive Lymph Nodes | 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. | Day 180 | 
| Prostate-Specific Antigen (PSA) Nadir | 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. | Day 195 | 
| Time to Prostate-Specific Antigen (PSA) Nadir | 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. | Day 195 | 
| Percentage of Participants With Reduction in Prostate-Specific Antigen (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. | Day 195 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With The Expanded Prostate Cancer Index Composite (EPIC) Sexual Domain Summary Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Function Subscale Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Sexual Bother Subscale Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Domain Summary Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Function Subscale Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Expanded Prostate Cancer Index Composite (EPIC) Hormonal Bother Subscale Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 General Health Domain Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Physical Functioning Domain Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Role-Emotional Domain Score | 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. | Day 180 | 
| Health-Related Quality of Life (HRQoL): Number of Participants With Twelve-Item Short Form Version 2 Mental Component Summary | 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. | Day 180 | 
| Pharmacodynamic Effects: Tissue Dihydrotestosterone (DHT) | To determine pharmacodynamic effects as measured by the amount of tissue DHT in prostatectomy specimens following radical prostatectomy. | Day 180 | 
| Pharmacodynamic Effects: Tissue Testosterone | To determine pharmacodynamic effects as measured by the amount of tissue testosterone in prostatectomy specimens following radical prostatectomy. | Day 180 | 
| Pharmacodynamic Effects: Assessment of Apoptosis | 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. | Day 180 | 
| Pharmacodynamic Effects: Assessment of Mitotic Index | 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. | Day 180 | 
| Pharmacodynamic Effects: Assessment of Androgen Receptor Signaling as Measured by Intensity of Androgen Receptor Immunohistochemical (IHC) Staining | 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. | Day 180 | 
| Serum Dihydrotestosterone (DHT): Baseline |  | Baseline | 
| Serum Dihydrotestosterone (DHT): Day 180 |  | Day 180 | 
| Change From Baseline in Serum Dihydrotestosterone (DHT) at Day 180 | To determine serum hormone effects as measured by change in DHT values from baseline to the completion of therapy. | Day 180 | 
| Serum Testosterone: Baseline |  | Baseline | 
| Serum Testosterone: Day 180 |  | Day 180 | 
| Change From Baseline in Serum Testosterone at Day 180 | To determine serum hormone effects as measured by change in testosterone at baseline and at completion of therapy. | Day 180 | 
| Number of Participants With Adverse Events (AEs) That Led to Dose Interruption, Dose Reduction, and Study Drug Discontinuation | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | From baseline up to 210 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, prostatectomy, neoadjuvant