Study of Enzalutamide in Patients With Castration-resistant Prostate Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01942837
• Collaborator: Medivation, Inc. (Industry)
• Enrollment: 67
• Locations: 5
• Arm: 1
• Anticipated Duration (Months): 105.6
• Patients Per Site: 13.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This research study is evaluating a drug called enzalutamide in metastatic castration resistant prostate cancer. Enzalutamide is already FDA approved for metastatic castration resistant prostate cancer after treatment with chemotherapy.

The purpose of this study is to analyze features of tumor specimens sampled prior to therapy and at disease progression to determine why patients respond or stop responding to treatment with Enzalutamide.

Prior chemotherapy is not a requirement of this trial.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Castration-resistant Prostate Cancer	Drug: Enzalutamide	Phase 2

Detailed Description

After the screening procedures confirm that the patient is able to participate in the study,

• The patient will have the first of two required prostate biopsies prior to starting study treatment.

• The patient will be given a prescription for study drug and a study drug-dosing diary for each treatment cycle. Each treatment cycle lasts 28 days (4 weeks), during which time the patient will be taking the study drug once daily. The diary will also include special instructions for taking the study drug. The study drug (enzalutamide) should be taken orally (by mouth) at home.

On Day 1 of each cycle (+/- 4 days), the following procedures will be performed in clinic:

• A medical history.

• A Physical examination

• Performance status

• Blood tests (2-3 tablespoons).

• The patient will be asked about medications they are currently taking, including over-the counter medications, herbal remedies, vitamins, and supplements.

• The patient will be asked about any disease-related symptoms they are experiencing.

• The patient will receive a new supply and the medication diary will be reviewed.

Every 12 weeks (+/-1 week) the following procedures will be performed in clinic:

• Blood tests. A small sample of the patient's blood (about 1-2 tablespoons) will be collected. This blood will be collected for specialized laboratory tests.

• A (CT) scan of the patient's chest and a CT or MRI scan of abdomen, and pelvis and a bone scan will be performed every 12 weeks (+/- 1 week) while the patient is on active treatment. If your baseline CT of the patient's chest does not show disease, the investigator may not asked for this to be repeated.

End of Study Visit in clinic:

• A medical history.

• A physical examination

• Performance status

• Blood tests (2-3 tablespoons)

• The patient will be asked about any disease-related symptoms If the patient completed at least 4 cycles of enzalutamide, the patient will undergo a second of two required biopsies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Enzalutamide for Castrate-resistant Prostate Cancer (CRPC) With Correlative Assessment of Androgen Receptor (AR) Signaling and Whole-exome and Transcriptome Sequencing
• Actual Study Start Date: Sep 13, 2013
• Actual Primary Completion Date: Dec 1, 2021
• Anticipated Study Completion Date: Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide Administration: 160 mg orally once daily with a 28-day cycle. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.	Drug: Enzalutamide; Enzalutamide, formerly known as MDV3100, is a rationally-designed second generation AR inhibitor which functions by blocking several steps in the AR signaling cascade. Enzalutamide competitively binds the AR with great potency. Additionally, enzalutamide inhibits nuclear translocation of activated AR and inhibits the association of activated AR with DNA.; Other Names: Xtandi

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Gene Alterations [Tumor biopsies were performed at pre-study and progression. Progression occurred up to 41 months after initiation of enzalutamide.]

   Serial biopsies was performed at pre-study and progression to analyze mechanisms of resistance to enzalutamide, such as alterations in AR (mutations, amplifications), tumor suppression genes, DNA repair genes, and SPOP. Whole exome sequencing was performed on tumor tissue biopsies.

Secondary Outcome Measures

1. Changes in Serum Androgen Concentrations Between Baseline and Subsequent Assessment Visits [Not collected.]

   Serum testosterone were be collected at pre-study (C1D1) and every cycle and changes over time from baseline were planned to be summarized descriptively.

2. Number of Participants With a PSA Response [PSA was measured at pre-treatment, each C1D1 (1 cycle=28 days), end of treatment, and follow-up visits (every 6 months). PSA were measured up to 52 months.]

   PSA response is defined per PCWG2 criteria (PSA decline >=50% relative to cycle 1 PSA) and is summarized as frequency and percent.

3. Duration of PSA Response [PSA was measured at pre-treatment, each C1D1 (1 cycle=28 days), end of treatment, and follow-up visits (every 6 months). PSA were measured up to 52 months.]

   Duration of PSA response is defined as time from the first achievement of PSA response (PSA decline >=50% from cycle 1) to the date of PSA progression or death, whichever occurs first.

4. Response of Measurable Disease at Baseline [Imaging was performed at pre-study and every 12 weeks on treatment. Treatment cycles is 28 days. Patients were assessed up to 41 months.]

   Objective responses for measurable disease was evaluated using RECIST 1.1 criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Response was tabulated with frequency.

5. Duration of Response of Measurable Disease [Imaging was performed at pre-study and every 12 weeks on treatment. Treatment cycles is 28 days. Patients were assessed up to 41 months.]

   Duration of response of measurable disease is defined as time from the date of first objective response (PR/CR) to date of progression or death, whichever comes first. Objective response is per RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

6. Toxicity Measurements [Toxicity was reported at pre-study, every cycle, and end of treatment visit. Patients reported toxicities up to 39 months.]

   For safety and tolerability, treatment-related grade 3 or higher toxicities was assessed using CTCAE v. 4.0 and was provided using frequency.

7. Number of Participants With PSA Response Stratified by Gene Alterations in Serial Tumor Biopsies [Tumor biopsies will be performed at pre-treatment and end of treatment visit. Treatment cycle is 28 days. PSA was collected up to 52 months.]

   Serial biopsies was performed at pre-study and progression to analyze mechanisms of resistance to enzalutamide, such as alterations in AR (mutations, amplifications), DNA repair genes, and SPOP. Whole exome sequencing was performed on tumor tissue biopsies. Gene alterations were tabulated with PSA response.

8. Subsequent Lines of Therapy [Subsequent treatments were followed up to 31 months after discontinuation of study drug.]

   Subsequent lines of therapy following study drug discontinuation was summarized descriptively.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants must meet the following criteria on screening examination to be eligible to participate in the study:

• Be a male ≥ 18 years of age.

• Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate without ≥50% neuroendocrine differentiation or small cell histology.

• Participants must have progressive disease as defined by either:

• Castrate resistant disease as defined by PCWG. Participants must have a rise in PSA on two successive determinations at least one week apart and PSA levels ≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml) and testosterone levels < 50 ng/dL, OR

• Soft tissue progression defined by RECIST 1.1, OR

• Bone disease progression defined by PCWG2 with two or more new lesions on bone scan.

• CRPC with metastatic disease with at least one site of metastatic disease must be amenable to needle biopsy. Soft tissue biopsy sites include: lymph node or visceral metastases. Bone sites include lumbar vertebrae, pelvic bones and long bones. Excluded sites are thoracic, cervical vertebrae, skull and rib lesions. Biopsy site will be selected with guidance of interventional radiologist determining best site to optimize balance of obtaining useful tissue for analysis and minimizing risk.

• Participants without orchiectomy must be maintained on LHRH agonist/antagonist therapy.

• Participants may have had any number of previous hormonal therapies (antiandrogens, steroids, estrogens, finasteride, dutasteride, ketoconazole, abiraterone) provided these were discontinued ≥ 4 weeks before enrollment.

• Participants may have had up to two previous cytotoxic therapeutic regimens provided these were discontinued ≥ 4 weeks before enrollment.

• At least a 4 week interval from previous prostate cancer treatment other than LHRH agonist/antagonist therapy or bisphosphonates to enrollment.

• Participants receiving bisphosphonates therapy can be maintained on this therapy. If participants have not started bisphosphonates, it is recommended that they start treatment after the first biopsy.

• ECOG performance status < 2 (Karnofsky >60%, see Appendix A).

• Participants must have normal organ and marrow function as defined below:

• WBC ≥ 3,000/mcL

• ANC ≥ 1,500/mcL

• Platelets ≥ 100,000/mcL

• Hemoglobin ≥ 9 g/dL

• Serum albumin ≥ 3.0 g/dL

• AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN

• Creatinine ≤ 1.5 Institutional ULN or a calculated creatinine clearance ≥ 50 mL/min using the Cockcroft Gault equation

• PTT ≤ 60, INR ≤ 1.5 Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy)

• Have signed an informed consent document indicating that the subjects understands the purpose of and procedures required for the study and are willing to participate in the study.

• Be willing/able to adhere to the prohibitions and restrictions specified in this protocol.

• Written Authorization for Use and Release of Health and Research Study Information (US sites only) has been obtained.

• Able to swallow the study drug whole as a tablet.

• Participants who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator during the treatment period and for 1 week after last dose of enzalutamide.

Exclusion Criteria:

• Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

• Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements within 6 months of enrollment.

Clinically significant heart disease as evidenced by:

• Myocardial infarction within 6 months of enrollment.

• Uncontrolled angina within 6 months of enrollment.

• Congestive heart failure NYHA Class III or IV, or a history of congestive heart failure NYHA Class III or IV in the past, unless a screening ECHO or MUGA within 3 months results in a left ventricular ejection fraction ≥ 45%.

• Clinically significant ventricular arrhythmias.

• History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.

• Bradycardia as indicated by a heart rate < 50 beats per minute at screening visit.

• Hypotension as indicated by SBP ≤ 85 on 2 consecutive measurements.

• Uncontrolled hypertension as indicated by SBP > 170 mmHg or DBP > 105 mmHg on 2 consecutive measurements at screening visit.

• Thromboembolism within 6 months of enrollment.

• History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug.

• History of seizure or any condition or concurrent medication that may predispose to seizure.

• Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin.

• Known brain metastasis. Participants with brain metastasis can only be included if they were treated > 4 week prior to enrollment with radiation and the effects of treatment have resolved. Subjects with treated brain metastases must have a post-treatment brain MRI showing no further progression of prior lesions and no new metastatic lesions. Subjects will be ineligible if they have any ongoing symptoms from brain metastases or if there continues to be radiographic evidence of cerebral edema.

• Have known allergies, hypersensitivity, or intolerance to enzalutamide or their excipients.

• Surgery or local prostatic intervention within 30 days of the first dose. In addition, any clinically relevant issues from the surgery must have resolved prior to enrollment.

• Major surgery or radiation therapy within 4 weeks of enrollment. Radium-223, strontium-89, or samarium-153 therapy within 4 weeks of enrollment. Radiotherapy, chemotherapy or immunotherapy within 4 weeks, or single fraction of palliative radiotherapy within 14 days of administration of enrollment.

• Prior treatment with enzalutamide.

• Current enrollment in an investigational drug or device study or participation in such a study within 30 days of enrollment.

• Concomitant use of medications that may alter pharmacokinetics of enzalutamide. See section 5.3.

• Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to a NCI CTCAE (version 4) grade of ≤ 1. Chemotherapy induced alopecia and grade 2 peripheral neuropathy are allowed.

• Condition or situation which, in the investigator's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with participant's participation in the study.

• Individuals not willing to comply with the procedural requirements of this protocol.

• HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with enzalutamide. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
4	South Shore Hospital	Weymouth	Massachusetts	United States	02190
5	University of Washington Medical Center/Seattle Cancer Care Alliance	Seattle	Washington	United States	98195

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Medivation, Inc.

Investigators

• Principal Investigator: Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 4, 2019

More Information

Publications

None provided.

• Responsible Party: Mary-Ellen Taplin, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01942837
• Other Study ID Numbers: 13-301
• First Posted: Sep 16, 2013
• Last Update Posted: Jul 21, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Mary-Ellen Taplin, MD, Principal Investigator, Dana-Farber Cancer Institute: Enzalutamide; Metastatic Castration-resistant Prostate Cancer
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally with 28-days cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C).
Period Title: Overall Study
STARTED	67
COMPLETED	0
NOT COMPLETED	67

Baseline Characteristics

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Overall Participants	65
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	70
Sex/Gender, Customized (Count of Participants)
Male	65 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 6.2%
White	51 78.5%
More than one race	1 1.5%
Unknown or Not Reported	8 12.3%
Institution (Count of Participants)
Dana-Farber Cancer Institute	39 60%
University of Washington	19 29.2%
Beth Israel Deaconess Medical Center	6 9.2%
South Shore Hospital	1 1.5%
Prior chemotherapy (Count of Participants)
Yes	16 24.6%
No	49 75.4%
Prior docetaxel (Count of Participants)
Yes	15 23.1%
No	50 76.9%
Prior abiraterone (Count of Participants)
Yes	22 33.8%
No	43 66.2%
Prior ketoconazole (Count of Participants)
Yes	9 13.8%
No	56 86.2%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Gene Alterations
Description	Serial biopsies was performed at pre-study and progression to analyze mechanisms of resistance to enzalutamide, such as alterations in AR (mutations, amplifications), tumor suppression genes, DNA repair genes, and SPOP. Whole exome sequencing was performed on tumor tissue biopsies.
Time Frame	Tumor biopsies were performed at pre-study and progression. Progression occurred up to 41 months after initiation of enzalutamide.

Outcome Measure Data

Analysis Population Description

Patients who had paired biopsies of pre-study and progression.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	10
AR amplifications at pre-study	7 10.8%
AR mutations at pre-study	4 6.2%
TP53 alteration at pre-study	7 10.8%
RB1 alteration at pre-study	7 10.8%
PTEN alteration at pre-study	6 9.2%
BRCA2 alteration at pre-study	4 6.2%
CDK12 alteration at pre-study	1 1.5%
ATM alteration at pre-study	1 1.5%
SPOP alteration at pre-study	4 6.2%

2. Secondary Outcome

Title	Changes in Serum Androgen Concentrations Between Baseline and Subsequent Assessment Visits
Description	Serum testosterone were be collected at pre-study (C1D1) and every cycle and changes over time from baseline were planned to be summarized descriptively.
Time Frame	Not collected.

Outcome Measure Data

Analysis Population Description

Serum data on the trial was collected but hormone assays were not run due to insufficient funding.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	0

3. Secondary Outcome

Title	Number of Participants With a PSA Response
Description	PSA response is defined per PCWG2 criteria (PSA decline >=50% relative to cycle 1 PSA) and is summarized as frequency and percent.
Time Frame	PSA was measured at pre-treatment, each C1D1 (1 cycle=28 days), end of treatment, and follow-up visits (every 6 months). PSA were measured up to 52 months.

Outcome Measure Data

Analysis Population Description

Patients who received ≥1 dose of enzalutamide

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	65
≥50% PSA reduction	38 58.5%
≥90% PSA reduction	20 30.8%

4. Secondary Outcome

Title	Duration of PSA Response
Description	Duration of PSA response is defined as time from the first achievement of PSA response (PSA decline >=50% from cycle 1) to the date of PSA progression or death, whichever occurs first.
Time Frame	PSA was measured at pre-treatment, each C1D1 (1 cycle=28 days), end of treatment, and follow-up visits (every 6 months). PSA were measured up to 52 months.

Outcome Measure Data

Analysis Population Description

Patients who experienced PSA response defined as more than equal to 50% decline from baseline.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	38
Median (Inter-Quartile Range) [months]	3.2

5. Secondary Outcome

Title	Response of Measurable Disease at Baseline
Description	Objective responses for measurable disease was evaluated using RECIST 1.1 criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Response was tabulated with frequency.
Time Frame	Imaging was performed at pre-study and every 12 weeks on treatment. Treatment cycles is 28 days. Patients were assessed up to 41 months.

Outcome Measure Data

Analysis Population Description

Patients with measurable disease at baseline.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	32
Complete response	0 0%
Partial response	11 16.9%
Stable disease	11 16.9%
Progressive disease	7 10.8%
Inevaluable/missing	3 4.6%

6. Secondary Outcome

Title	Duration of Response of Measurable Disease
Description	Duration of response of measurable disease is defined as time from the date of first objective response (PR/CR) to date of progression or death, whichever comes first. Objective response is per RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Imaging was performed at pre-study and every 12 weeks on treatment. Treatment cycles is 28 days. Patients were assessed up to 41 months.

Outcome Measure Data

Analysis Population Description

Patients with CR or PR to enzalutamide. There was no CR achieved and 11 PRs.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	11
Median (Inter-Quartile Range) [months]	2.8

7. Secondary Outcome

Title	Toxicity Measurements
Description	For safety and tolerability, treatment-related grade 3 or higher toxicities was assessed using CTCAE v. 4.0 and was provided using frequency.
Time Frame	Toxicity was reported at pre-study, every cycle, and end of treatment visit. Patients reported toxicities up to 39 months.

Outcome Measure Data

Analysis Population Description

Patients who received at least one dose of enzalutamide.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally with 28-days cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	65
Grade 3 hypertension	4 6.2%
Grade 3 colitis	1 1.5%
Grade 3 fatigue	1 1.5%

8. Secondary Outcome

Title	Number of Participants With PSA Response Stratified by Gene Alterations in Serial Tumor Biopsies
Description	Serial biopsies was performed at pre-study and progression to analyze mechanisms of resistance to enzalutamide, such as alterations in AR (mutations, amplifications), DNA repair genes, and SPOP. Whole exome sequencing was performed on tumor tissue biopsies. Gene alterations were tabulated with PSA response.
Time Frame	Tumor biopsies will be performed at pre-treatment and end of treatment visit. Treatment cycle is 28 days. PSA was collected up to 52 months.

Outcome Measure Data

Analysis Population Description

Patients who had paired biopsies of pre-study and progression.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	10
PSA response among patients in Patients with AR amplification	3 4.6%
PSA response among patients with AR mutation	1 1.5%
PSA response among patients with SPOP alteration	2 3.1%

9. Secondary Outcome

Title	Subsequent Lines of Therapy
Description	Subsequent lines of therapy following study drug discontinuation was summarized descriptively.
Time Frame	Subsequent treatments were followed up to 31 months after discontinuation of study drug.

Outcome Measure Data

Analysis Population Description

Patients who received at least one dose of enzalutamide.

Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally. All participants without orchiectomy will be maintained on LHRH agonist/antagonist therapy. Participants will be evaluated clinically and with laboratory studies on day 1 of every 28 day cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C). Enzalutamide: Administration: 160 mg orally once daily. Treatment will be continued until evidence of symptomatic or radiographic progression or the participant is taken off the study for another reason. Dosing: 160 mg orally taken once daily as four 40 mg capsules.
Measure Participants	65
Median (Inter-Quartile Range) [Lines of treatment]	2

Adverse Events

Time Frame	Toxicities were assessed every cycle and up to 30 days after coming off from the treatment. Toxicities were collected up to ~ 44 months.
Adverse Event Reporting Description	A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that: Results in death Is life-threatening. Life-threatening means that the person was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form. Requires or prolongs inpatient hospitalization Results in persistent or significant disability/incapacity
Arm/Group Title	Enzalutamide
Arm/Group Description	Participants will be treated with four 40 mg capsules (160 mg) once daily of enzalutamide taken orally with 28-days cycle. Participants will maintain a drug diary from time of initiation of study treatment to time of discontinuation from the study (Appendix C).
All Cause Mortality
	Enzalutamide
	Affected / at Risk (%)	# Events
Total	41/65 (63.1%)
Serious Adverse Events
	Enzalutamide
	Affected / at Risk (%)	# Events
Total	8/65 (12.3%)
Cardiac disorders
Cardiac arrest	1/65 (1.5%)
Myocardial infarction	1/65 (1.5%)
Gastrointestinal disorders
Colitis	1/65 (1.5%)
Diarrhea	1/65 (1.5%)
Nausea	1/65 (1.5%)
Vomiting	1/65 (1.5%)
Gastrointestinal disorders - Other, specify	2/65 (3.1%)
Infections and infestations
Lung infection	1/65 (1.5%)
Sepsis	1/65 (1.5%)
Urinary tract infection	1/65 (1.5%)
Infections and infestations - Other, specify	1/65 (1.5%)
Investigations
Alkaline phosphatase increased	1/65 (1.5%)
Aspartate aminotransferase increased	1/65 (1.5%)
Blood bilirubin increased	1/65 (1.5%)
Metabolism and nutrition disorders
Hypomagnesemia	1/65 (1.5%)
Hyponatremia	1/65 (1.5%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/65 (1.5%)
Nervous system disorders
Dizziness	1/65 (1.5%)
Presyncope	1/65 (1.5%)
Stroke	1/65 (1.5%)
Other (Not Including Serious) Adverse Events
	Enzalutamide
	Affected / at Risk (%)	# Events
Total	65/65 (100%)
Blood and lymphatic system disorders
Anemia	11/65 (16.9%)
Hemolytic uremic syndrome	1/65 (1.5%)
Leukocytosis	2/65 (3.1%)
Thrombotic thrombocytopenic purpura	1/65 (1.5%)
Cardiac disorders
Atrial fibrillation	1/65 (1.5%)
Atrioventricular block first degree	1/65 (1.5%)
Chest pain - cardiac	1/65 (1.5%)
Sinus tachycardia	2/65 (3.1%)
Cardiac disorders - Other, specify	1/65 (1.5%)
Ear and labyrinth disorders
Hearing impaired	2/65 (3.1%)
Tinnitus	3/65 (4.6%)
Vertigo	4/65 (6.2%)
Ear and labyrinth disorders - Other, specify	1/65 (1.5%)
Eye disorders
Blurred vision	1/65 (1.5%)
Eye pain	1/65 (1.5%)
Floaters	1/65 (1.5%)
Retinal vascular disorder	1/65 (1.5%)
Watering eyes	2/65 (3.1%)
Eye disorders - Other, specify	5/65 (7.7%)
Gastrointestinal disorders
Abdominal pain	3/65 (4.6%)
Bloating	1/65 (1.5%)
Constipation	9/65 (13.8%)
Diarrhea	12/65 (18.5%)
Dry mouth	1/65 (1.5%)
Dyspepsia	1/65 (1.5%)
Dysphagia	1/65 (1.5%)
Esophageal obstruction	1/65 (1.5%)
Gastritis	1/65 (1.5%)
Gastrointestinal pain	1/65 (1.5%)
Lip pain	1/65 (1.5%)
Nausea	10/65 (15.4%)
Oral pain	1/65 (1.5%)
Stomach pain	2/65 (3.1%)
Vomiting	4/65 (6.2%)
Gastrointestinal disorders - Other, specify	3/65 (4.6%)
General disorders
Chills	1/65 (1.5%)
Edema limbs	7/65 (10.8%)
Fatigue	34/65 (52.3%)
Fever	3/65 (4.6%)
Gait disturbance	1/65 (1.5%)
Irritability	1/65 (1.5%)
Non-cardiac chest pain	4/65 (6.2%)
Pain	23/65 (35.4%)
General disorders and administration site conditions - Other, specify	2/65 (3.1%)
Infections and infestations
Bronchial infection	3/65 (4.6%)
Eye infection	1/65 (1.5%)
Lung infection	1/65 (1.5%)
Papulopustular rash	1/65 (1.5%)
Paronychia	1/65 (1.5%)
Skin infection	1/65 (1.5%)
Upper respiratory infection	9/65 (13.8%)
Urinary tract infection	3/65 (4.6%)
Infections and infestations - Other, specify	1/65 (1.5%)
Injury, poisoning and procedural complications
Burn	1/65 (1.5%)
Fall	6/65 (9.2%)
Fracture	1/65 (1.5%)
Investigations
Alanine aminotransferase increased	2/65 (3.1%)
Alkaline phosphatase increased	3/65 (4.6%)
Aspartate aminotransferase increased	2/65 (3.1%)
Blood bilirubin increased	2/65 (3.1%)
Cholesterol high	1/65 (1.5%)
Creatinine increased	4/65 (6.2%)
Lymphocyte count decreased	1/65 (1.5%)
Lymphocyte count increased	1/65 (1.5%)
Neutrophil count decreased	1/65 (1.5%)
Platelet count decreased	4/65 (6.2%)
Weight loss	2/65 (3.1%)
White blood cell decreased	2/65 (3.1%)
Metabolism and nutrition disorders
Anorexia	9/65 (13.8%)
Dehydration	3/65 (4.6%)
Hypercalcemia	4/65 (6.2%)
Hyperglycemia	7/65 (10.8%)
Hyperkalemia	1/65 (1.5%)
Hypocalcemia	2/65 (3.1%)
Hypokalemia	10/65 (15.4%)
Hypomagnesemia	3/65 (4.6%)
Hyponatremia	2/65 (3.1%)
Metabolism and nutrition disorders - Other, specify	1/65 (1.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/65 (6.2%)
Back pain	20/65 (30.8%)
Bone pain	5/65 (7.7%)
Buttock pain	1/65 (1.5%)
Chest wall pain	1/65 (1.5%)
Flank pain	4/65 (6.2%)
Generalized muscle weakness	4/65 (6.2%)
Joint range of motion decreased	1/65 (1.5%)
Muscle weakness left-sided	1/65 (1.5%)
Muscle weakness lower limb	1/65 (1.5%)
Myalgia	2/65 (3.1%)
Neck pain	1/65 (1.5%)
Pain in extremity	5/65 (7.7%)
Musculoskeletal and connective tissue disorder - Other, specify	4/65 (6.2%)
Nervous system disorders
Concentration impairment	1/65 (1.5%)
Dizziness	11/65 (16.9%)
Dysesthesia	1/65 (1.5%)
Dysgeusia	4/65 (6.2%)
Encephalopathy	1/65 (1.5%)
Facial muscle weakness	1/65 (1.5%)
Headache	5/65 (7.7%)
Lethargy	1/65 (1.5%)
Memory impairment	4/65 (6.2%)
Paresthesia	2/65 (3.1%)
Peripheral sensory neuropathy	3/65 (4.6%)
Syncope	1/65 (1.5%)
Nervous system disorders - Other, specify	4/65 (6.2%)
Psychiatric disorders
Anxiety	1/65 (1.5%)
Depression	4/65 (6.2%)
Insomnia	6/65 (9.2%)
Libido decreased	1/65 (1.5%)
Restlessness	1/65 (1.5%)
Psychiatric disorders - Other, specify	1/65 (1.5%)
Renal and urinary disorders
Acute kidney injury	2/65 (3.1%)
Chronic kidney disease	1/65 (1.5%)
Hematuria	5/65 (7.7%)
Renal calculi	3/65 (4.6%)
Urinary frequency	8/65 (12.3%)
Urinary incontinence	3/65 (4.6%)
Urinary urgency	1/65 (1.5%)
Renal and urinary disorders - Other, specify	3/65 (4.6%)
Reproductive system and breast disorders
Breast pain	4/65 (6.2%)
Erectile dysfunction	2/65 (3.1%)
Genital edema	1/65 (1.5%)
Gynecomastia	5/65 (7.7%)
Pelvic pain	4/65 (6.2%)
Reproductive system and breast disorders - Other, specify	2/65 (3.1%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/65 (4.6%)
Cough	7/65 (10.8%)
Dyspnea	5/65 (7.7%)
Epistaxis	3/65 (4.6%)
Hypoxia	1/65 (1.5%)
Nasal congestion	1/65 (1.5%)
Postnasal drip	1/65 (1.5%)
Sneezing	1/65 (1.5%)
Tracheal fistula	1/65 (1.5%)
Voice alteration	1/65 (1.5%)
Respiratory, thoracic and mediastinal disorders - Other, specify	4/65 (6.2%)
Skin and subcutaneous tissue disorders
Alopecia	1/65 (1.5%)
Dry skin	1/65 (1.5%)
Rash acneiform	1/65 (1.5%)
Rash maculo-papular	4/65 (6.2%)
Skin and subcutaneous tissue disorders - Other, specify	4/65 (6.2%)
Vascular disorders
Flushing	2/65 (3.1%)
Hematoma	1/65 (1.5%)
Hot flashes	20/65 (30.8%)
Hypertension	18/65 (27.7%)
Hypotension	3/65 (4.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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