A Study of Enzalutamide Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer

The purpose of this study was to determine the efficacy and safety of oral enzalutamide compared to bicalutamide in castrate men with metastatic prostate cancer who have progressed while on Luteinizing Hormone Receptor Hormone (LHRH) agonist/antagonist or after receiving a bilateral orchiectomy.

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms
• Intervention / Treatment: Drug: enzalutamide; Drug: bicalutamide

Detailed Description

An open-label period was added to the main protocol. Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over bicalutamide as assessed by the primary endpoint, all ongoing enzalutamide treated participants and ongoing or previous bicalutamide treated participants that met entry criteria were offered open-label enzalutamide at the discretion of the participant and study investigators.

• Study Type: Interventional
• Enrollment (Actual): 375
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1090
    • Site BE3015
  • Gent, Belgium, 9000
    • Site BE1322
  • Kortrijk, Belgium, 8500
    • Site BE3018
  • Leuven, Belgium, 3000
    • Site BE3288
  • Liege, Belgium
    • Site BE3289
  • Turnhout, Belgium, 2300
    • Site BE3013
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2V 1P9
      • Site CA3104
  • British Columbia
    • Abbotsford, British Columbia, Canada, V2S 3N5
      • Site CA3242
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Site CA2646
    • Toronto, Ontario, Canada, M4N 3M5
      • Site CA166
    • Toronto, Ontario, Canada, M5G 2M9
      • Site CA3084
  • Quebec
    • Granby, Quebec, Canada, J2G 8Z9
      • Site CA2984
    • Montreal, Quebec, Canada, H3G 1A4
      • Site CA170
• Denmark
  • Aalborg, Denmark, 9000
    • Site DK3354
  • Aarhus, Denmark, 8200
    • Site DK3356
  • Copenhagen, Denmark, 2200
    • Site DK1857
  • Herlev, Denmark, 2730
    • Site DK1263
• France
  • Creteil, France, 94010
    • Site FR1091
  • Lille, France, 59037
    • Site FR3009
  • Lyon Cedex 3, France, 69437
    • Site FR442
  • Paris Cedex 10, France, 75020
    • Site FR3002
  • Poitiers Cedex, France, 86000
    • Site FR3003
  • Rennes Cedex, France, 35033
    • Site FR3000
  • Rouen, France, 76031
    • Site FR3007
  • Suresnes Cedex, France, 92151
    • Site FR3005
• Germany
  • Aachen, Germany, 51074
    • Site DE2989
  • Bergisch Gladbach, Germany, D-51465
    • Site DE3287
  • Bonn, Germany, 53105
    • Site DE2993
  • Bonn, Germany, 53111
    • Site DE2995
  • Bonn, Germany, 53117
    • Site DE2994
  • Hamburg, Germany, 22081
    • Site DE2990
  • Hannover, Germany, 30625
    • Site DE3270
  • Reutlingen, Germany, 72764
    • Site DE2992
  • Waldshut-Tiengen, Germany, 29761
    • Site DE3286
  • Wuppertal, Germany, 42103
    • Site DE2988
  • Baden-Wuerttemberg
    • Nuertingen, Baden-Wuerttemberg, Germany, 72622
      • Site DE4000
• Romania
  • Bucharest, Romania, 041345
    • Site RO3035
  • RO
    • Bucharest, RO, Romania, 022328
      • Site RO3042
    • Bucharest, RO, Romania, 050659
      • Site RO3039
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Site GB3244
  • Cambridge, United Kingdom, CB2 0QQ
    • Site GB2702
  • Glasgow, United Kingdom, G12 0YN
    • Site GB3166
  • Leicher, United Kingdom, LE5 4PW
    • Site GB1862
  • London, United Kingdom, NW1 2PG
    • Site GB3163
  • Manchester, United Kingdom, M20 4BX
    • Site GB2624
  • Merseyside, United Kingdom, CH63 4JY
    • Site GB3355
  • Northwood, Middlesex, United Kingdom, HA6 2RN
    • Site GB3245
  • Preston, United Kingdom, PR2 9HT
    • Site GB3290
  • UK
    • Bristol, UK, United Kingdom, BS2 8HW
      • Site GB3029
    • London, UK, United Kingdom, SE19RT
      • Site GB3027
    • London, UK, United Kingdom, SW17 0QT
      • Site GB3030
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • Site GB3028
• United States
  • Alabama
    • Homewood, Alabama, United States, 35209
      • Site US1934
  • Alaska
    • Anchorage, Alaska, United States, 99503
      • Site US1527
  • Arizona
    • Tucson, Arizona, United States, 85715
      • Site US3026
  • California
    • Highland, California, United States, 92346
      • Site US2977
    • San Diego, California, United States, 92123
      • Site US3630
  • Colorado
    • Denver, Colorado, United States, 80211
      • Site US2935
  • Connecticut
    • Middlebury, Connecticut, United States, 06762
      • Site US2945
  • Illinois
    • Melrose Park, Illinois, United States, 60160
      • Site US2014
    • Springfield, Illinois, United States, 62703
      • Site US2067
  • Indiana
    • Jeffersonville, Indiana, United States, 47130
      • Site US2027
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Site US1838
  • Kansas
    • Kansas City, Kansas, United States, 66160-7233
      • Site US62
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Site US2976
    • Bethesda, Maryland, United States, 20889-5600
      • Site US3182
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Site US2975
    • Grand Rapids, Michigan, United States, 49546
      • Site US892
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Site US20
  • Montana
    • Billings, Montana, United States, 59101
      • Site US3078
  • New Jersey
    • Lawrenceville, New Jersey, United States, 08648
      • Site US2968
  • New York
    • Poughkeepsie, New York, United States, 12601
      • Site US3025
    • Rochester, New York, United States, 14642
      • Site US1675
    • Staten Island, New York, United States, 10304
      • Site US2934
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Site US81
    • Greensboro, North Carolina, United States, 27403
      • Site US2104
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Site US44
    • Columbus, Ohio, United States, 43221
      • Site US2185
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • Site US1598
    • Lancaster, Pennsylvania, United States, 17604
      • Site US1680
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Site US2926
  • Tennessee
    • Nashville, Tennessee, United States, 37209
      • Site US1657
  • Texas
    • Houston, Texas, United States, 77030
      • Site US464
    • San Antonio, Texas, United States, 78229
      • Site US2978
  • Virginia
    • Virginia Beach, Virginia, United States, 23462
      • Site US1653
  • Washington
    • Burien, Washington, United States, 98166
      • Site US1580
    • Wenatchee, Washington, United States, 98801
      • Site US1709
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Site US51

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
• Ongoing androgen deprivation therapy with a Luteinizing Hormone Receptor Hormone (LHRH) agonist or antagonist at a stable dose and schedule within 4 weeks of randomization or bilateral orchiectomy (i.e., surgical or medical castration)

• Metastatic disease documented by one of the following:

  • At least two bone lesions on bone scan, or
  • Soft tissue disease documented by computed tomography (CT)/ magnetic resonance imaging (MRI), or
  • Unequivocal pelvic adenopathy short axis > 2.0 cm in diameter by CT/MRI

• Progressive disease at study entry defined as one or more of the following three criteria occurring in the setting of castrate levels of testosterone:

  • Prostate Specific Antigen (PSA) progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value should be ≥ 2 µg/L (2 ng/mL);
  • Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;
  • Bone disease progression defined by two or more new lesions on bone scan
• Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 must be < 4); no use of opiate analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior to randomization
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer
• Estimated life expectancy of ≥ 12 months
• Able to swallow the study drug and comply with study requirements

• A male subject and his female spouse/partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:

  1. Condom (barrier method of contraception), AND

  2. In addition to a condom, one of the following acceptable forms of contraception is required:

     • Established use of oral, injected or implanted hormonal methods of contraception.
     • Placement of an intrauterine device (IUD) or intrauterine system (IUS).
     • Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
     • Tubal ligation for at least 6 months prior to Screening
     • Vasectomy or other surgical castration at least 6 months prior to Screening

Exclusion Criteria:

• Prior cytotoxic chemotherapy for prostate cancer
• Severe concurrent disease, infection, or comorbidity that would make the subject inappropriate for enrollment
• Known or suspected brain and/or skull metastasis or active epidural disease
• History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer
• Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/day, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization
• Current or prior use of ketoconazole for the treatment of prostate cancer
• Use of antiandrogens within 6 weeks prior to randomization
• Documented prior disease progression while receiving antiandrogens. Disease progression defined as PSA progression, radiographic progression and/or clinical deterioration.
• Current or prior treatment with 5-α reductase inhibitors or anabolic steroids within 6 months prior to randomization
• Prior use of systemic glucocorticoids (the equivalent of 10 mg of prednisone) within 3 months prior to randomization or expectation of their use during the study
• Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to randomization
• Major surgery within 2 months prior to randomization
• History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with anti-epileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months prior to randomization
• Clinically significant cardiovascular disease including myocardial infarction within past six months or uncontrolled angina within past three months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enzalutamide; Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.	Drug: enzalutamide; capsules; Other Names: MDV3100
Active Comparator: Bicalutamide; Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.	Drug: bicalutamide; tablets; Other Names: Casodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Based on Independent Central Review (ICR) Assessment	PFS is the time from randomization to the date of the first progression event detected. A progression event was defined as objective evidence of radiographic disease progression based on the assessments by the ICR, skeletal-related event, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Radiographic disease progression was defined as either a progression in soft tissue on computed tomography (CT)/magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and/or a progression in bone lesions on bone scan (≥ 2 new bone lesions) confirmed by the next bone scan. A skeletal-related event was any radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change in antineoplastic therapy to treat bone pain. The initiation of new antineoplastic therapy included any new therapy for the treatment of disease progression after the study drug administration started.	From randomization until the data cut-off date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS Based on Investigator Assessment	PFS was calculated as the time from randomization to the date of the first progression event detected. A progression event was defined as objective evidence of radiographic disease progression based on the assessments by investigators, skeletal-related event, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Radiographic disease progression was defined as either a progression in soft tissue on CT/MRI scan according to RECIST 1.1, and/or a progression in bone lesions on bone scan (≥ 2 new bone lesions) confirmed by the next bone scan. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change in antineoplastic therapy to treat bone pain. The initiation of new antineoplastic therapy included any new therapy for the treatment of disease progression after the study drug administration started.	From randomization until the data cut-off date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Prostate-specific Antigen (PSA) Response by Week 13	The PSA response by Week 13 was defined as the percentage change from Baseline to the smallest PSA value after Baseline (i.e., a decrease of 100% represents the largest possible decrease to a value below the lower limit of quantification) and on or before day 99 (i.e., upper boundary of the Week 13 visit window). For participants with no decrease in PSA post-baseline by Week 13, the PSA response by Week 13 was the smallest increase in PSA up to day 99. For participants with no post-baseline PSA values up to day 99, the PSA response by Week 13 was set to missing. PSA was analyzed at a central laboratory.	Baseline to Week 13
Best PSA Response	The best PSA response was defined as the percentage change from Baseline to the smallest PSA value after Baseline including PSA results from samples taken after the study drug was stopped. For participants with no decrease in PSA post-baseline, the best PSA response was the smallest increase in PSA. For participants with no post-baseline PSA values, the PSA response was set to missing. PSA was analyzed at a central laboratory.	Baseline to the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Time to PSA Progression	Time to PSA progression was calculated as the time interval from the date of randomization to the date of first observation of PSA progression. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir (or above the baseline value for participants who did not have a decline in PSA post-baseline values), and confirmed by a second consecutive PSA assessment at least 3 weeks later. For participants with no documented PSA progression, the time to PSA progression was censored on the date the last PSA sample was taken.	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Time to PSA ≤ 4 ng/mL	Time to PSA ≤ 4 ng/mL was defined as the time interval from the date of randomization to the first date a decline in PSA to a result of 4 ng/mL or below was recorded. In participants without PSA results ≤ 4 ng/mL, the time to PSA ≤ 4 ng/mL was censored on the date of the last PSA sample taken. Participants with a PSA result ≤ 4 ng/mL at Baseline, participants with no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Time to ≥ 30% PSA Decline From Baseline	The time to ≥ 30% PSA decline from Baseline was defined as the time interval from the date of randomization to the first date a PSA decline from Baseline of at least 30% was recorded. In participants without ≥ 30% PSA decline from Baseline, the time to ≥ 30% PSA decline from Baseline was censored on the date of the last PSA sample taken. Participants who had no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization.	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Time to ≥ 50% PSA Decline From Baseline	The time to ≥ 50% PSA decline from Baseline was defined as the time interval from the date of randomization to the first date a PSA decline from Baseline of at least 50% was recorded. In participants without ≥ 50% PSA decline from Baseline, the time to ≥ 50% PSA decline from Baseline was censored on the date of the last PSA sample taken. Participants who had no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization.	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Time to ≥ 90% PSA Decline From Baseline	The time to ≥ 90% PSA decline from Baseline was defined as the time interval from the date of randomization to the first date a PSA decline from Baseline of at least 90% was recorded. In participants without ≥ 90% PSA decline from Baseline, the time to ≥ 90% PSA decline from Baseline was censored on the date of the last PSA sample taken. Participants who had no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization.	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Radiographic PFS Based on ICR Assessment	Radiographic PFS was calculated as the time interval from the date of randomization to the first date of radiographic disease progression. Radiographic disease progression was defined as either a progression in soft tissue on CT/MRI scan according to RECIST 1.1, and/or a progression in bone lesions (a minimum of 2 new bone lesions as compared to previous scan) on bone scan and confirmed by the next bone scan.	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Percentage of Participants With an Objective Response	Response assessments were reported by ICR for target lesions in soft tissues and non-target lesions in soft tissues based on CT and/or MRI according to RECIST version 1.1. Objective response was defined as the number of participants achieving either a complete response (CR) or a partial response (PR) based on participant's best overall response assessed at the end of the treatment.	From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
Percentage of Participants With Adverse Events	A serious adverse event was defined as any untoward medical occurrence that at any dose: Resulted in death; Was life threatening; Resulted in persistent or significant disability/incapacity; Resulted in congenital anomaly or birth defect; Required inpatient hospitalization or led to prolongation of hospitalization; Other medically important events. Treatment-related indicates adverse events assessed by the Investigator as probably or possibly related to study treatment. Treatment emergent adverse events (TEAEs) were defined as adverse events (AEs) that started or worsened after starting administration of study drug through end of the study (i.e., the treatment-emergent period).	From initiation of study drug up to 30 days after last dose of study drug or the 30-day safety follow-up visit, whichever was last (Median duration of treatment was 11.6 months in enzalutamide arm and 5.8 in bicalutamide arm, 12.6 in the total arm).

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Investigators: Principal Investigator: Principal Investigator, Carolina Urologic Research Center; Study Director: Associate Medical Science Director, Astellas Pharma Global Development

Publications and helpful links

General Publications

• Heidenreich A, Chowdhury S, Klotz L, Siemens DR, Villers A, Ivanescu C, Holmstrom S, Baron B, Wang F, Lin P, Shore ND. Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial. Eur Urol. 2017 Apr;71(4):534-542. doi: 10.1016/j.eururo.2016.07.027. Epub 2016 Aug 3.
• Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-163. doi: 10.1016/S1470-2045(15)00518-5. Epub 2016 Jan 14.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2011
• Primary Completion (Actual): October 19, 2014
• Study Completion (Actual): November 8, 2017

Study Registration Dates

• First Submitted: February 1, 2011
• First Submitted That Met QC Criteria: February 1, 2011
• First Posted (Estimate): February 3, 2011

Study Record Updates

• Last Update Posted (Actual): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 22, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Cancer; Metastatic; MDV3100; enzalutamide; Prostate; progressive
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Androgen Antagonists; Bicalutamide
• Other Study ID Numbers: 9785-CL-0222; 2010-021868-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No