Clinical trial NCT01288911: A Study of Enzalutamide Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer
Official title: A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostatic Neoplasms
Keywords: Metastatic
MDV3100
Prostate
progressive
Cancer
enzalutamide
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
First posted: 2011-02-03
Enrollment: 375
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival (PFS) Based on Independent Central Review (ICR) Assessment
timeFrame: 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 outcomes:
measure: PFS Based on Investigator Assessment
timeFrame: 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.
measure: Prostate-specific Antigen (PSA) Response by Week 13
timeFrame: Baseline to Week 13
measure: Best PSA Response
timeFrame: 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.
measure: Time to PSA Progression
timeFrame: 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.
measure: Time to PSA ≤ 4 ng/mL
timeFrame: 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.
measure: Time to ≥ 30% PSA Decline From Baseline
timeFrame: 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.
measure: Time to ≥ 50% PSA Decline From Baseline
timeFrame: 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.
measure: Time to ≥ 90% PSA Decline From Baseline
timeFrame: 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.
measure: Radiographic PFS Based on ICR Assessment
timeFrame: 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.
measure: Percentage of Participants With an Objective Response
timeFrame: 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.
measure: Percentage of Participants With Adverse Events
timeFrame: 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).
Other outcomes:
Locations:
city: Homewood
country: United States
facility: Site US1934
state: Alabama
city: Anchorage
country: United States
facility: Site US1527
state: Alaska
city: Tucson
country: United States
facility: Site US3026
state: Arizona
city: Highland
country: United States
facility: Site US2977
state: California
city: San Diego
country: United States
facility: Site US3630
state: California
city: Denver
country: United States
facility: Site US2935
state: Colorado
city: Middlebury
country: United States
facility: Site US2945
state: Connecticut
city: Melrose Park
country: United States
facility: Site US2014
state: Illinois
city: Springfield
country: United States
facility: Site US2067
state: Illinois
city: Jeffersonville
country: United States
facility: Site US2027
state: Indiana
city: West Des Moines
country: United States
facility: Site US1838
state: Iowa
city: Kansas City
country: United States
facility: Site US62
state: Kansas
city: Baltimore
country: United States
facility: Site US2976
state: Maryland
city: Bethesda
country: United States
facility: Site US3182
state: Maryland
city: Ann Arbor
country: United States
facility: Site US2975
state: Michigan
city: Grand Rapids
country: United States
facility: Site US892
state: Michigan
city: Minneapolis
country: United States
facility: Site US20
state: Minnesota
city: Billings
country: United States
facility: Site US3078
state: Montana
city: Lawrenceville
country: United States
facility: Site US2968
state: New Jersey
city: Poughkeepsie
country: United States
facility: Site US3025
state: New York
city: Rochester
country: United States
facility: Site US1675
state: New York
city: Staten Island
country: United States
facility: Site US2934
state: New York
city: Chapel Hill
country: United States
facility: Site US81
state: North Carolina
city: Greensboro
country: United States
facility: Site US2104
state: North Carolina
city: Cincinnati
country: United States
facility: Site US44
state: Ohio
city: Columbus
country: United States
facility: Site US2185
state: Ohio
city: Bala-Cynwyd
country: United States
facility: Site US1598
state: Pennsylvania
city: Lancaster
country: United States
facility: Site US1680
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Site US2926
state: South Carolina
city: Nashville
country: United States
facility: Site US1657
state: Tennessee
city: Houston
country: United States
facility: Site US464
state: Texas
city: San Antonio
country: United States
facility: Site US2978
state: Texas
city: Virginia Beach
country: United States
facility: Site US1653
state: Virginia
city: Burien
country: United States
facility: Site US1580
state: Washington
city: Wenatchee
country: United States
facility: Site US1709
state: Washington
city: Milwaukee
country: United States
facility: Site US51
state: Wisconsin
city: Brussels
country: Belgium
facility: Site BE3015
city: Gent
country: Belgium
facility: Site BE1322
city: Kortrijk
country: Belgium
facility: Site BE3018
city: Leuven
country: Belgium
facility: Site BE3288
city: Liege
country: Belgium
facility: Site BE3289
city: Turnhout
country: Belgium
facility: Site BE3013
city: Calgary
country: Canada
facility: Site CA3104
state: Alberta
city: Abbotsford
country: Canada
facility: Site CA3242
state: British Columbia
city: Kingston
country: Canada
facility: Site CA2646
state: Ontario
city: Toronto
country: Canada
facility: Site CA166
state: Ontario
city: Toronto
country: Canada
facility: Site CA3084
state: Ontario
city: Granby
country: Canada
facility: Site CA2984
state: Quebec
city: Montreal
country: Canada
facility: Site CA170
state: Quebec
city: Aalborg
country: Denmark
facility: Site DK3354
city: Aarhus
country: Denmark
facility: Site DK3356
city: Copenhagen
country: Denmark
facility: Site DK1857
city: Herlev
country: Denmark
facility: Site DK1263
city: Creteil
country: France
facility: Site FR1091
city: Lille
country: France
facility: Site FR3009
city: Lyon Cedex 3
country: France
facility: Site FR442
city: Paris Cedex 10
country: France
facility: Site FR3002
city: Poitiers Cedex
country: France
facility: Site FR3003
city: Rennes Cedex
country: France
facility: Site FR3000
city: Rouen
country: France
facility: Site FR3007
city: Suresnes Cedex
country: France
facility: Site FR3005
city: Nuertingen
country: Germany
facility: Site DE4000
state: Baden-Wuerttemberg
city: Aachen
country: Germany
facility: Site DE2989
city: Bergisch Gladbach
country: Germany
facility: Site DE3287
city: Bonn
country: Germany
facility: Site DE2993
city: Bonn
country: Germany
facility: Site DE2995
city: Bonn
country: Germany
facility: Site DE2994
city: Hamburg
country: Germany
facility: Site DE2990
city: Hannover
country: Germany
facility: Site DE3270
city: Reutlingen
country: Germany
facility: Site DE2992
city: Waldshut-Tiengen
country: Germany
facility: Site DE3286
city: Wuppertal
country: Germany
facility: Site DE2988
city: Bucharest
country: Romania
facility: Site RO3042
state: RO
city: Bucharest
country: Romania
facility: Site RO3039
state: RO
city: Bucharest
country: Romania
facility: Site RO3035
city: Bristol
country: United Kingdom
facility: Site GB3029
state: UK
city: London
country: United Kingdom
facility: Site GB3027
state: UK
city: London
country: United Kingdom
facility: Site GB3030
state: UK
city: Cardiff
country: United Kingdom
facility: Site GB3028
state: Wales
city: Belfast
country: United Kingdom
facility: Site GB3244
city: Cambridge
country: United Kingdom
facility: Site GB2702
city: Glasgow
country: United Kingdom
facility: Site GB3166
city: Leicher
country: United Kingdom
facility: Site GB1862
city: London
country: United Kingdom
facility: Site GB3163
city: Manchester
country: United Kingdom
facility: Site GB2624
city: Merseyside
country: United Kingdom
facility: Site GB3355
city: Northwood, Middlesex
country: United Kingdom
facility: Site GB3245
city: Preston
country: United Kingdom
facility: Site GB3290
Study officials:
affiliation: Carolina Urologic Research Center
name: Principal Investigator
role: PRINCIPAL_INVESTIGATOR
affiliation: Astellas Pharma Global Development
name: Associate Medical Science Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.