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

Prostatic Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01288911
• Other study ID #: 9785-CL-0222
• Secondary ID: 2010-021868-15
• Status: Completed
• Phase: Phase 2
• Start date: March 22, 2011
• Est. completion date: November 8, 2017

Study information

• Verified date: July 2022
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 375
• Est. completion date: November 8, 2017
• Est. primary completion date: October 19, 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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-a 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

Related Conditions & MeSH terms

• Prostatic Neoplasms

Intervention

Drug:
• enzalutamide
capsules
• bicalutamide
tablets

Locations

Country	Name	City	State
Belgium	Site BE3015	Brussels
Belgium	Site BE1322	Gent
Belgium	Site BE3018	Kortrijk
Belgium	Site BE3288	Leuven
Belgium	Site BE3289	Liege
Belgium	Site BE3013	Turnhout
Canada	Site CA3242	Abbotsford	British Columbia
Canada	Site CA3104	Calgary	Alberta
Canada	Site CA2984	Granby	Quebec
Canada	Site CA2646	Kingston	Ontario
Canada	Site CA170	Montreal	Quebec
Canada	Site CA166	Toronto	Ontario
Canada	Site CA3084	Toronto	Ontario
Denmark	Site DK3354	Aalborg
Denmark	Site DK3356	Aarhus
Denmark	Site DK1857	Copenhagen
Denmark	Site DK1263	Herlev
France	Site FR1091	Creteil
France	Site FR3009	Lille
France	Site FR442	Lyon Cedex 3
France	Site FR3002	Paris Cedex 10
France	Site FR3003	Poitiers Cedex
France	Site FR3000	Rennes Cedex
France	Site FR3007	Rouen
France	Site FR3005	Suresnes Cedex
Germany	Site DE2989	Aachen
Germany	Site DE3287	Bergisch Gladbach
Germany	Site DE2993	Bonn
Germany	Site DE2994	Bonn
Germany	Site DE2995	Bonn
Germany	Site DE2990	Hamburg
Germany	Site DE3270	Hannover
Germany	Site DE4000	Nuertingen	Baden-Wuerttemberg
Germany	Site DE2992	Reutlingen
Germany	Site DE3286	Waldshut-Tiengen
Germany	Site DE2988	Wuppertal
Romania	Site RO3035	Bucharest
Romania	Site RO3039	Bucharest	RO
Romania	Site RO3042	Bucharest	RO
United Kingdom	Site GB3244	Belfast
United Kingdom	Site GB3029	Bristol	UK
United Kingdom	Site GB2702	Cambridge
United Kingdom	Site GB3028	Cardiff	Wales
United Kingdom	Site GB3166	Glasgow
United Kingdom	Site GB1862	Leicher
United Kingdom	Site GB3027	London	UK
United Kingdom	Site GB3030	London	UK
United Kingdom	Site GB3163	London
United Kingdom	Site GB2624	Manchester
United Kingdom	Site GB3355	Merseyside
United Kingdom	Site GB3245	Northwood, Middlesex
United Kingdom	Site GB3290	Preston
United States	Site US1527	Anchorage	Alaska
United States	Site US2975	Ann Arbor	Michigan
United States	Site US1598	Bala-Cynwyd	Pennsylvania
United States	Site US2976	Baltimore	Maryland
United States	Site US3182	Bethesda	Maryland
United States	Site US3078	Billings	Montana
United States	Site US1580	Burien	Washington
United States	Site US81	Chapel Hill	North Carolina
United States	Site US44	Cincinnati	Ohio
United States	Site US2185	Columbus	Ohio
United States	Site US2935	Denver	Colorado
United States	Site US892	Grand Rapids	Michigan
United States	Site US2104	Greensboro	North Carolina
United States	Site US2977	Highland	California
United States	Site US1934	Homewood	Alabama
United States	Site US464	Houston	Texas
United States	Site US2027	Jeffersonville	Indiana
United States	Site US62	Kansas City	Kansas
United States	Site US1680	Lancaster	Pennsylvania
United States	Site US2968	Lawrenceville	New Jersey
United States	Site US2014	Melrose Park	Illinois
United States	Site US2945	Middlebury	Connecticut
United States	Site US51	Milwaukee	Wisconsin
United States	Site US20	Minneapolis	Minnesota
United States	Site US2926	Myrtle Beach	South Carolina
United States	Site US1657	Nashville	Tennessee
United States	Site US3025	Poughkeepsie	New York
United States	Site US1675	Rochester	New York
United States	Site US2978	San Antonio	Texas
United States	Site US3630	San Diego	California
United States	Site US2067	Springfield	Illinois
United States	Site US2934	Staten Island	New York
United States	Site US3026	Tucson	Arizona
United States	Site US1653	Virginia Beach	Virginia
United States	Site US1709	Wenatchee	Washington
United States	Site US1838	West Des Moines	Iowa

Sponsors (2)

Lead Sponsor	Collaborator
Astellas Pharma Inc	Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Germany,  Romania,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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).

External Links

•   Link to results on the Astellas Clinical Study Results website