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

Primary Purpose

Prostatic Neoplasms

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

enzalutamide

bicalutamide

About this trial

This is an interventional treatment trial for Prostatic Neoplasms focused on measuring Metastatic, MDV3100, Prostate, progressive, Cancer, enzalutamide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Enzalutamide

Bicalutamide

Arm Description

Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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).

Full Information

NCT ID

NCT01288911

First Posted

February 1, 2011

Last Updated

July 22, 2022

Sponsor

Astellas Pharma Inc

Collaborators

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01288911

Brief Title

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

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

March 22, 2011 (Actual)

Primary Completion Date

October 19, 2014 (Actual)

Study Completion Date

November 8, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Astellas Pharma Inc

Collaborators

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Prostatic Neoplasms

Keywords

Metastatic, MDV3100, Prostate, progressive, Cancer, enzalutamide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

375 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Enzalutamide

Arm Type

Experimental

Arm Description

Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

Arm Title

Bicalutamide

Arm Type

Active Comparator

Arm Description

Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

Intervention Type

Drug

Intervention Name(s)

enzalutamide

Other Intervention Name(s)

MDV3100

Intervention Description

capsules

Intervention Type

Drug

Intervention Name(s)

bicalutamide

Other Intervention Name(s)

Casodex

Intervention Description

tablets

Primary Outcome Measure Information:

Title

Progression Free Survival (PFS) Based on Independent Central Review (ICR) Assessment

Description

Time Frame

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 Measure Information:

Title

PFS Based on Investigator Assessment

Description

Time Frame

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.

Title

Prostate-specific Antigen (PSA) Response by Week 13

Description

Time Frame

Baseline to Week 13

Title

Best PSA Response

Description

Time Frame

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.

Title

Time to PSA Progression

Description

Time Frame