Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Astellas Pharma Inc
Information provided by (Responsible Party):
Medivation, Inc.
ClinicalTrials.gov Identifier:
NCT00974311
First received: September 9, 2009
Last updated: February 22, 2014
Last verified: February 2014
Results First Received: September 28, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Castration-Resistant Prostate Cancer
Interventions: Drug: Enzalutamide
Drug: Placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Multicenter, global clinical trial

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients were randomized 2:1 to receive either Enzalutamide or placebo

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Participant Flow:   Overall Study
    Enzalutamide     Placebo  
STARTED     800     399  
COMPLETED     254 [1]   163 [1]
NOT COMPLETED     546     236  
Lost to Follow-up                 1                 1  
Death                 305                 211  
Withdrawal of consent                 9                 5  
Continuing Treatment                 231                 19  
[1] Indicates participants continuing long-term follow-up as of 25 September 2011.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Total Total of all reporting groups

Baseline Measures
    Enzalutamide     Placebo     Total  
Number of Participants  
[units: participants]
  800     399     1199  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     232     130     362  
>=65 years     568     269     837  
Age  
[units: years]
Mean ± Standard Deviation
  68.8  ± 7.96     68.6  ± 8.39     68.7  ± 8.11  
Gender  
[units: participants]
     
Female     0     0     0  
Male     800     399     1199  
Region of Enrollment  
[units: participants]
     
United States     181     107     288  
Spain     23     13     36  
Austria     15     10     25  
Chile     6     5     11  
United Kingdom     82     50     132  
Italy     20     10     30  
France     193     80     273  
Canada     82     25     107  
Argentina     7     3     10  
Belgium     27     18     45  
Poland     7     4     11  
Australia     60     33     93  
South Africa     3     3     6  
Germany     62     24     86  
Netherlands     32     14     46  



  Outcome Measures
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1.  Primary:   Overall Survival   [ Time Frame: During study period (up to 3 years) ]

Measure Type Primary
Measure Title Overall Survival
Measure Description Survival is defined as time from randomization to death due to any cause. The duration of overall survival was right-censored for patients who were lost to follow-up since randomization or not known to have died at the data analysis cutoff date (this included patients who were known to have died after the data analysis cutoff date).
Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat (ITT) - All Patients Randomized

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  800     399  
Overall Survival  
[units: Months]
Median ( 95% Confidence Interval )
  18.4  
  ( 17.3 to NA ) [1]
  13.6  
  ( 11.3 to 15.8 )  
[1] The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.63
95% Confidence Interval ( 0.53 to 0.75 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3)
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard Ratio and 95% confidence interval are from Cox regression model.



2.  Secondary:   Radiographic Progression-free Survival   [ Time Frame: During study period (up to 3 years) ]

Measure Type Secondary
Measure Title Radiographic Progression-free Survival
Measure Description Radiographic progression-free survival was defined as time from randomization to the earliest objective evidence of radiographic progression or death due to any cause. Patients were assessed for objective disease progression at regularly scheduled visits. The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 were taken into consideration for the determination of disease progression. Radiographic disease progression was defined by RECIST 1.1 for soft tissue disease, or the appearance of two or more new bone lesions on bone scan. Progression at the first scheduled reassessment at Week 13 required a confirmatory scan 6 or more weeks later. Patients who did not reach the endpoint were right censored at their last assessment.
Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat (ITT) - All Patients Randomized

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  800     399  
Radiographic Progression-free Survival  
[units: Months]
Median ( 95% Confidence Interval )
  8.3  
  ( 8.2 to 9.4 )  
  2.9  
  ( 2.8 to 3.4 )  


Statistical Analysis 1 for Radiographic Progression-free Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.40
95% Confidence Interval ( 0.35 to 0.47 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3)
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard Ratio and 95% confidence interval are from Cox regression model.



3.  Secondary:   Time to First Skeletal-related Event   [ Time Frame: During study period (up to 3 years) ]

Measure Type Secondary
Measure Title Time to First Skeletal-related Event
Measure Description The time to first skeletal-related event was defined as time from randomization to the occurrence of the first skeletal-related event. Patients were assessed for skeletal-related events at regularly scheduled visits. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. Patients who did not reach the endpoint were right censored at their last assessment.
Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat (ITT) - All Patients Randomized

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  800     399  
Time to First Skeletal-related Event  
[units: Months]
Median ( 95% Confidence Interval )
  16.7  
  ( 14.6 to 19.1 )  
  13.3  
  ( 9.9 to NA ) [1]
[1] The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment


Statistical Analysis 1 for Time to First Skeletal-related Event
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0001
Hazard Ratio (HR) [4] 0.69
95% Confidence Interval ( 0.566 to 0.835 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3)
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard Ratio and 95% confidence interval are from Cox regression model.



4.  Secondary:   Functional Assessment of Cancer Therapy - Prostate (FACT-P)   [ Time Frame: During study period (up to 3 years) ]

Measure Type Secondary
Measure Title Functional Assessment of Cancer Therapy - Prostate (FACT-P)
Measure Description

The FACT-P questionnaire is a 39-item questionnaire consisting of 5 domains; “physical well-being,” “social/family well-being,” “emotional well-being,” “functional well-being,” and “additional concerns” (consisting of items relating to prostate cancer and its treatment). Each item can be answered on a scale of 0–4. The sum of scores on all 5 domains constitutes the FACT-P.

Patients were defined as having a quality of life response if they had a 10-point improvement in their global FACT-P score, as compared with baseline, on two consecutive measurements obtained at least 3 weeks apart.

Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Evaluable Intent to Treat (ITT) - all patients who were part of the ITT Population and had a global FACT-P score at baseline and at least 1 post-baseline assessment.

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  651     257  
Functional Assessment of Cancer Therapy - Prostate (FACT-P)  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
  43.2  
  ( 39.3 to 47.1 )  
  18.3  
  ( 13.8 to 23.6 )  


Statistical Analysis 1 for Functional Assessment of Cancer Therapy - Prostate (FACT-P)
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.0001
Difference in Response Rate [4] 24.9
95% Confidence Interval ( 18.8 to 30.9 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by baseline ECOG performance status and mean Brief Pain Inventory – Short Form score (Question #3)
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Confidence Interval based on standard normal approximation



5.  Secondary:   Time to Prostate-specific Antigen (PSA) Progression   [ Time Frame: Baseline and at every study visit from week 13 while on study drug (up to 3 years) ]

Measure Type Secondary
Measure Title Time to Prostate-specific Antigen (PSA) Progression
Measure Description

Time to PSA progression was defined as time from randomization to PSA progression. Patients who did not reach the endpoint were right censored at their last assessment or for patients with no post-baseline PSA assessment, date of randomization.

For patients with PSA declines at Week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir was documented, which was confirmed by a second consecutive value obtained 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment). For patients with no PSA declines at Week 13, PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline was documented, which was confirmed by a second consecutive value 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment).

Time Frame Baseline and at every study visit from week 13 while on study drug (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat (ITT) - All Patients Randomized

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  800     399  
Time to Prostate-specific Antigen (PSA) Progression  
[units: Months]
Median ( 95% Confidence Interval )
  8.3  
  ( 5.8 to 8.3 )  
  3.0  
  ( 2.9 to 3.7 )  


Statistical Analysis 1 for Time to Prostate-specific Antigen (PSA) Progression
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.0001
Hazard Ratio (HR) [4] 0.248
95% Confidence Interval ( 0.204 to 0.303 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Stratified
[4] Other relevant estimation information:
  Hazard Ratio and 95% confidence interval are from Cox regression model.



6.  Secondary:   Percentage of Patients With Pain Palliation   [ Time Frame: During study period (up to 3 years) ]

Measure Type Secondary
Measure Title Percentage of Patients With Pain Palliation
Measure Description The proportion of patients with pain palliation was assessed for patients with a stable and sufficient pain burden at study entry. Pain burden was measured by question #3 of the Brief Pain Inventory (Short Form). This scale measures pain on a 0 to 10 scale with 0 indicating no pain and 10 indicating pain as bad as you can imagine. Pain palliation at Week 13 was determined for the proportion of men with baseline bone metastasis(es) who had baseline pain attributable to the metastasis(es). Palliation was defined as ≥ 30% reduction in average pain score at Week 13 compared to baseline without a ≥ 30% increase in analgesic use.
Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Evaluable ITT Population. Patients with metastatic bone disease at baseline; provided answers to Question #3 of the Brief Pain Inventory – Short Form for a minimum of 4 out of 7 days in the baseline run-in period; stable baseline pain; stable analgesic use; and had an average pain score during the baseline run-in period of ≥ 4.

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  49     15  
Percentage of Patients With Pain Palliation  
[units: Percentage of Participants]
Number ( 95% Confidence Interval )
  44.9  
  ( 30.7 to 59.8 )  
  6.7  
  ( 0.2 to 31.9 )  


Statistical Analysis 1 for Percentage of Patients With Pain Palliation
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.0079
Difference in Rate of Pain Palliation [4] 38.2
95% Confidence Interval ( 19.4 to 57.0 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Stratified by baseline Eastern Cooperative Oncology Group performance status (0–1 vs. 2)
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Confidence Interval based on standard normal approximation



7.  Secondary:   Percentage of Patients With Prostate Specific Antigen (PSA) Response   [ Time Frame: During study period (up to 3 years) ]

Measure Type Secondary
Measure Title Percentage of Patients With Prostate Specific Antigen (PSA) Response
Measure Description Patients were evaluable for PSA response rate if they had a PSA level measured at baseline and at least 1 post-baseline assessment. Both PSA responses of > 50% and > 90% were determined. PSA responses required confirmation with a subsequent assessment that was conducted at least 3 weeks later.
Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Evaluable Intent to Treat. Patients who were part of the ITT Population and had a PSA level measured at baseline and at least 1 post-baseline assessment.

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  731     330  
Percentage of Patients With Prostate Specific Antigen (PSA) Response  
[units: Percentage of Participants]
   
Decline >=50% from baseline     54     2  
Decline >=90% from baseline     25     1  

No statistical analysis provided for Percentage of Patients With Prostate Specific Antigen (PSA) Response



8.  Secondary:   Percentage of Patients With Soft-tissue Objective Response   [ Time Frame: During study period (up to 3 years) ]

Measure Type Secondary
Measure Title Percentage of Patients With Soft-tissue Objective Response
Measure Description

The best overall soft tissue response as assessed using RECIST v1.1 during the study was summarized using the Investigators’ response assessments and also the derived response assessments by treatment group. Only patients with measurable soft tissue disease at screening were included in this analysis. Patients with measurable disease at screening are patients who had at least 1 target lesion identified per RECIST v1.1 at screening.

Percentage of Participants summarizes the number of patients with complete or partial objective response (%).

Soft Tissue assessment based on Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.

Time Frame During study period (up to 3 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat (ITT) with Measurable Disease. Patients who were part of the ITT Population and had measurable soft tissue disease at screening, defined by at least 1 target lesion according to RECIST v1.1.

Reporting Groups
  Description
Enzalutamide Participants received 160 mg Enzalutamide orally per day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.
Placebo Participants received placebo tablets orally once a day. Treatment continued until unacceptable toxicity, confirmed disease progression and the patient was scheduled to initiate a new systemic antineoplastic therapy, death, or withdrawal.

Measured Values
    Enzalutamide     Placebo  
Number of Participants Analyzed  
[units: participants]
  446     208  
Percentage of Patients With Soft-tissue Objective Response  
[units: Percentage of participants]
  29     4  

No statistical analysis provided for Percentage of Patients With Soft-tissue Objective Response



9.  Secondary:   European Quality of Life Five-Domain Scale (EQ-5D)   [ Time Frame: At Week 13 visit ]
Results not yet reported.   Anticipated Reporting Date:   12/2013   Safety Issue:   No

10.  Secondary:   Circulating Tumor Cell (CTC) Conversion Rate   [ Time Frame: During study period (up to 3 years) ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information