Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
MDV3100, Xtandi, Abiraterone, Metastatic Castration-Resistant Prostate Cancer, Enzalutamide
Brief summary
The objective of this study was to evaluate the efficacy and safety of enzalutamide treatment in patients with progressive metastatic castration-resistant prostate cancer previously treated with abiraterone acetate.
Interventions
DRUGEnzalutamide
Participants received 160 mg of enzalutamide (soft capsules) orally once daily.
Sponsors
Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Astellas Pharma Europe B.V.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject has histologically confirmed adenocarcinoma of the prostate without neuro-endocrine differentiation or small cell features. * Subject has metastatic disease documented by bone scan or by soft tissue disease observed by Computed Tomography/Magnetic Resonance Imaging (CT/MRI) at screening, or within ≤30 days prior to Day 1. * In the setting of castrate levels of testosterone ≤1.7 nmol/L (or ≤50 ng/dL), subject has progressive disease at study entry defined as PSA rise determined by a minimum of 2 rising PSA levels with an interval of ≥ 1 week between each assessment. The PSA value at the screening visit should be ≥ 2 ng/mL WITH or WITHOUT: * Soft tissue disease progression defined by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) at screening, or within ≤30 days prior to Day 1. Measurable disease is not required for entry. Lymph nodes ≥ 2 cm are considered measurable disease (Prostate Cancer Clinical Trials Working Group (PCWG2)). * Bone disease progression defined by at least 2 new lesions on bone scan at screening, or within ≤30 days prior to Day 1. * Subject must have received a minimum of 24 weeks of treatment with abiraterone acetate within its approved label indication and has discontinued use at least 4 weeks prior to start of study drug at Day 1. * If the subject has received previous treatment with chemotherapy for prostate cancer, this must be limited to no more than one prior line of docetaxel, and must have been used prior to abiraterone acetate therapy. * Subject receives and will continue to receive ongoing androgen deprivation with Luteinizing-hormone-releasing hormone (LHRH) analogue therapy throughout the course of the study or has had a bilateral orchiectomy. * Subject is asymptomatic or mildly symptomatic from prostate cancer: * The score on 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 screening.
Exclusion criteria
* Subject has prior use of ketoconazole for the treatment of prostate cancer. * Subject has prior use of cabazitaxel. * Subject has prior use of enzalutamide. * Subject has received ANY anti-neoplastic therapy (including antiandrogens and chemotherapy) following abiraterone acetate discontinuation and prior to start of study drug at Day 1. * Subject has a known or suspected hypersensitivity to enzalutamide, or any components of the formulation used. * Subject has known or suspected brain metastases or active leptomeningeal disease. * Subject has history of seizure or any condition that may predispose to seizure (e.g., prior stroke or significant brain trauma).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression-free Survival (rPFS) | From the first dose of study drug administration up to treatment discontinuation or the data cut-off date of 08 May 2016, whichever occurred first; the median duration of treatment was 5.7 months. | Radiographic PFS, was defined as the time from first dose to the first objective evidence of radiographic disease progression or death from any cause, whichever occurred first. For patients with no documented progression event, it was censored on the date of the last disease assessment performed prior to the analysis data cut-off point. Radiographic progression (RP) for soft tissue disease was defined by Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 criteria. RP for bone disease was determined according to the consensus guidelines of a modification of the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) guidelines. The 50th percentile of Kaplan-Meier (KM) estimates was used as the estimate of the rPFS median. A 2-sided 95% Confidence Interval (CI) was provided for this estimate using the Brookmeyer & Crowley (BC) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the first dose of study drug administration up to the data cut-off date of 08 May 2016; up to 2 years. | OS was defined as the time from first dose to death from any cause. All events of death were included. If patients discontinued study drug before the analysis data cut-off point, only OS status was assessed every 12 weeks until the data cut-off point date or until death, whichever occurred first. For patients who were alive at the time of the analysis data cut-off point, the OS time was censored on the last date the patient was known to be alive. Death from any cause was included, regardless of whether the event occurred while the patient was still taking study drug or after the patient discontinued study drug. OS median was estimated using the KM method. A 2-sided 95% CI was provided for this estimate using the BC method. |
| Percentage of Participants With a Prostate-specific Antigen (PSA) Response | From the first dose of study drug administration up to the data cut-off date for end-of-study completion 29 Sep 2017; the median duration of treatment was 5.7 months. | PSA response was defined as at least a 50% decrease from baseline in PSA, and was a binary variable for achieving this criteria (or not) based on the lowest PSA value observed postbaseline. Participants with no postbaseline PSA value were regarded as non-responders. 95% CI for PSA response rate was computed using the Clopper-Pearson method based on the exact binomial distribution. |
| Time to PSA Progression | From the first dose of study drug administration up to the data cut-off date of 08 May 2016; the median duration of treatment was 5.7 months. | The time to PSA progression was calculated as the time interval from the date of first dose to the date of first observation of PSA progression. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 μg/L (i.e., 2 ng/mL or more) above the nadir or above the baseline value for patients who did not have a decline in PSA postbaseline values, and which was confirmed by a second consecutive value obtained at least 3 or more weeks later (i.e., a confirmed rising trend) (PCWG2 criteria). The 50th percentile of KM estimates was used as the estimate of the time to PSA progression median. A 2-sided 95% CI was provided for this estimate using the BC method. |
| Number of Participants With Adverse Events (AEs) | From the first dose of study drug administration up to data cut-off date for end-of-study completion (29 Sep 2017); the median duration of treatment was 5.7 months. | A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03). |
Countries
Belgium, France, Germany, Spain, United Kingdom
Participant flow
Recruitment details
Male participants with progressive metastatic castration-resistant prostate cancer were enrolled in this study.
Pre-assignment details
A total of 272 participants were screened for enrollment & signed an informed consent form, & 57 of those screen failed. The primary reason for screening failure was not fulfilling inclusion/exclusion criteria (52 participants, 19.1%), followed by withdrawal (5 participants, 1.8%).
Participants by arm
| Arm | Count |
|---|---|
| Enzalutamide Participants received 160 mg of enzalutamide orally once daily until they experienced an adverse event, disease progression, started new anti-cancer therapy, withdrew consent, or other protocol-specified criteria. | 215 |
| Total | 215 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 22 |
| Overall Study | Death | 9 |
| Overall Study | Enrolled but Never Received Study Drug | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other: Miscellaneous | 11 |
| Overall Study | Other: Transitioned to 9785-CL-0123 | 12 |
| Overall Study | Progressive Disease | 148 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Enzalutamide |
|---|---|
| Age, Continuous | 73.2 Years STANDARD_DEVIATION 7.6 |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 47 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 165 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 215 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 73 / 214 |
| other Total, other adverse events | 182 / 214 |
| serious Total, serious adverse events | 82 / 214 |
Outcome results
Primary
Radiographic Progression-free Survival (rPFS)
Radiographic PFS, was defined as the time from first dose to the first objective evidence of radiographic disease progression or death from any cause, whichever occurred first. For patients with no documented progression event, it was censored on the date of the last disease assessment performed prior to the analysis data cut-off point. Radiographic progression (RP) for soft tissue disease was defined by Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 criteria. RP for bone disease was determined according to the consensus guidelines of a modification of the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) guidelines. The 50th percentile of Kaplan-Meier (KM) estimates was used as the estimate of the rPFS median. A 2-sided 95% Confidence Interval (CI) was provided for this estimate using the Brookmeyer & Crowley (BC) method.
Time frame: From the first dose of study drug administration up to treatment discontinuation or the data cut-off date of 08 May 2016, whichever occurred first; the median duration of treatment was 5.7 months.
Population: The analysis population consisted of the safety analysis set (SAF) which consisted of all participants who took at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Radiographic Progression-free Survival (rPFS) | 8.1 Months |
Secondary
Number of Participants With Adverse Events (AEs)
A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03).
Time frame: From the first dose of study drug administration up to data cut-off date for end-of-study completion (29 Sep 2017); the median duration of treatment was 5.7 months.
Population: The analysis population consisted of the SAF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Any TEAE | 199 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | NCI-CTCAE Grade ≥3 | 95 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Study Drug-Related | 127 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Study Drug-Related NCI-CTCAE Grade ≥3 | 18 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | TEAEs with Death as an Outcome | 22 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Serious Adverse Event (SAE) | 82 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Study Drug-related SAE | 8 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | TEAEs Leading to Study Drug Discontinuation | 76 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Study Drug-Related TEAEs Leading to Drug Disc. | 23 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from first dose to death from any cause. All events of death were included. If patients discontinued study drug before the analysis data cut-off point, only OS status was assessed every 12 weeks until the data cut-off point date or until death, whichever occurred first. For patients who were alive at the time of the analysis data cut-off point, the OS time was censored on the last date the patient was known to be alive. Death from any cause was included, regardless of whether the event occurred while the patient was still taking study drug or after the patient discontinued study drug. OS median was estimated using the KM method. A 2-sided 95% CI was provided for this estimate using the BC method.
Time frame: From the first dose of study drug administration up to the data cut-off date of 08 May 2016; up to 2 years.
Population: The analysis population consisted of the SAF.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Overall Survival (OS) | NA Months |
Secondary
Percentage of Participants With a Prostate-specific Antigen (PSA) Response
PSA response was defined as at least a 50% decrease from baseline in PSA, and was a binary variable for achieving this criteria (or not) based on the lowest PSA value observed postbaseline. Participants with no postbaseline PSA value were regarded as non-responders. 95% CI for PSA response rate was computed using the Clopper-Pearson method based on the exact binomial distribution.
Time frame: From the first dose of study drug administration up to the data cut-off date for end-of-study completion 29 Sep 2017; the median duration of treatment was 5.7 months.
Population: The analysis population consisted of the SAF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enzalutamide | Percentage of Participants With a Prostate-specific Antigen (PSA) Response | 22.0 Percentage of participants |
Secondary
Time to PSA Progression
The time to PSA progression was calculated as the time interval from the date of first dose to the date of first observation of PSA progression. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 μg/L (i.e., 2 ng/mL or more) above the nadir or above the baseline value for patients who did not have a decline in PSA postbaseline values, and which was confirmed by a second consecutive value obtained at least 3 or more weeks later (i.e., a confirmed rising trend) (PCWG2 criteria). The 50th percentile of KM estimates was used as the estimate of the time to PSA progression median. A 2-sided 95% CI was provided for this estimate using the BC method.
Time frame: From the first dose of study drug administration up to the data cut-off date of 08 May 2016; the median duration of treatment was 5.7 months.
Population: The analysis population consisted of the SAF.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzalutamide | Time to PSA Progression | 5.7 Months |