MDV3100-03

Medivation, Inc.

525 Market St., San Francisco, United States, 94105

Phillip Cole, MD, Medivation, Inc., phillip.cole@medivation.com

Phillip Cole, MD, Medivation, Inc., phillip.cole@medivation.com

No

No

No

Interim

16 Sep 2013

Yes

16 Sep 2013

No

The purpose of this study was to determine the benefit of enzalutamide versus placebo as assessed by overall survival and radiographic progression-free survival in patients with progressive metastatic prostate cancer who have failed androgen deprivation therapy and had not yet received cytotoxic chemotherapy.

This study was conducted in conformance with the principles of the Declaration of Helsinki or with the laws and regulations of the country in which the research was conducted, whichever provided greater protection of the individual. In addition, the study was conducted using Good Clinical Practice (GCP) according to International Conference on Harmonisation (ICH) guidelines. Specifically, this study was based on adequately performed laboratory and animal experimentation; the study was conducted under a protocol reviewed and approved by an IRB/IEC; the study was conducted by scientifically and medically qualified persons; the benefits of the study were in proportion to the risks; the rights and welfare of the patients were respected; the physicians conducting the study did not find the hazards to outweigh the potential benefits.

28 Sep 2010

Yes

Yes

United States: 247

Slovakia: 27

Finland: 33

Spain: 81

Lithuania: 14

Austria: 18

Israel: 25

Russian Federation: 22

United Kingdom: 153

Italy: 30

France: 175

Canada: 179

Poland: 39

Belgium: 57

Singapore: 9

Australia: 232

Denmark: 87

Netherlands: 28

Germany: 83

Japan: 61

Sweden: 39

Korea, Republic of: 78

1717

864

0

0

0

0

0

0

358

1264

95

Overall Study (overall period)

Randomised - controlled

Yes

Enzalutamide

Capsule

Oral use

Patients received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.

Placebo

Capsule

Oral use

Patients received placebo, administered as four capsules, once per day by mouth.

Enzalutamide

Placebo

Enzalutamide

Placebo

Intent-to-treat: Radiographic Progression-free Survival

All patients randomly assigned to treatment excluding 84 patients who were not randomized before the radiographic progression-free survival data cutoff date of 06 May 2012.

Evaluable Intent-to-treat Population

All patients randomly assigned to treatment with PSA values at baseline and at least one postbaseline assessment.

Intent-to-treat With Measurable Disease

All participants who were randomly assigned to treatment and had at least one target lesion at screening.

Intent-to-treat

All patients randomly assigned to treatment.

Overall survival was defined as the time from randomization to death due to any cause. For patients who were alive at the time of the analysis data cutoff, overall survival was censored at the last date the patient was known to be alive or analysis data cutoff date, whichever was first. This included patients who were known to have died after the data analysis cutoff date. Patients with no post-baseline survival information were censored on the date of randomization. '99999' indicates that the upper limit of the 95% confidence interval was not calculable because an insufficient number of patients reached the event at the final time point for assessment.

Primary

During study period (up to 3 years)

Enzalutamide v Placebo

1717

Pre-specified

0.706

2-sided

Radiographic progression-free survival (rPFS) was defined as the time from randomization to the first objective evidence of radiographic disease progression (rDP) assessed by blinded independent central radiology review or death due to any cause within 168 days after treatment discontinuation, whichever was first. RDP was evaluated by CT scan or MRI and radionuclide bone scans at regularly scheduled visits. RDP in bone required a confirmatory scan. RDP in soft tissue did not require a confirmatory scan for purposes of analysis. RDP was evaluated using RECIST 1.1 for soft tissue disease and PCWG2 guidelines for bone disease. Patients who did not reach the endpoint were censored at their last assessment. '99999' indicates the median time to rPFS and its upper 95% confidence limit were not yet reached in the enzalutamide group because an insufficient number of patients had an event at the time of analysis.

Primary

During study period (up to 20 months)

Placebo v Enzalutamide

1633

Pre-specified

0.186

2-sided

Time to first skeletal-related event (SRE) was defined as the time from randomization to the date of the first occurrence of an SRE for each patient. An SRE was defined as radiation therapy or surgery to bone for prostate cancer, pathological bone fracture, spinal cord compression, or initiation/change in antineoplastic therapy to treat bone pain from prostate cancer. SREs were recorded at each scheduled and unscheduled study visit and during long-term follow-up if an SRE was not documented previously. Patients who did not have an SRE at the time of the analysis data cutoff were censored at the date of last assessment indicating no evidence of SRE. Patients with no postbaseline assessments were censored on the date of randomization. '99999' indicates that the upper limit of the 95% confidence interval was not calculable because an insufficient number of patients reached the event at the final time point for assessment.

Secondary

During study period (up to 3 years)

Enzalutamide v Placebo

1717

Pre-specified

0.718

2-sided

The time to initiation of cytotoxic chemotherapy was defined as the time from randomization to the date of initiation of cytotoxic chemotherapy for the treatment of prostate cancer for each patient. For patients who did not start cytotoxic chemotherapy at the time of the analysis data cutoff, time to initiation of cytotoxic chemotherapy was censored at the date of last assessment where no cytotoxic chemotherapy was indicated or at the analysis data cutoff date, whichever was first. Time to initiation of cytotoxic chemotherapy for patients with no postbaseline assessments was censored on the date of randomization. '99999' indicates that the upper limit of the 95% confidence interval was not calculable because an insufficient number of patients in the enzalutamide group reached the event at the final time point for assessment.

Secondary

During study period (up to 3 years)

Enzalutamide v Placebo

1717

Pre-specified

0.349

2-sided

Time to PSA progression was defined as the time from randomization to date of first confirmed observation of PSA progression for each patient. 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, and confirmed 3 or more weeks later. For patients with no PSA decline 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 baseline was documented, and confirmed 3 or more weeks later. For patients who did not have confirmed PSA progression at the time of the analysis data cutoff, time to PSA progression was censored at the date of the last PSA assessment showing no evidence of confirmed PSA progression or the analysis data cutoff date, whichever was first. Time to PSA progression for patients with no postbaseline assessments was censored on the date of randomization.

Secondary

During study period (up to 3 years)

Enzalutamide v Placebo

1717

Pre-specified

0.169

2-sided

PSA response was defined as a ≥ 50% reduction in PSA from baseline to the lowest postbaseline PSA value and required confirmation by a consecutive assessment at least 3 weeks later. Patients were evaluable for PSA response rate if a patient had a PSA level measured at baseline and at least one postbaseline assessment.

Secondary

During study period (up to 3 years)

Enzalutamide v Placebo

1631

Pre-specified

74.51

2-sided

The best overall soft tissue objective response was defined as partial response [PR] or complete response [CR] while on study treatment based on investigator assessments of target, nontarget, and new lesions using RECIST 1.1. Soft tissue was assessed by CT or MRI at regularly scheduled visits. Only patients with measurable soft tissue disease (ie, at least 1 target lesion identified per RECIST 1.1) at screening are included in this analysis. All percentages are based on number of patients with measurable soft tissue disease at screening in each treatment group.

Secondary

During study period (up to 3 years)

Enzalutamide v Placebo

777

Pre-specified

53.85

2-sided

The period of time from the date of the first dose of study drug to 28 days after last dose of study drug or 1 day before the date of initiation of cytotoxic chemotherapy or an investigational agent for prostate cancer, whichever was first.

Safety population (patients at risk) was defined as patients that received at least 1 dose of study drug. 1717 patients were randomly assigned 1:1 to treatment with enzalutamide (872 patients) or placebo (845 patients), however only 1715 patients received at least 1 dose of enzalutamide (871 patients) or placebo (844 patients).

16.1

Enzalutamide

Placebo