9785-CL-0335

Astellas Pharma Global Development, Inc. (APGD)

1 Astellas Way, Northbrook, IL, United States, 60062

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), astellas.resultsdisclosure@astellas.com

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), astellas.resultsdisclosure@astellas.com

No

No

No

Interim

14 Oct 2018

Yes

14 Oct 2018

No

The primary objective of this study was to determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed by radiographic progression-free survival (rPFS) based on independent central review (ICR).

This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

09 Mar 2016

Yes

Yes

Japan: 92

Taiwan: 30

Korea, Republic of: 25

Australia: 47

New Zealand: 23

Russian Federation: 139

Slovakia: 81

Italy: 68

Denmark: 62

Romania: 57

Spain: 55

Netherlands: 54

Poland: 47

France: 44

Finland: 39

Belgium: 15

Sweden: 12

Germany: 10

United Kingdom: 2

United States: 122

Canada: 41

Argentina: 10

Chile: 52

Israel: 23

1150

546

0

0

0

0

0

0

300

824

26

Overall Study (overall period)

Randomised - controlled

Yes

Enzalutamide

MDV3100

Capsule

Oral use

Participants received 4 capsules (40 mg each) of enzalutamide orally once a day, for a total daily dose of 160 mg. Treatment was given with or without food and as close as possible to the same time each day.

Placebo

Capsule

Oral use

Participants received 4 capsules of matching placebo orally once a day. Treatment was given with or without food and as close as possible to the same time each day.

Enzalutamide + Androgen Deprivation Therapy (ADT)

Placebo + Androgen Deprivation Therapy (ADT)

Enzalutamide + Androgen Deprivation Therapy (ADT)

Placebo + Androgen Deprivation Therapy (ADT)

Enzalutamide + ADT

Participants received enzalutamide orally once daily. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site’s pharmacy stock.

Placebo + ADT

Participants received matching placebo orally once daily. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site’s pharmacy stock.

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by RECIST version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline or week 13 according to PCWG2 criteria, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as “not evaluable (NE),” rPFS was censored on the date of randomization. ITT population. "99999" denotes data not reached due to low number of events.

Primary

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

rPFS Treatment Comparison

Placebo + ADT v Enzalutamide + ADT

1150

Pre-specified

0.39

2-sided

rPFS was calculated as the time from the date of randomization to the first objective evidence of rPD at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by RECIST version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline for week 13 or the best response on treatment for week 25 or later assessments, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as “not evaluable(NE),” rPFS was censored on the date of randomization.ITT population."99999" denotes data not reached due to low number of events.

Primary

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months.

rPFS Treatment Comparision

Enzalutamide + ADT v Placebo + ADT

1150

Pre-specified

0.39

2-sided

OS was defined as the time from randomization to death due to any cause. In participants still alive at the date of the analysis cutoff point, OS was censored on the last date the participant was known to be alive.

Secondary

Up to 78 months

Time to PSA progression was calculated as the time from the date of randomization to the first observation of PSA progression. A PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir, which was confirmed by a second consecutive value at least 3 weeks later. In participants with no PSA progression, time to PSA progression was censored on the date of the last PSA sample taken (or last value prior to 2 or more consecutive missed PSA assessments). ITT population. "99999" denotes data not reached due to low number of events.

Secondary

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to PSA Progression Treatment Comparison

Enzalutamide + ADT v Placebo + ADT

1150

Pre-specified

0.19

2-sided

In participants with a new antineoplastic therapy initiated for prostate cancer after randomization, time to start of a new antineoplastic therapy was defined as the time interval from randomization to the date of the first dose administration of the first antineoplastic therapy. In participants with no new antineoplastic therapy initiated for prostate cancer after randomization, time to start of new antineoplastic therapy was censored on the last visit date or the date of randomization, whichever occurred last. ITT population. "-99999" and "99999 denotes data not reached due to low number of events.

Secondary

From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to Start of New Therapy Treatment Comparison

Enzalutamide + ADT v Placebo + ADT

1150

Pre-specified

0.28

2-sided

The PSA undetectable rate was defined as the percentage of participants with undetectable (< 0.2 ng/mL) PSA values at any time during study treatment, of those participants with detectable (≥ 0.2 ng/mL) PSA values at baseline. ITT with detectable PSA at baseline.

Secondary

Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

PSA Undetectable Rate Treatment Comparison

Enzalutamide + ADT v Placebo + ADT

1017

Pre-specified

50.5

2-sided

The ORR was calculated as the percentage of participants who achieved a completed response (CR) or a partial response (PR) (unconfirmed responses) in their soft tissue disease using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 assessed by ICR. ITT participants with measurable disease at baseline.

Secondary

Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

ORR Treatment Comparison

Placebo + ADT v Enzalutamide + ADT

359

Pre-specified

19.3

2-sided

In participants with deterioration, time to deterioration was calculated as the time interval between randomization and the first deterioration in urinary symptoms at any postbaseline visit. Deterioration in urinary symptoms was defined as an increase in the Quality of Life Prostate-specific Questionnaire(QLQ-PR25) modified urinary symptoms. Subscale score by ≥50% of the standard deviation observed in the QLQ-PR25 modified urinary symptoms subscale score at baseline. Modified urinary symptoms subscale score consisted of 3-items(Q31–Q33) from the QLQ-PR25,each scored from 1(not at all) to 4(very much). Total modified urinary symptoms subscale score ranges from 0-100,higher scores represents a higher level of symptomatology/problems. In participants without deterioration in urinary symptoms, the time to deterioration in urinary symptoms was censored on the date the last urinary symptoms QLQ-PR25 score was calculable. ITT. "99999" denotes data not reached due to low number of events.

Secondary

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to Deterioration of Urinary Symptoms Treatment Comparison

Placebo + ADT v Enzalutamide + ADT

1150

Pre-specified

0.88

2-sided

Time to first SSE was calculated as the time from randomization to the occurrence of the first SSE prior to the data analysis cut-off date. An SSE was defined as radiation to bone, surgery to bone, clinically apparent pathological bone fracture, or spinal cord compression. In participants with no SSE by the time of the data cut-off point, time to SSE was censored on the last visit date or the date of randomization, whichever occurred last. ITT population. "99999" denotes data not reached due to low number of events.

Secondary

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to SSE Treatment Comparison

Placebo + ADT v Enzalutamide + ADT

1150

Pre-specified

0.52

2-sided

Time to castration resistance was calculated as the time from randomization to the first castration-resistant event. A castration resistance event was defined as any of the following in the presence of castrate levels of testosterone (< 50 ng/dL): radiographic disease progression, PSA progression or SSE, whichever occurred first. In participants with no documented castration resistance event, the time to castration resistance was censored on the latest date from: the date of last radiologic assessment, the last PSA sample taken prior to the start of any new prostate cancer therapy and prior to 2 or more consecutive missed PSA assessments (if applicable), and the last visit date performed. ITT population. "99999" denotes data not reached due to low number of events.

Secondary

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to Castration Resistance Treatment Comparison

Enzalutamide + ADT v Placebo + ADT

1150

Pre-specified

0.28

2-sided

Time to deterioration of QoL was calculated as the time interval from the date of randomization to the first date a decline from baseline of 10 points or more in the FACT-P total score was recorded. The FACT-P consists of 27 core items that assess participant function in 4 domains and 12 prostate cancer-related items grouped into 5 subscales as follows: physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing and prostate cancer subscale. Each item is rated on a 0 to 4 Likert-type scale. The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0 to 156), where high score represent better quality of life. In participants without FACT-P progression, the time to deterioration of QoL was censored on the date of the last FACT-P total score was calculable. ITT population.

Secondary

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to Deterioration of QoL in FACT-P Treatment Comparison

Placebo + ADT v Enzalutamide + ADT

1150

Pre-specified

0.96

2-sided

Time to pain progression was defined as time from randomization to the first pain progression event. Pain progression was defined as an increase of ≥ 30% from baseline in the average BPI-SF pain severity score. BPI-SF contains 9 questions with rating scales from 0 (no pain/no interference) to 10 (worst pain/interferes completely). Total score was calculated as the average of each question. Higher scores represent a higher level of pain or interference. In participants with no pain progression event, time to pain progression was censored on the last visit date where BPI-SF was collected. ITT population.

Secondary

From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Time to Pain Progression Based on BPI-SF Treatment Comparison

Enzalutamide + ADT v Placebo + ADT

1150

Pre-specified

0.92

2-sided

From first dose of study drug up to 30 days after last dose of study or prior to initiation of new therapy for prostate cancer, whichever occurred first. Maximum duration of treatment to the data cut-off date of 14 October 2018 was 26.6 months.

Safety Analysis Set (SAF) consisted of all randomized participants who received at least one dose of study drug.

21

Enzalutamide + ADT

Placebo + ADT