9785-CL-0222

Astellas Pharma Global Development, Inc. (APGD)

1 Astellas Way, Northbrook, United States, 60062

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), 800 888-7704, astellas.resultsdisclosure@astellas.com

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), 800 888-7704, astellas.resultsdisclosure@astellas.com

No

No

No

Final

16 Feb 2018

No

Yes

08 Nov 2017

No

The primary objective of this study was to determine the progression-free survival (PFS) of enzalutamide as compared to bicalutamide. All participants that entered the open-label period of the study received enzalutamide, including those that received biculatamide in the double-blind period.

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.

22 Mar 2011

No

Yes

Canada: 39

Belgium: 26

Denmark: 22

France: 32

Germany: 40

Romania: 15

United Kingdom: 86

United States: 115

375

221

0

0

0

0

0

0

92

260

23

Double-blind Period

Randomised - controlled

Yes

Enzalutamide

Capsule

Oral use

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

Bicalutamide

Tablet

Oral use

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

Open-label Period (all enzalutamide)

Non-randomised - controlled

Yes

Enzalutamide

Capsule

Oral use

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

Enzalutamide

Capsule

Oral use

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

Enzalutamide

Bicalutamide

Enzalutamide

Bicalutamide

OL Phase: Enzalutamide/Enzalutamide

OL Phase: Bicalutamide/Enzalutamide

Full Analysis Set (FAS)

The FAS consisted of all randomized participants.

Total Enzalutamide

Participants received enzalutamide in the double-blind and/or open-label period (including participants who switched from bicalutamide to enzalutamide).

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. FAS.

Primary

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.

The (unstratified) log-rank test with an overall significance level of 0.05 (two-sided) was used to compare the PFS of enzalutamide to bicalutamide. The (unstratified) Cox proportional hazards model was used to estimate the hazard ratio of enzalutamide to bicalutamide, calculate the corresponding two-sided 95% confidence intervals and test the hypothesis that the hazard ratio is equal to 1.

Enzalutamide v Bicalutamide

375

Pre-specified

0.44

2-sided

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. The analysis population consisted of the FAS.

Secondary

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.

Bicalutamide v Enzalutamide

375

Pre-specified

0.42

2-sided

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. The analysis population consisted of the FAS with available PSA data.

Secondary

Baseline to Week 13

Enzalutamide v Bicalutamide

334

Pre-specified

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. The analysis population consisted of the FAS with available PSA data.

Secondary

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.

Bicalutamide v Enzalutamide

342

Pre-specified

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. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.

Secondary

From randomization until 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.

Enzalutamide v Bicalutamide

375

Pre-specified

0.28

2-sided

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. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.

Secondary

From randomization until 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.

Bicalutamide v Enzalutamide

375

Pre-specified

5.07

2-sided

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. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.

Secondary

From randomization until 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.

Bicalutamide v Enzalutamide

375

Pre-specified

5.55

2-sided

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. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.

Secondary

From randomization until 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.

Enzalutamide v Bicalutamide

375

Pre-specified

7.01

2-sided

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. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.

Secondary

From randomization until 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.

Enzalutamide v Bicalutamide

375

Pre-specified

13.91

2-sided

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. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.

Secondary

From randomization until 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.

Enzalutamide v Bicalutamide

375

Pre-specified

0.51

2-sided

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. The analysis population consisted of the FAS.

Secondary

From randomization until 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.

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. The analysis population consisted of the safety analysis set (SAF), which consisted of all participants who had initiated at least 1 dose of study drug. TEAEs were defined as AEs that started or worsened after starting administration of study drug through end of the study (i.e., the treatment-emergent period).

Secondary

From initiation of study drug up to 30 days after last dose of study drug or the 30-day safety follow-up visit, whichever was last (Median duration of treatment was 11.6 months in enzalutamide arm and 5.8 in bicalutamide arm, 12.6 in the total arm).

From initiation of study drug start up to 30 days after last dose or 30-day safety follow-up visit, whichever was last. Median duration of treatment (months) DB Phase: Enzalutamide 11.6, Bicalutamide 5.8, OL Phase: Enza./Enza. 21.6, Bica./Enza. 20.9.

The total number of deaths (all causes) includes deaths reported after the time frame above.

16.1

DB Phase: Enzalutamide

DB Phase: Bicalutamide

OL Phase: Enzalutamide/Enzalutamide

OL Phase: Bicalutamide/Enzalutamide