Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Prostatic Neoplasms

Disease Progression

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Docetaxel

Prednisolone

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Tubulin Modulators

Antimitotic Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2, confirmation of ineligibility for period 2, intolerable toxicity, withdrawal, or death. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 milligrams per square meter (mg/m\^2) in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB period 2. Docetaxel and prednisolone were administered up to 10 cycles (3 weeks/cycle) or more as assessed by the investigator. Enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death. Participants could continue the extension period, until investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death.

Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2, confirmation of ineligibility for period 2, intolerable toxicity, withdrawal, or death. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in period 2. Docetaxel and prednisolone were administered up to 10 cycles (3 weeks/cyle) or more as assessed by the investigator. Enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death. Participants could continue the extension period, until investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death.

Enzalutamide

Placebo

Medical Director

The purpose of the study was to understand if there was benefit in continued treatment with a medicine called enzalutamide, when starting treatment with docetaxel and prednisolone (a standard chemotherapy for prostate cancer), after the prostate cancer had gotten worse when treated with enzalutamide alone.

The study was conducted in consecutive periods of open label treatment with enzalutamide followed by randomized double-blind treatment with continued enzalutamide or placebo, in combination with docetaxel and prednisolone.

Open Label (Period 1)

Participants received open label treatment (OL) with enzalutamide. At week 13, all participants were assessed by prostate-specific antigen (PSA) and imaging. Participants with no confirmed PSA response or evidence of radiographic progression were ineligible for participation in Period 2 and typically had safety follow up; however, Period 1 treatment continued for some participants as long as the investigator considered it to be of clinical benefit (stopping on initiation of any new antineoplastic therapy). Participants with confirmed PSA response continued Period 1 until disease progression.

Enrollment to Period 2 ceased after approximately 274 participants had been enrolled or 182 primary endpoint events had been reached, whichever occurred first. Participants who were not randomized into period 2 at this time continued to receive open label treatment in an extension period.

Randomization (Double Blind \[DB\]) (Period 2)

Participants with confirmed disease progression on enzalutamide alone who continued to meet all eligibility criteria proceeded to randomization. Treatment allocation was in a 1:1 ratio, stratified by disease progression in Period 1 to the following treatments:

* Enzalutamide with docetaxel and prednisolone
* Placebo with docetaxel and prednisolone

Any ongoing participants in Period 2 at the point of unblinding in the enzalutamide+docetaxel arm that were still receiving and benefitting from enzalutamide treatment, had the option to continue treatment via an extension period.

A Study to Assess the Benefit of Treatment Beyond Progression With Enzalutamide in Men Who Are Starting Treatment With Docetaxel After Worsening of Their Prostate Cancer When Taking Enzalutamide Alone

A Randomized, Double Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer Patients Treated With Docetaxel Plus Prednisolone Who Have Progressed on Enzalutamide Alone

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

PFS: time from randomization (Period 2 Week 1) to earliest progression event. Progression is defined as radiographic progression, unequivocal clinical progression, or death on study. Radiographic progression is defined for bone disease by appearance of ≥ 2 new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that needs to be confirmed in the next assessment (i.e., progressive disease in the next assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unequivocal clinical progression is defined as new onset cancer pain requiring chronic administration of opiate analgesia or deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to ≥ 3, or initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression.

Time to PSA progression, defined as the time from randomization (Period 2 Week 1) to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later.

PSA response, defined as a decrease in percentage change from randomization (Period 2 Week 1) of 50% or more. PSA response was derived at Week 13 and at any time after randomization in Period 2. PSA response at any time is defined as a decrease in percentage change from randomization (Period 2 Week 1) at any time after randomization of 50% or more. Percentage of participants with PSA response was reported.

ORR, defined as the best overall radiographic response after randomization (Period 2 Week 1) as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in participants who had a measurable tumor. ORR was reported as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

The time to an increase of \>=30% from randomization (Period 2 Week 1) in average BPI-SF item scores (items 3, 4, 5, 6) at two consecutive evaluations \>=3 weeks apart without decrease in analgesic score according to the World health Organization (WHO). Only participants with an average pain intensity item score \>=4 were considered. The BPI-SF was an instrument to document pain-related functional impairment and contains 7 questions which included pain intensity \[(items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, with scales from 0 (no pain) to 10 (pain as bad as you can imagine)\] and pain interference \](items 9A to 9G): general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with scales from 0 (does not interfere) to 10 (completely interferes)\]. The BPI-SF total score for pain intensity was calculated as the mean of the 4 scores for the 4 items of pain intensity.

Time to opiate use for cancer-related pain, defined as the time from randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia \[parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks\].

Time to first SRE, defined as the time from randomization (Period 2 Week 1) to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.

FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer participants. It consists of 27 core items which assess participant function in four domains rated on 0 to 4 Likert-type scale: physical well-being (PWB) (7 items; 0 \[worst\] to 4 \[better\], score range 0-28), social/family well-being (SWB) (7 items; 0 \[worst\] to 4 \[better\], score range 0-28), emotional well-being (EWB) (6 items; 0 \[worst\] to 4 \[better\], score range 0-24), and functional well-being (FWB) (7 items; 0 \[worst\] to 4 \[better\], score range 0-28), which is further supplemented by 12 site-specific items to assess for prostate-related symptoms (Prostate Cancer Subscale \[PCS\] 12 items rated on Likert-type scale 0 \[worst\] to 4 \[better\], score range 0-48). The total domain scores and PCS subscale score are then combined to a global quality of life score ranging between 0 to 156; higher scores representing better quality of life.

The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are labelled from 0 (worst health imaginable) to 100 (best health imaginable).

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Astellas Pharma Europe Ltd.

Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first.

Period 1: Enzalutamide

Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

Period 2: Enzalutamide

Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

Period 2: Placebo

Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules/placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

Age, Continuous

Sex: Female, Male

Race

Race/Ethnicity, Customized

Safety Analysis Set 1 included all participants who received at least one dose of investigational medicinal product (IMP) in period 1.

Clinical Trial Disclosure

Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.

The Full Analysis Set (FAS) consisted of all participants who were randomized and received at least one dose of IMP.

Progression Free Survival (PFS)

Time to Prostate-specific Antigen (PSA) Progression

Week 13

Any time after randomization (median of 35 weeks)

Prostate-specific Antigen (PSA) Response

Objective Response Rate (ORR)

Data was not estimable as none of the participants met the criteria for pain progression

Time to Pain Progression

Data was not estimable as none of the participants had cancer-related pain.

Time to Opiate Use for Cancer-related Pain

Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first

Time to First Skeletal-related Event (SRE)

EWB: Baseline

EWB: Change at Week 1

EWB: Change at Week 13

EWB: Change at Week 25

EWB: Change at Week 37

EWB: Change at Week 49

EWB: Change at Week 61

EWB: Change at Week 73

EWB: Change at Week 85

EWB: Change at Week 97

EWB: Change at Week 109

EWB: Change at Week 121

EWB: Change at Week 133

EWB: Change at Week 145

EWB: Change at Week 157

EWB: Change at Week 169

EWB: Change at Week 181

FWB: Baseline

FWB: Change at Week 1

FWB: Change at Week 13

FWB: Change at Week 25

FWB: Change at Week 37

FWB: Change at Week 49

FWB: Change at Week 61

FWB: Change at Week 73

FWB: Change at Week 85

FWB: Change at Week 97

FWB: Change at Week 109

FWB: Change at Week 121

FWB: Change at Week 133

FWB: Change at Week 145

FWB: Change at Week 157

FWB: Change at Week 169

FWB: Change at Week 181

Global Score: Baseline

Global Score: Change at Week 1

Global Score: Change at Week 13

Global Score: Change at Week 25

Global Score: Change at Week 37

Global Score: Change at Week 49

Global Score: Change at Week 61

Global Score: Change at Week 73

Global Score: Change at Week 85

Global Score: Change at Week 97

Global Score: Change at Week 109

Global Score: Change at Week 121

Global Score: Change at Week 133

Global Score: Change at Week 145

Global Score: Change at Week 157

Global Score: Change at Week 169

Global Score: Change at Week 181

PWB: Baseline

PWB: Change at Week 1

PWB: Change at Week 13

PWB: Change at Week 25

PWB: Change at Week 37

PWB: Change at Week 49

PWB: Change at Week 61

PWB: Change at Week 73

PWB: Change at Week 85

PWB: Change at Week 97

PWB: Change at Week 109

PWB: Change at Week 121

PWB: Change at Week 133

PWB: Change at Week 145

PWB: Change at Week 157

PWB: Change at Week 169

PWB: Change at Week 181

PCS: Baseline

PCS: Change at Week 1

PCS: Change at Week 13

PCS: Change at Week 25

PCS: Change at Week 37

PCS: Change at Week 49

PCS: Change at Week 61

PCS: Change at Week 73

PCS: Change at Week 85

PCS: Change at Week 97

PCS: Change at Week 109

PCS: Change at Week 121

PCS: Change at Week 133

PCS: Change at Week 145

PCS: Change at Week 157

PCS: Change at Week 169

PCS: Change at Week 181

SWB: Baseline

SWB: Change at Week 1

SWB: Change at Week 13

SWB: Change at Week 25

SWB: Change at Week 37

SWB: Change at Week 49

SWB: Change at Week 61

SWB: Change at Week 73

SWB: Change at Week 85

SWB: Change at Week 97

SWB: Change at Week 109

SWB: Change at Week 121

SWB: Change at Week 133

SWB: Change at Week 145

SWB: Change at Week 157

Participants in the FAS population with available data were analyzed.

Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)

Baseline

Change at Week 1

Change at Week 13

Change at Week 25

Change at Week 37

Change at Week 49

Change at Week 61

Change at Week 73

Change at Week 85

Change at Week 97

Change at Week 109

Change at Week 121

Change at Week 133

Change at Week 145

Change at Week 157

Change at Week 169

Change at Week 181

Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)

Spots Global Cancer Trial Database for chemotherapy naïve metastatic castration resistant prostate cancer