Efficacy and Safety Study of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer

PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD according to RECIST 1.1, was defined as \>= 20% increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first.

Time frame: From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)

Population: Dx+ population: Subset of ITT population, defined prior to the first unblinded analysis as meeting the threshold for diagnostic score based on ribonucleic acid (RNA) sequencing data from tumor tissue. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

PFS was defined as the time in months from randomization to the first documentation of progression of disease (PD) or death on study due to any cause, whichever occurred first. PD according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) was defined as greater than or equal to (\>=) 20 percent (%) increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first.

Time frame: From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)

Population: ITT population included all the participants randomly assigned to double-blind study treatment.

Best objective response rate: Percentage of participants with measurable disease and with a best response of CR or PR according to RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (\<10 mm short axis). PR: Atleast 30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. Response evaluation was based on investigators' judgment.

Time frame: From randomization until CR or PR, whichever occurred first (up to 3 years)

Population: ITT population included all the participants randomly assigned to double-blind study treatment. Here 'Number of participants analyzed' signifies participants with measurable response.

CBR-24: Percentage of participants with a best response of complete response (CR), partial response (PR), or stable disease (SD) sustained for atleast 24 weeks, as determined by investigator using RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (less than \[\<\] 10 millimeter \[mm\] short axis). PR: \>=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during study as reference. PD: \>=20% increase (an absolute increase of \>=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions.

Time frame: From randomization up to 3 years

Population: ITT population included all the participants randomly assigned to double-blind study treatment.

Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero.

Time frame: Predose on Day 29, 57 and 113

Population: Pharmacokinetic (PK) population for enzalutamide included all participants in safety population who received any amount of enzalutamide and had at least 1 reportable concentration value for enzalutamide or its active metabolite (N-desmethyl enzalutamide).

Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero.

Time frame: Predose, 1 and 6 hour postdose on Day 29, 57, 113 and 169

Population: PK population for exemestane was defined as all participants in the safety population who received any amount of exemestane and had at least 1 reportable plasma concentration value for exemestane.

N-desmethyl enzalutamide was the active metabolite of enzalutamide. Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero.

Time frame: Predose on Day 29, 57 and 113

Population: PK population for N-desmethyl enzalutamide included all the participants in safety population who received any amount of enzalutamide and had at least 1 reportable concentration value for N-desmethyl enzalutamide.

Duration of objective response: Time from first documentation of CR or PR, to the first documentation of PD or death due to any cause, whichever occurred first as determined by investigator using RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (\<10 mm short axis). PR: \>=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. PD: \>=20% increase (an absolute increase of \>=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. Participants with no PD or death (after initial CR or PR) at the analysis date were censored at last tumor assessment date prior to date of new antitumor treatment or data cutoff.

Time frame: From first documentation of CR or PR until PD, or last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)

Population: ITT population included all the participants randomly assigned to double-blind study treatment. Here 'Number of participants analyzed' signifies participants evaluable for this outcome measure.

PFS at 6 months was defined as the percentage of participants with no event of disease progression at Month 6 landmark, estimated by Kaplan-Meier methods. PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD: \>=20% increase (an absolute increase of \>=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. The analysis of PFS was based on investigator assessment of disease progression.

Time frame: Month 6

Population: ITT population included all the participants randomly assigned to double-blind study treatment.

Time to progression was defined as the time from the date of randomization to PD defined by the investigator using RECIST 1.1. PD: \>=20% increase (an absolute increase of \>=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. Participants who did not experience disease progression, time to progression was right censored at the date of the last tumor assessment prior to data cutoff or date of new antitumor treatment, whichever occurred first.

Time frame: From randomization until PD or last tumor assessment without PD before new antitumor treatment initiation, whichever occurred first (up to 3 years)

Population: ITT population included all the participants randomly assigned to double-blind study treatment.

Time to response: Time from randomization to first documentation of CR or PR. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (\<10 mm short axis). PR: \>=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. PD: \>=20% increase (an absolute increase of \>=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. Participants who were not known to have had a CR or PR were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first.

Time frame: From randomization until first documentation of CR or PR, or last tumor assessment without PD or death prior to new antitumor treatment initiation, whichever occurred first (up to 3 years)

Population: ITT population included all the participants randomly assigned to double-blind study treatment. Here 'Number of participants analyzed' signifies participants evaluable for this outcome measure.

EORTC QLQ-BR23 was disease-specific module for breast cancer developed as supplement for EORTC QLQ-C30 that assessed quality of life of participants with breast cancer.Participants self-rated on frequent symptoms or problems reported by participants with breast cancer,e.g., pain/discomfort, body satisfaction, and self-esteem during past week by choosing 1 of 4 possible responses that recorded level of intensity (not at all, a little, quite a bit, and very much) within each dimension.Raw scores were then transformed to 0-100 scale for analysis and interpretation, where higher scores=more level of intensity, as per EORTC guidelines.Participants also self-rated on sexual health/interest during last 4 weeks using same scale. In this outcome measure body image functioning, sexual functioning, systemic therapy side effects, upset by hair loss parameters were assessed by EORTC QLQ-BR23 questionnaire,total score for each parameter ranged from 0-100,where higher scores=more level of intensity.

Time frame: Baseline; Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133

Population: ITT population included all the participants randomly assigned to double-blind study treatment. Here, Overall Number of Participants Analyzed contributed data to table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for the specified rows and value as 0 indicated no participants filled the questionnaire for the specified reporting group at specified timepoint.

The EORTC QLQ-C30 questionnaire was a standardized instrument developed to assess the quality of life of people with cancer. Participants self-rated their self-care, activity level, pain/discomfort, and mental health during the past week by choosing 1 of 4 possible responses that recorded the level of intensity (not at all, a little, quite a bit, and very much) within each dimension, where higher score=more level of intensity. The questionnaire also asked the participants to rate their overall health or quality of life within the past week on a scale of 1 to 7, where 1 is very poor and 7 is excellent. Higher global health or quality of life scores indicated better overall health or quality of life. In this outcome measure, global health/quality of life scores are presented.

Time frame: Baseline; Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133

Population: ITT population included all the participants randomly assigned to double-blind study treatment. Here, Overall Number of Participants Analyzed contributed data to table but may not have evaluable data for every row and Number Analyzed signifies participants evaluable for the specified rows and value as 0 indicated no participants filled the questionnaire for the specified reporting group at specified timepoint.

Laboratory tests included hematology (hematocrit, hemoglobin, platelet count, red blood cell count, total neutrophils \[absolute\] and white blood cell count with differential) and serum chemistry (albumin, alkaline phosphatase, alanine aminotransferase \[ALT\], aspartate transaminase \[AST\], blood urea nitrogen and creatinine, calcium, sodium, potassium, chloride, glucose (non-fasting), lactate dehydrogenase, magnesium, phosphorus/phosphate, total bilirubin, total bicarbonate, total protein and uric acid). Clinically significant abnormality evaluation was based on clinical investigator's judgment.

Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 3 years)

Population: Safety population included all the participants who received study drug either in double blind or in open label treatment period.

Criteria for clinically significant vital sign abnormalities: Systolic blood pressure (SBP): absolute SBP \<90 millimeters of mercury (mmHg) and decrease from baseline (DFB) \>30 mmHg, absolute SBP\>180 mmHg and increase from baseline (IFB) \>40 mmHg, final visit or 2 consecutive visits SBP \>=20 mmHg change from baseline (CFB), most extreme post-baseline SBP \>=140 mmHg, most extreme post-baseline SBP \>=180 mmHg, most extreme SBP \>=140 mmHg and \>=20 mmHg CFB, most extreme SBP \>=180 mmHg and \>=20 mmHg CFB; diastolic blood pressure (DBP): absolute DBP \> 105 mmHg and IFB \>30 mmHg, absolute DBP \<50 mmHg and DFB \>20 mmHg, final visit or 2 consecutive visits DBP \>=15 mmHg CFB, most extreme post-baseline DBP \>=90 mmHg, most extreme post-baseline DBP \>=105 mmHg, most extreme DBP \>=90 mmHg and \>=15 mmHg CFB, most extreme DBP \>=105 mmHg and \>=15 mmHg CFB; heart rate \<50 beats per minute (BPM) and DFB \>20 BPM or heart rate \>120 BPM and IFB \>30 BPM.

Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (approximately up to 10.13 years)

Population: Safety population included all the participants who received study drug either in double blind or in open label treatment period.

Time frame: Day 1, 29, 57, 113 and 169

Population: Protocol of this study was amended and data for this outcome measure was not analyzed as per planned analysis.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious AEs.

Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (approximately up to 10.13 years)

Population: Safety population included all the participants who received study drug either in double blind or in open label treatment period.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Only the participants with treatment-emergent AEs of grade 3 (severe) or higher grade were reported in this outcome measure.

Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (approximately up to 10.13 years)

Population: Safety population included all the participants who received study drug either in double blind or in open label treatment period.

PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD according to RECIST 1.1 was defined \>=20 % increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. Cht 1: Enz + Exe = Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg; Cht 2: Enz + Exe= Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg

Time frame: From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)

Population: Analysis was performed on all randomized participants. Randomization to cohort was based on participant's exposure to advance setting hormonal therapy. Initial randomization was done by IWRS. Later, upon detailed data entry in EDC, it was determined 1 participant was incorrectly assigned to Cht1:Enz+Exe by IWRS,hence counted in Cht2:Enz+Exe by EDC.

PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD according to RECIST 1.1, was defined as \>= 20% increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first.

Time frame: From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)

Population: Dx+ population: Subset of ITT population, defined prior to the first unblinded analysis as meeting the threshold for diagnostic score based on ribonucleic acid (RNA) sequencing data from tumor tissue. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.