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

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02007512
• Collaborator: Astellas Pharma Inc (Industry), Medivation, Inc. (Industry)
• Enrollment: 247
• Locations: 133
• Arms: 2
• Anticipated Duration (Months): 108.6
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if enzalutamide given in combination with exemestane is safe and effective in patients with advanced breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Enzalutamide; Drug: exemestane; Drug: Placebo (for enzalutamide); Drug: exemestane	Phase 2

Detailed Description

This is a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Efficacy and Safety of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer That Is Estrogen or Progesterone Receptor Positive and HER2-Normal.

Study Design

• Study Type: Interventional
• Actual Enrollment: 247 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF EFFICACY AND SAFETY OF ENZALUTAMIDE IN COMBINATION WITH EXEMESTANE IN PATIENTS WITH ADVANCED BREAST CANCER THAT IS ESTROGEN OR PROGESTERONE RECEPTOR-POSITIVE AND HER2-NORMAL
• Actual Study Start Date: Dec 13, 2013
• Actual Primary Completion Date: Sep 23, 2016
• Anticipated Study Completion Date: Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide & exemestane Enzalutamide 160 mg/day administered as four 40mg soft gelatin capsules by mouth once daily with or without food and exemestane 50mg (two 25mg tablets overencapsulated as a single capsule during the blinded portion of the study and two 25mg tablets after unblinding) once daily after food.	Drug: Enzalutamide; 160 mg/day administered as four 40mg soft gelatin capsules by mouth once daily with or without food.; Other Names: MDV3100 XTANDI ; Drug: exemestane; 50mg (two 25mg tablets overencapsulated as a single capsule during the blinded portion of the study and two 25mg tablets after unblinding) by mouth once daily after food.; Other Names: Aromasin
Active Comparator: Placebo & exemestane Placebo and exemestane 25mg (overencapsulated to match 50mg dose during the blinded portion of the study and one 25mg tablet without placebo after unblinding) once daily after food.	Drug: exemestane; 25mg (overencapsulated to match 50mg dose during the blinded portion of the study and one 25mg tablet after unblinding) by mouth once daily after food.; Other Names: Aromasin ; Drug: Placebo (for enzalutamide); Sugar pill manufactured to mimic enzalutamide administered as four soft gelatin capsules by mouth once daily with or without food.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS) [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)]

   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.

2. Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Interactive Web Recognition System (IWRS) [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)]

   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.

Secondary Outcome Measures

1. Clinical Benefit Rate-24 (CBR-24) [From randomization up to 3 years]

   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.

2. Best Objective Response Rate [From randomization until CR or PR, whichever occurred first (up to 3 years)]

   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.

3. Duration of Objective Response [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)]

   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.

4. Time to Response [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)]

   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.

5. Time to Progression [From randomization until PD or last tumor assessment without PD before new antitumor treatment initiation, whichever occurred first (up to 3 years)]

   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.

6. Progression Free Survival (PFS) at 6 Months [Month 6]

   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.

7. Concentration Versus Time Summary of Enzalutamide [Predose on Day 29, 57 and 113]

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

8. Concentration Versus Time Summary of Exemestane [Predose, 1 and 6 hour postdose on Day 29, 57, 113 and 169]

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

9. Concentration Versus Time Summary of N-desmethyl Enzalutamide [Predose on Day 29, 57 and 113]

   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.

Other Outcome Measures

1. European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30) [Month 24]

2. European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23) [Month 24]

3. Number of Participants With Positive Androgen Receptor (AR) Expression by Immunohistochemistry (IHC) [Day 1, 29, 57, 113 and 169]

4. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [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)]

   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.

5. Number of Participants With Treatment-Emergent Adverse Events of Grade 3 or Higher Severity [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)]

   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.

6. Number of Participants With Clinically Significant Vital Sign Abnormalities [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)]

   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.

7. Number of Participants With Clinically Significant Laboratory Abnormalities [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)]

   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.

8. Progression Free Survival (PFS): By Electronic Data Capture (EDC) [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)]

   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

9. Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Electronic Data Capture (EDC) [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)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Willing and able to provide informed consent;

• Postmenopausal;

• Advanced histologically confirmed breast cancer that is ER+, PgR+, or both, and HER-2 normal;

• Up to one prior hormone therapy and up to one prior chemotherapy in the advanced setting is allowed;

• Availability of a representative, formalin-fixed, paraffin-embedded tumor specimen that enabled the diagnosis of breast cancer with viable tumor cells in a tissue block or unstained serial slides accompanied bay an associated pathology report;

• Measurable disease. Patients with non-measurable bone or skin disease as their only manifestation of advanced breast cancer are also eligible;

• Eastern Cooperative Oncology Group (ECOG) status of 0 or 1;

Exclusion Criteria:

• Any severe concurrent disease, infection, or comorbid condition that renders the patient inappropriate for enrollment in the opinion of the investigator;

• Any condition or reason that interferes with the patient's ability to participate in the trial, that may cause undue risk, or complicates the interpretation of safety data, in the opinion of the investigator;

• Current or previously treated brain metastasis or leptomeningeal disease;

• Prior therapy (> 28 days) with exemestane in the metastatic setting (Patients receiving exemestane in the adjuvant setting and having disease recurrence more than 1 year after treatment discontinuation are eligible);

• Requires treatment for tuberculosis or HIV infection;

• Radiation therapy within 7 days before randomization;

• History of another invasive cancer within 5 years before randomization;

• History of seizure or any condition that may predispose to seizure;

• Clinically significant cardiovascular disease;

• Active gastrointestinal disorder;

• Major surgery within 28 days prior to randomization;

• Treatment with any oral anticancer or with any non-hormonal anticancer agent within 14 days before randomization;

• Treatment with any approved or investigational agent that blocks androgen synthesis or targets the androgen receptor;

• Treatments with any of the following medications within 14 days before randomization: Estrogens, Androgens, or Systemic radionuclides;

• Hypersensitivity reaction to exemestane.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ATTN-Research Pharmacist	Aurora	Colorado	United States	80045
2	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
3	University of Colorado Hospital, Anschutz Outpatient Pavilion	Aurora	Colorado	United States	80045
4	Rocky Mountain Cancer Centers	Colorado Springs	Colorado	United States	80907
5	Rocky Mountain Cancer Centers	Lakewood	Colorado	United States	80228
6	Rocky Mountain Cancer Centers	Lone Tree	Colorado	United States	80124
7	Florida Cancer Specialists	Altamonte Springs	Florida	United States	32701
8	Florida Cancer Specialists	Bonita Springs	Florida	United States	34135
9	Florida Cancer Specialists	Bradenton	Florida	United States	34209
10	Florida Cancer Specialists	Brandon	Florida	United States	33511
11	Florida Cancer Specialists	Cape Coral	Florida	United States	33909
12	Florida Cancer Specialists	Cape Coral	Florida	United States	33914
13	Florida Cancer Specialists	Clearwater	Florida	United States	33761
14	Florida Cancer Specialists	Englewood	Florida	United States	34223
15	Florida Cancer Specialists	Fort Myers	Florida	United States	33901
16	Florida Cancer Specialists	Fort Myers	Florida	United States	33905
17	Florida Cancer Specialists	Fort Myers	Florida	United States	33908
18	Florida Cancer Specialists	Gainesville	Florida	United States	32605
19	Florida Cancer Specialists	Hudson	Florida	United States	34667
20	Florida Cancer Specialists	Largo	Florida	United States	33770
21	Florida Cancer Specialists	Naples	Florida	United States	34102
22	Florida Cancer Specialists	New Port Richey	Florida	United States	34655
23	Florida Cancer Specialists	Orange City	Florida	United States	32763
24	Florida Cancer Specialists	Orlando	Florida	United States	32806
25	Florida Cancer Specialists	Port Charlotte	Florida	United States	33980
26	Florida Cancer Specialists	Saint Petersburg	Florida	United States	33705
27	Florida Cancer Specialists	Sarasota	Florida	United States	34232
28	Florida Cancer Specialists	Sarasota	Florida	United States	34236
29	Florida Cancer Specialists	Spring Hill	Florida	United States	34608
30	Florida Cancer Specialists	Tampa	Florida	United States	33607
31	Florida Cancer Specialists	Tavares	Florida	United States	32778
32	Florida Cancer Specialists	Venice	Florida	United States	34285
33	Florida Cancer Specialists	Venice	Florida	United States	34292
34	Northwestern Medical Faculty Foundation	Chicago	Illinois	United States	60611
35	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
36	The University of Chicago Medical Center,	Chicago	Illinois	United States	60637
37	The University of Chicago	Chicago	Illinois	United States	60637
38	University of Chicago Comprehensive Cancer Center at Silver Cross Hospital	New Lenox	Illinois	United States	60451
39	Indiana University Health Hospital	Indianapolis	Indiana	United States	46202
40	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
41	Investigational Drug Services	Indianapolis	Indiana	United States	46202
42	Sidney and Lois Eskenazi Hospital	Indianapolis	Indiana	United States	46202
43	Springmill Medical Clinic	Indianapolis	Indiana	United States	46290
44	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
45	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
46	Minnesota Oncology Hematology, P.A	Minneapolis	Minnesota	United States	55404
47	Abbott Northwestern Hospital	Minneapolis	Minnesota	United States	55407
48	Allina Health System DBA Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
49	Dr.Michaela Tsai	Minneapolis	Minnesota	United States	55407
50	The West Clinic, P.C.	Corinth	Mississippi	United States	38834
51	The West Clinic, P.C. d/b/a West Cancer Center	Southaven	Mississippi	United States	38671
52	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
53	Washington University Infusion Center Pharmacy	Saint Louis	Missouri	United States	63110
54	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
55	Siteman Cancer Center-South County	Saint Louis	Missouri	United States	63129
56	Siteman Cancer Center- West County	Saint Louis	Missouri	United States	63141
57	Siteman Cancer Center	Saint Peters	Missouri	United States	63376
58	Hematology Oncology Associates of Northern NJ	Morristown	New Jersey	United States	07962
59	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
60	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45202
61	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45211
62	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45230
63	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45236
64	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45242
65	Oncology Hematology Care, Inc.	Fairfield	Ohio	United States	45014
66	Greenville Health System	Greenville	South Carolina	United States	29605
67	Greenville Health System	Seneca	South Carolina	United States	29672
68	Greenville Health System	Spartanburg	South Carolina	United States	29307
69	The West Clinic, P.C. d/b/a West Cancer Center	Germantown	Tennessee	United States	38138
70	The West Clinic, P.C. d/b/a West Cancer Center	Memphis	Tennessee	United States	38104
71	The Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
72	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee	United States	37204
73	Vanderbilt Health Pharmacy One Hundred Oaks	Nashville	Tennessee	United States	37204
74	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37211
75	Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
76	Investigational Products Center (IPC)	Fort Worth	Texas	United States	76177
77	Investigational Products Center(IPC)	Fort Worth	Texas	United States	76177
78	Investigational Products center	Fort Worth	Texas	United States	76177
79	lnvestigational Products Center (IPC)	Fort Worth	Texas	United States	76177
80	Texas Oncology - Memorial City	Houston	Texas	United States	77024
81	Texas Oncology-Longview Cancer Center	Longview	Texas	United States	75601
82	Texas Oncology - Tyler	Tyler	Texas	United States	75702
83	Virginia Cancer Institute	Mechanicsville	Virginia	United States	23116-1844
84	Virginia Cancer Institute	Midlothian	Virginia	United States	23114
85	Virginia Cancer Institute	Richmond	Virginia	United States	23230
86	Virginia Cancer Institute	Richmond	Virginia	United States	23235-4730
87	UZA	Edegem	Antwerpen	Belgium	2650
88	GZA	Wilrijk	Antwerpen	Belgium	2610
89	Institut Jules Bordet	Brussels		Belgium	1000
90	Sunnybrook Research Institute	Toronto	Ontario	Canada	M4N 3M5
91	McGill University Health Center- Cedars Cancer Center	Montreal	Quebec	Canada	H4A 3J1
92	McGill University Health Centre - Cedars Cancer Centre	Montreal	Quebec	Canada	H4A 3J1
93	Institute for Cancer Research	Dublin 7		Ireland
94	Mater Private Hospital	Dublin 7		Ireland
95	Pharmacy Department	Dublin		Ireland	4
96	Radiology Department	Dublin		Ireland	4
97	St Vincent's University Hospital	Dublin		Ireland	4
98	Institute for Cancer Research	Dublin		Ireland	7
99	Mater Private Hospital	Dublin		Ireland	7
100	Pharmacy Department	Dublin		Ireland	7
101	Radiology Department	Dublin		Ireland	7
102	Cancer Clinical Trials Unit	Dublin		Ireland	D9
103	Pharmacy Department	Dublin		Ireland	D9
104	Radiology Department	Dublin		Ireland	D9
105	Pharmacy Department	Dublin		Ireland
106	Radiology Department	Dublin		Ireland
107	IRCCS Ospedale San Raffaele	Milano	MI	Italy	20132
108	Divisione di Senologia Medica; Istituto Europeo di Oncologia	Milano	MI	Italy	20141
109	A.O.di Perugia S. Maria Della Misericoridia	Perugia	PG	Italy	06132
110	Azienda Ospedaliera S.Orsola Malpighi	Bologna		Italy	40138
111	IRCCS Ospedale San Raffaele	Milano		Italy	20132
112	U.O. Farmaceutica, Nuovo Ospedale di Prato	Prato		Italy	59100
113	U.O. Oncologia Medica, Nuovo Ospedale di Prato	Prato		Italy	59100
114	Dipartimento di Oncologia Medica, Istituto Nazionale Tumori Regina Elena	Roma		Italy	00144
115	Hospital Universitario HM Monteprincipe	Boadilla del Monte	Madrid	Spain	28660
116	Grupo Hospitalario Quiron - Hospital Universitari Quiron Dexeus	Barcelona		Spain	08028
117	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
118	Hospital Universitario Ramon Y Cajal	Madrid		Spain	28034
119	Hospital Universitario 12 Octubre	Madrid		Spain	28041
120	Centro Integral Oncologico Clara Campal	Madrid		Spain	28050
121	Hospital de Madrid Norte Sanchinarro	Madrid		Spain	28050
122	Brighton and Sussex University Hospital NHS Trust	Brighton	England	United Kingdom	BN2 5BE
123	Pharmacy Department	Brighton	England	United Kingdom	BN2 5BE
124	Radiation Safety Service, Medical Physics Department	Brighton	England	United Kingdom	BN2 5BE
125	Histopathology Department	Nottingham	England	United Kingdom	NG5 1PB
126	Nottingham University Hospital	Nottingham	England	United Kingdom	NG5 1PB
127	Pharmacy Department	Nottingham	England	United Kingdom	NG5 1PB
128	Radiology Department	Nottingham	England	United Kingdom	NG5 1PB
129	Radiology Department	Nottingham	England	United Kingdom	NG7 2UH
130	Department of Radiology	Truro	England	United Kingdom	TR1 3LJ
131	Pharmacy Department	Truro	England	United Kingdom	TR1 3LJ
132	Royal Cornwall Hospitals NHS trust	Truro	England	United Kingdom	TR1 3LJ
133	Clinical Investigation & Research Unit	Brighton	Sussex	United Kingdom	BN2 5BE

Sponsors and Collaborators

• Pfizer
• Astellas Pharma Inc
• Medivation, Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02007512
• Other Study ID Numbers: MDV3100-12; 2013-002717-35; C3431008
• First Posted: Dec 10, 2013
• Last Update Posted: May 19, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Pfizer: advanced breast cancer; enzalutamide; MDV3100; Estrogen receptor positive (ER +); Progesterone receptor positive (PgR +); HER-2 normal
• Additional relevant MeSH terms: Breast Neoplasms; Exemestane

Study Results

Participant Flow

Pre-assignment Detail	This was a phase 2, randomized, double blind, placebo-controlled study. The results disclosed in this draft were based on the data collected till 23 Sep 2016.

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Period Title: Double Blind Treatment Period
STARTED	63	64	60	60
Treated	62	63	60	60
COMPLETED	0	0	0	0
NOT COMPLETED	63	64	60	60
Period Title: Double Blind Treatment Period
STARTED	0	21	0	12
COMPLETED	0	0	0	0
NOT COMPLETED	0	21	0	12

Baseline Characteristics

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg	Total
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Total of all reporting groups
Overall Participants	63	64	60	60	247
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	42 66.7%	32 50%	37 61.7%	40 66.7%	151 61.1%
>=65 years	21 33.3%	32 50%	23 38.3%	20 33.3%	96 38.9%
Sex: Female, Male (Count of Participants)
Female	63 100%	64 100%	60 100%	60 100%	247 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS)
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	63	64	60	60
Median (95% Confidence Interval) [months]	11.8	5.8	3.6	3.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 1: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3631
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.820
	Confidence Interval	(2-Sided) 95%; 0.535 to 1.257
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 2: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9212
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.022
	Confidence Interval	(2-Sided) 95%; 0.659 to 1.586
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Interactive Web Recognition System (IWRS)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	24	26	15	20
Median (95% Confidence Interval) [months]	16.5	4.3	6.0	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 1: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0335
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.442
	Confidence Interval	(2-Sided) 95%; 0.205 to 0.955
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 2: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1936
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.554
	Confidence Interval	(2-Sided) 95%; 0.225 to 1.363
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Clinical Benefit Rate-24 (CBR-24)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	63	64	60	60
Number (95% Confidence Interval) [percentage of participants]	61.9 98.3%	45.3 70.8%	20.0 33.3%	31.7 52.8%

4. Secondary Outcome

Title	Best Objective Response Rate
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	39	42	42	42
Number (95% Confidence Interval) [percentage of participants]	30.8 48.9%	19.0 29.7%	9.5 15.8%	4.8 8%

5. Secondary Outcome

Title	Duration of Objective Response
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	39	42	42	42
Median (95% Confidence Interval) [months]	14.0	9.1	18.3	4.6

6. Secondary Outcome

Title	Time to Response
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	39	42	42	42
Median (95% Confidence Interval) [months]	12.9	14.0	NA	NA

7. Secondary Outcome

Title	Time to Progression
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	63	64	60	60
Median (95% Confidence Interval) [months]	11.8	7.4	3.6	3.9

8. Secondary Outcome

Title	Progression Free Survival (PFS) at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	63	64	60	60
Number (95% Confidence Interval) [percentage of participants]	66.7 105.9%	50.0 78.1%	31.5 52.5%	33.3 55.5%

9. Secondary Outcome

Title	Concentration Versus Time Summary of Enzalutamide
Description	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

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	Participants received enzalutamide 160 mg dose orally, once daily, either in double blind treatment period or in open label treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	114
Day 29	14.2 (2.97)
Day 57	14.2 (3.21)
Day 113	13.2 (4.51)

10. Secondary Outcome

Title	Concentration Versus Time Summary of Exemestane
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Exemestane 25 mg	Exemestane 50 mg
Arm/Group Description	Participants received exemestane 25 mg dose orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants received exemestane 50 mg dose orally, once daily until disease progression or permanent treatment discontinuation, either in double blind treatment period or in open label treatment period. Participants were followed-up until 30 days after the last dose of study drug, the date of death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	114	115
Day 29: Predose	1010 (1600)	943 (939)
Day 29: 1 hour Postdose	17000 (16400)	19200 (17800)
Day 29: 6 hour Postdose	5590 (4750)	6850 (9090)
Day 57: Predose	1160 (2590)	1100 (2650)
Day 57: 1 hour Postdose	19900 (18600)	15300 (14500)
Day 57: 6 hour Postdose	5890 (4880)	5650 (6200)
Day 113: Predose	1160 (2870)	1330 (3380)
Day 113: 1 hour Postdose	20800 (18100)	19400 (18500)
Day 113: 6 hour Postdose	3510 (3850)	5600 (5290)
Day 169: 1 hour Postdose	22800 (NA)
Day 169: 6 hour Postdose	6020 (NA)

11. Secondary Outcome

Title	Concentration Versus Time Summary of N-desmethyl Enzalutamide
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Enzalutamide 160 mg
Arm/Group Description	Participants received enzalutamide 160 mg dose orally, once daily, either in double blind treatment period or in open label treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	114
Day 29	11.6 (4.10)
Day 57	15.2 (4.76)
Day 113	15.2 (5.81)

12. Other Pre-specified Outcome

Title	European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30)
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23)
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Number of Participants With Positive Androgen Receptor (AR) Expression by Immunohistochemistry (IHC)
Time Frame	Day 1, 29, 57, 113 and 169

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	0	0	0	0

15. Other Pre-specified Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	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 (up to 3 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	62	63	60	60
AEs	59 93.7%	58 90.6%	58 96.7%	53 88.3%
SAEs	15 23.8%	12 18.8%	10 16.7%	8 13.3%

16. Other Pre-specified Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events of Grade 3 or Higher Severity
Description	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 (up to 3 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	62	63	60	60
Number [participants]	20 31.7%	15 23.4%	22 36.7%	12 20%

17. Other Pre-specified Outcome

Title	Number of Participants With Clinically Significant Vital Sign Abnormalities
Description	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 (up to 3 years)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	62	63	60	60
Blood pressure	36 57.1%	39 60.9%	43 71.7%	24 40%
Heart rate	0 0%	2 3.1%	0 0%	0 0%

18. Other Pre-specified Outcome

Title	Number of Participants With Clinically Significant Laboratory Abnormalities
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	62	63	60	60
Number [participants]	0 0%	0 0%	0 0%	0 0%

19. Other Pre-specified Outcome

Title	Progression Free Survival (PFS): By Electronic Data Capture (EDC)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	62	64	61	60
Median (95% Confidence Interval) [months]	11.8	5.8	3.6	3.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 1: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7378
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.928
	Confidence Interval	(2-Sided) 95%; 0.599 to 1.438
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 2: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8817
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.968
	Confidence Interval	(2-Sided) 95%; 0.632 to 1.483
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Other Pre-specified Outcome

Title	Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Electronic Data Capture (EDC)
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 1: Placebo + Exemestane 25 mg	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg	Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.	Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
Measure Participants	23	26	16	20
Median (95% Confidence Interval) [months]	16.9	4.3	6.0	5.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 1: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1270
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.522
	Confidence Interval	(2-Sided) 95%; 0.224 to 1.217
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg, Cohort 2: Placebo + Exemestane 25 mg
	Comments	Hazard ratio was based on stratified Cox regression model.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0359
	Comments
	Method	Stratified log-rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.370
	Confidence Interval	(2-Sided) 95%; 0.143 to 0.961
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

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)
Adverse Event Reporting Description	Same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study. AEs and SAEs were collected for safety population.
Arm/Group Title	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 1: Placebo + Exemestane 25 mg		Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 2: Placebo + Exemestane 25 mg
Arm/Group Description	Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.		Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.		Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.		Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
All Cause Mortality
	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 1: Placebo + Exemestane 25 mg		Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 2: Placebo + Exemestane 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 1: Placebo + Exemestane 25 mg		Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 2: Placebo + Exemestane 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/62 (24.2%)		12/63 (19%)		10/60 (16.7%)		8/60 (13.3%)
Blood and lymphatic system disorders
ANAEMIA	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
THROMBOCYTOPENIA	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
Cardiac disorders
CARDIAC FAILURE CONGESTIVE	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
Gastrointestinal disorders
FAECES DISCOLOURED	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
GASTROINTESTINAL HAEMORRHAGE	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
INTESTINAL OBSTRUCTION	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
OESOPHAGEAL STENOSIS	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
VOMITING	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
General disorders
ASTHENIA	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
CHILLS	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
DISEASE PROGRESSION	0/62 (0%)		1/63 (1.6%)		1/60 (1.7%)		0/60 (0%)
FACIAL PAIN	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
FATIGUE	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
GENERAL PHYSICAL HEALTH DETERIORATION	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
INFLUENZA LIKE ILLNESS	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
NON-CARDIAC CHEST PAIN	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
PAIN	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
Hepatobiliary disorders
CHOLECYSTITIS	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
HEPATIC HAEMORRHAGE	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
Immune system disorders
ANAPHYLACTIC REACTION	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
DRUG HYPERSENSITIVITY	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
Infections and infestations
BREAST CELLULITIS	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
PNEUMONIA	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
POSTOPERATIVE WOUND INFECTION	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
PYELONEPHRITIS	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
URINARY TRACT INFECTION	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
WOUND INFECTION	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
Injury, poisoning and procedural complications
FALL	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
HUMERUS FRACTURE	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		1/60 (1.7%)
LACERATION	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
OPTIC NERVE INJURY	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
RADIATION PNEUMONITIS	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
SPINAL COMPRESSION FRACTURE	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
TRAUMATIC HAEMORRHAGE	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
Metabolism and nutrition disorders
HYPERCALCAEMIA	2/62 (3.2%)		0/63 (0%)		2/60 (3.3%)		1/60 (1.7%)
HYPONATRAEMIA	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
HYPOPHOSPHATAEMIA	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
Musculoskeletal and connective tissue disorders
BACK PAIN	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
MASTICATION DISORDER	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
NECK PAIN	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
PAIN IN EXTREMITY	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
PATHOLOGICAL FRACTURE	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA PANCREAS	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
BREAST CANCER	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
BREAST CANCER METASTATIC	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
CONTRALATERAL BREAST CANCER	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
LYMPHANGIOSIS CARCINOMATOSA	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
MALIGNANT ASCITES	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
MALIGNANT PLEURAL EFFUSION	2/62 (3.2%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
METASTASES TO CENTRAL NERVOUS SYSTEM	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
METASTATIC PAIN	1/62 (1.6%)		1/63 (1.6%)		1/60 (1.7%)		0/60 (0%)
PLASMA CELL MYELOMA	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
Nervous system disorders
BRACHIAL PLEXOPATHY	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
CEREBROVASCULAR ACCIDENT	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
DIZZINESS	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
EMBOLIC STROKE	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
GRAND MAL CONVULSION	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
HAEMORRHAGE INTRACRANIAL	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
INTRACRANIAL HAEMATOMA	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
SPEECH DISORDER	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
SPINAL CORD COMPRESSION	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
STATUS EPILEPTICUS	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
SYNCOPE	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
Psychiatric disorders
DELIRIUM	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		0/60 (0%)
SUICIDAL IDEATION	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
Renal and urinary disorders
RENAL FAILURE	0/62 (0%)		0/63 (0%)		0/60 (0%)		1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	1/62 (1.6%)		1/63 (1.6%)		0/60 (0%)		1/60 (1.7%)
DYSPNOEA EXERTIONAL	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
PLEURAL EFFUSION	0/62 (0%)		1/63 (1.6%)		0/60 (0%)		1/60 (1.7%)
PULMONARY EMBOLISM	1/62 (1.6%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 1: Placebo + Exemestane 25 mg		Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg		Cohort 2: Placebo + Exemestane 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/62 (95.2%)		58/63 (92.1%)		58/60 (96.7%)		53/60 (88.3%)
Blood and lymphatic system disorders
ANAEMIA	4/62 (6.5%)		1/63 (1.6%)		6/60 (10%)		3/60 (5%)
Gastrointestinal disorders
CONSTIPATION	10/62 (16.1%)		7/63 (11.1%)		8/60 (13.3%)		8/60 (13.3%)
DIARRHOEA	12/62 (19.4%)		10/63 (15.9%)		6/60 (10%)		10/60 (16.7%)
DYSPEPSIA	1/62 (1.6%)		6/63 (9.5%)		5/60 (8.3%)		4/60 (6.7%)
NAUSEA	24/62 (38.7%)		10/63 (15.9%)		18/60 (30%)		11/60 (18.3%)
VOMITING	11/62 (17.7%)		7/63 (11.1%)		6/60 (10%)		3/60 (5%)
ABDOMINAL PAIN UPPER	0/62 (0%)		0/63 (0%)		4/60 (6.7%)		2/60 (3.3%)
ABDOMINAL PAIN	0/62 (0%)		0/63 (0%)		2/60 (3.3%)		4/60 (6.7%)
General disorders
ASTHENIA	10/62 (16.1%)		7/63 (11.1%)		6/60 (10%)		4/60 (6.7%)
FATIGUE	23/62 (37.1%)		21/63 (33.3%)		22/60 (36.7%)		13/60 (21.7%)
OEDEMA PERIPHERAL	0/62 (0%)		0/63 (0%)		2/60 (3.3%)		3/60 (5%)
PAIN	0/62 (0%)		0/63 (0%)		0/60 (0%)		3/60 (5%)
PYREXIA	0/62 (0%)		0/63 (0%)		0/60 (0%)		3/60 (5%)
Infections and infestations
URINARY TRACT INFECTION	0/62 (0%)		0/63 (0%)		1/60 (1.7%)		4/60 (6.7%)
NASOPHARYNGITIS	0/62 (0%)		0/63 (0%)		3/60 (5%)		1/60 (1.7%)
UPPER RESPIRATORY TRACT INFECTION	2/62 (3.2%)		4/63 (6.3%)		1/60 (1.7%)		3/60 (5%)
INFLUENZA	2/62 (3.2%)		4/63 (6.3%)		0/60 (0%)		0/60 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/62 (0%)		0/63 (0%)		2/60 (3.3%)		4/60 (6.7%)
ASPARTATE AMINOTRANSFERASE INCREASED	0/62 (0%)		4/63 (6.3%)		2/60 (3.3%)		3/60 (5%)
WHITE BLOOD CELL COUNT DECREASED	0/62 (0%)		0/63 (0%)		3/60 (5%)		1/60 (1.7%)
Metabolism and nutrition disorders
DECREASED APPETITE	6/62 (9.7%)		6/63 (9.5%)		6/60 (10%)		2/60 (3.3%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	14/62 (22.6%)		11/63 (17.5%)		10/60 (16.7%)		7/60 (11.7%)
BACK PAIN	11/62 (17.7%)		5/63 (7.9%)		4/60 (6.7%)		12/60 (20%)
BONE PAIN	2/62 (3.2%)		4/63 (6.3%)		5/60 (8.3%)		2/60 (3.3%)
MUSCULOSKELETAL CHEST PAIN	7/62 (11.3%)		4/63 (6.3%)		2/60 (3.3%)		3/60 (5%)
MUSCULOSKELETAL PAIN	7/62 (11.3%)		1/63 (1.6%)		0/60 (0%)		0/60 (0%)
MYALGIA	0/62 (0%)		0/63 (0%)		0/60 (0%)		4/60 (6.7%)
PAIN IN EXTREMITY	8/62 (12.9%)		8/63 (12.7%)		3/60 (5%)		5/60 (8.3%)
MUSCULOSKELETAL STIFFNESS	0/62 (0%)		0/63 (0%)		3/60 (5%)		1/60 (1.7%)
Nervous system disorders
DIZZINESS	8/62 (12.9%)		4/63 (6.3%)		5/60 (8.3%)		2/60 (3.3%)
HEADACHE	9/62 (14.5%)		6/63 (9.5%)		9/60 (15%)		10/60 (16.7%)
PARAESTHESIA	4/62 (6.5%)		2/63 (3.2%)		0/60 (0%)		0/60 (0%)
NEUROPATHY PERIPHERAL	4/62 (6.5%)		3/63 (4.8%)		0/60 (0%)		0/60 (0%)
AMNESIA	4/62 (6.5%)		0/63 (0%)		0/60 (0%)		0/60 (0%)
DISTURBANCE IN ATTENTION	0/62 (0%)		0/63 (0%)		3/60 (5%)		0/60 (0%)
COGNITIVE DISORDER	0/62 (0%)		0/63 (0%)		3/60 (5%)		1/60 (1.7%)
SOMNOLENCE	0/62 (0%)		0/63 (0%)		3/60 (5%)		0/60 (0%)
Psychiatric disorders
ANXIETY	7/62 (11.3%)		4/63 (6.3%)		0/60 (0%)		0/60 (0%)
INSOMNIA	5/62 (8.1%)		4/63 (6.3%)		5/60 (8.3%)		4/60 (6.7%)
DEPRESSED MOOD	0/62 (0%)		0/63 (0%)		4/60 (6.7%)		0/60 (0%)
DEPRESSION	0/62 (0%)		0/63 (0%)		3/60 (5%)		3/60 (5%)
Respiratory, thoracic and mediastinal disorders
COUGH	9/62 (14.5%)		6/63 (9.5%)		2/60 (3.3%)		4/60 (6.7%)
DYSPNOEA	9/62 (14.5%)		7/63 (11.1%)		5/60 (8.3%)		5/60 (8.3%)
OROPHARYNGEAL PAIN	4/62 (6.5%)		2/63 (3.2%)		0/60 (0%)		0/60 (0%)
Skin and subcutaneous tissue disorders
ALOPECIA	8/62 (12.9%)		3/63 (4.8%)		5/60 (8.3%)		2/60 (3.3%)
RASH	0/62 (0%)		0/63 (0%)		3/60 (5%)		0/60 (0%)
Vascular disorders
HOT FLUSH	19/62 (30.6%)		14/63 (22.2%)		14/60 (23.3%)		9/60 (15%)
HYPERTENSION	6/62 (9.7%)		4/63 (6.3%)		0/60 (0%)		0/60 (0%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.