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    Clinical Trial Results:
    A Phase II Randomised, Double-Blind, Parallel Cohort Study of Neoadjuvant Letrozole + GDC-0032 versus Letrozole + Placebo in Post-Menopausal Women with ER+/HER2-Primary Breast Cancer

    Summary
    EudraCT number
    		 2013-000568-28
    Trial protocol
    		 BE   DE   AT   CZ   PT   HU   IT   GB   ES   PL  
    Global end of trial date
    13 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2018
    First version publication date
    22 Mar 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO28888
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02273973
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Acroynm: LORELEI
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of taselisib plus letrozole (taselisib+L) versus placebo plus letrozole (placebo+L) in women with ER + /HER2- early stage breast cancer.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Nov 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Austria: 33
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    El Salvador: 6
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Guatemala: 6
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Panama: 3
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Spain: 78
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    334
    EEA total number of subjects
    239
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    176
    From 65 to 84 years
    158
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study recruited post-menopausal subjects with breast cancer in 22 countries from November 2014 to March 2017.

    Pre-assignment
    Screening details
    		 A total of 334 subjects were randomised: 166 subjects to the taselisib+L arm and 168 subjects to the placebo+L arm. One subject was randomised to the placebo+L arm but received taselisib+L in safety population.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental: Taselisib + Letrozole
    Arm description
    		 Subjects received 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Taselisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.

    Arm title
    		 Placebo Comparator: Placebo + Letrozole
    Arm description
    		 Subjects received 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks.

    Number of subjects in period 1
    		Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Started
    166
    168
    Completed
    157
    160
    Not completed
    9
    8
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    3
         Physician decision
    -
    1
         Adverse event, non-fatal
    4
    -
         Non-compliance
    1
    -
         Lost to follow-up
    -
    1
         Progression of disease
    -
    2
         Reason not specified
    -
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: Taselisib + Letrozole
    Reporting group description
    		 Subjects received 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.

    Reporting group title
    Placebo Comparator: Placebo + Letrozole
    Reporting group description
    		 Subjects received 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks.

    Reporting group values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole Total
    Number of subjects
    		 166 168 334
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ± 8.5 64.7 ± 8.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 166 168 334
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    		 143 140 283
        American Indian or Alaskan Native|
    		 11 11 22
        Asian|
    		 6 6 12
        Black or African American|
    		 1 5 6
        Multiple|
    		 1 0 1
        Other|
    		 3 6 9
        Missing|
    		 1 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino|
    		 36 48 84
        Not Hispanic or Latino|
    		 114 109 223
        Not Reported|
    		 13 10 23
        Unknown|
    		 3 1 4

    End points

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    End points reporting groups
    Reporting group title
    Experimental: Taselisib + Letrozole
    Reporting group description
    		 Subjects received 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.

    Reporting group title
    Placebo Comparator: Placebo + Letrozole
    Reporting group description
    		 Subjects received 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks.

    Subject analysis set title
    Taselisib + Letrozole
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.

    Subject analysis set title
    Placebo + Letrozole
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks.

    Primary: Percentage of Subjects With Objective Response (OR) by Centrally Assessed Breast Magnetic Resonance Imaging (MRI) via Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Version 1.1

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    End point title
    		 Percentage of Subjects With Objective Response (OR) by Centrally Assessed Breast Magnetic Resonance Imaging (MRI) via Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Version 1.1
    End point description
    Objective response rate (ORR) was defined as proportion of subjects achieving complete response (CR) or partial response (PR). As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Primary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    166
    168
    Units: percentage of subjects
        number (not applicable)
    50.0
    39.3
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.049
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    10.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 21.32

    Primary: Percentage of Subjects with Total Pathologic Complete Response (total pCR), Defined as Having pCR in Both Breast and Axilla, Using American Joint Committee on Cancer (AJCC) Staging System

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    End point title
    		 Percentage of Subjects with Total Pathologic Complete Response (total pCR), Defined as Having pCR in Both Breast and Axilla, Using American Joint Committee on Cancer (AJCC) Staging System
    End point description
    Total pCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( i.e., ypT0/Tis, ypN0 in the AJCC staging system, 7th edition). ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Primary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    166
    168
    Units: percentage of subjects
        number (not applicable)
    1.8
    0.6
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3698
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Response Rates
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 3.55

    Primary: Percentage of Subjects With OR by Centrally Assessed Breast MRI via mRECIST Version 1.1 in Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha (PIK3CA) Mutant (MT) Subjects

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    End point title
    		 Percentage of Subjects With OR by Centrally Assessed Breast MRI via mRECIST Version 1.1 in Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha (PIK3CA) Mutant (MT) Subjects
    End point description
    ORR was defined as proportion of participants achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Primary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    73
    79
    Units: percentage of subjects
        number (not applicable)
    56.2
    38.0
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0332
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    18.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.57
         upper limit
    		 33.81

    Primary: Percentage of Subjects With Total pCR , Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA MT Subjects

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    End point title
    		 Percentage of Subjects With Total pCR , Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA MT Subjects
    End point description
    Total pCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes (i.e., ypT0/Tis, ypN0 in the AJCC staging system, 7th edition). ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Primary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    73
    79
    Units: percentage of subjects
        number (not applicable)
    1.4
    0
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4803
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Response Rates
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 4.04

    Secondary: Percentage of Subjects With OR by Centrally Assessed Breast MRI via mRECIST Version 1.1 in PIK3CA Wildtype (WT) Subjects

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    End point title
    		 Percentage of Subjects With OR by Centrally Assessed Breast MRI via mRECIST Version 1.1 in PIK3CA Wildtype (WT) Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    92
    89
    Units: percentage of subjects
        number (not applicable)
    45.7
    40.4
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5017
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 19.61

    Secondary: Percentage of Subjects With Total pCR Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA WT Subjects

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    End point title
    		 Percentage of Subjects With Total pCR Defined as Having pCR in Both Breast and Axilla, Using AJCC Staging System in PIK3CA WT Subjects
    End point description
    Total pCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes (i.e., ypT0/Tis, ypN0 in the AJCC staging system, 7th edition). ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    92
    89
    Units: percentage of subjects
        number (not applicable)
    2.2
    1.1
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Response Rates
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 4.75

    Secondary: Percentage of Subjects With OR by Breast Ultrasound via mRECIST Version 1.1 in PIK3CA MT Subjects

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    End point title
    		 Percentage of Subjects With OR by Breast Ultrasound via mRECIST Version 1.1 in PIK3CA MT Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    73
    79
    Units: percentage of subjects
        number (not applicable)
    61.6
    40.5
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0115
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    21.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.59
         upper limit
    		 36.68

    Secondary: Percentage of Subjects With OR by Breast Ultrasound via mRECIST Version 1.1 in PIK3CA WT Subjects

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    End point title
    		 Percentage of Subjects With OR by Breast Ultrasound via mRECIST Version 1.1 in PIK3CA WT Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    92
    89
    Units: percentage of subjects
        number (not applicable)
    54.3
    51.7
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7928
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    2.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.88
         upper limit
    		 17.2

    Secondary: Percentage of Subjects With OR by Mammography via mRECIST Version 1.1 in PIK3CA MT Subjects

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    End point title
    		 Percentage of Subjects With OR by Mammography via mRECIST Version 1.1 in PIK3CA MT Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    73
    79
    Units: percentage of subjects
        number (not applicable)
    41.1
    31.6
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2659
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    9.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 24.7

    Secondary: Percentage of Subjects With OR by Mammography via mRECIST Version 1.1 in PIK3CA WT Subjects

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    End point title
    		 Percentage of Subjects With OR by Mammography via mRECIST Version 1.1 in PIK3CA WT Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    92
    89
    Units: percentage of subjects
        number (not applicable)
    40.2
    32.6
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3299
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    7.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.34
         upper limit
    		 21.6

    Secondary: Percentage of Subjects With OR by Clinical Breast Exam (Palpation) via mRECIST Version 1.1 in PIK3CA MT Subjects

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    End point title
    		 Percentage of Subjects With OR by Clinical Breast Exam (Palpation) via mRECIST Version 1.1 in PIK3CA MT Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    73
    79
    Units: percentage of subjects
        number (not applicable)
    74.0
    63.3
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1554
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    10.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.96
         upper limit
    		 25.32

    Secondary: Percentage of Subjects With OR by Clinical Breast Exam (Palpation) via mRECIST Version 1.1 in PIK3CA WT Subjects

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    End point title
    		 Percentage of Subjects With OR by Clinical Breast Exam (Palpation) via mRECIST Version 1.1 in PIK3CA WT Subjects
    End point description
    ORR was defined as proportion of subjects achieving CR or PR. As per modified RECIST v1.1, CR: disappearance of all target lesions, PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to 16 weeks
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    92
    89
    Units: percentage of subjects
        number (not applicable)
    62.0
    59.6
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.787
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.82
         upper limit
    		 16.63

    Secondary: Central Assessments of Changes in Ki67 levels

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    End point title
    		 Central Assessments of Changes in Ki67 levels
    End point description
    Ki67 is a prognostic marker and is used to evaluate the proliferative activity of breast cancer. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 3 and Surgery (Weeks 17-18); and Week 3 to Surgery (Weeks 17-18)
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    166
    168
    Units: percentage
    number (confidence interval 95%)
        From Baseline to Week 3
    -83.81 (-86.73 to -80.23)
    -80.44 (-83.93 to -76.19)
        From Baseline to Surgery
    -75.58 (-80.45 to -69.49)
    -80.51 (-84.41 to -75.64)
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for changes in Ki67 levels from Baseline to Week 3.
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.117
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of Least square mean
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.05
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Statistical analysis description
    Statistical analysis for changes in Ki67 levels from Baseline to Surgery.
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.105
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of Least square mean
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.65

    Secondary: Preoperative Endocrine Prognostic Index (PEPI ) Score

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    End point title
    		 Preoperative Endocrine Prognostic Index (PEPI ) Score
    End point description
    To obtain the PEPI score, risk points for relapse-free survival (RFS) and breast cancer-specific survival (BCSS) are assigned depending on the hazard ratio (HR) from the multivariable analysis. The total PEPI score assigned to each subject is the sum of the risk points derived from the primary tumor (pT) stage, regional lymph nodes (pN) stage, Ki67 level, and estrogen receptor status of the surgical specimen. A HR in the range of 1 to 2 receives one risk point; a HR in the 2 to 2.5 range, two risk points; a HR greater than 2.5, three risk points. The total risk point score for each participant is the sum of all the risk points accumulated from the four factors in the model, ranges from 0 (best possible outcome) to 12 (worst possible outcome). ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo). Here, 99999 indicates that the centrally derived PEPI score was not interpretable; therefore, analysis was not performed.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    149
    155
    Units: score on a scale
        number (not applicable)
    99999
    99999
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline to Surgery in Enhancing Tumor Volume as Measured by Breast MRI

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    End point title
    		 Percent Change from Baseline to Surgery in Enhancing Tumor Volume as Measured by Breast MRI
    End point description
    ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    From Baseline to Surgery (Weeks 17-18)
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    166
    168
    Units: percent change
        number (confidence interval 95%)
    -70.60 (-77.53 to -63.66)
    -57.28 (-64.21 to -50.35)
    Statistical analysis title
    		 Taselisib + Letrozole vs Placebo + Letrozole
    Comparison groups
    Experimental: Taselisib + Letrozole v Placebo Comparator: Placebo + Letrozole
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.002
    Method
    		 Regression, Linear
    Parameter type
    		 Least squares mean difference
    Point estimate
    -13.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.67
         upper limit
    		 -4.96

    Secondary: Mean Score for Health-Related Quality of Life Measured by the European Organization for Research C30 (EORTC QLQ-C30)

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    End point title
    		 Mean Score for Health-Related Quality of Life Measured by the European Organization for Research C30 (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30 includes 30 questions used to assess overall quality of life(QOL)in cancer subjects. The first 28 questions used a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) for evaluating 5 functional scales (physical, role, social, cognitive, emotional), 8 symptom scales/items (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea and vomiting, constipation and pain) and a single item (financial [fin.] difficulties). The last 2 questions, the subject’s assessment of overall health and quality of life, used a 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 global scores were linearly transformed on scale of 0 to 100, with high score indicating better QOL. Negative change from Baseline values indicated deterioration in QOL or functioning and positive values indicated improvement. Here, Post surgery= PS. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    166
    168
    Units: score on a scale
    arithmetic mean (standard deviation)
        Appetite Loss: Baseline (n=157,165)
    6.2 ± 16.4
    5.9 ± 14.2
        Appetite Loss: Change at Week 5 (n=155,160)
    3.0 ± 18.4
    1.9 ± 18.8
        Appetite Loss: Change at Week 9 (n=152,158)
    5.3 ± 21.4
    3.0 ± 17.8
        Appetite Loss: Change at Week 13 (n=152,157)
    5.5 ± 23.8
    2.1 ± 16.3
        Appetite Loss: Change at Week 16 (n=146,151)
    6.8 ± 24.1
    0.9 ± 16.3
        Appetite Loss: Change at PS Visit (n=140,146)
    5.0 ± 24.9
    5.0 ± 23.3
        Cognitive function: Baseline (n=158,163)
    90.8 ± 15.8
    90.9 ± 16.6
        Cognitive function: Change at Week 5 (n=154,157)
    0.4 ± 12.8
    -2.5 ± 12.3
        Cognitive function: Change at Week 9 (n=151,157)
    -1.1 ± 14.4
    -4.2 ± 14.7
        Cognitive function: Change at Week 13 (n=153,156)
    -3.4 ± 15.8
    -5.1 ± 15.7
        Cognitive function: Change at Week 16 (n=147,147)
    -4.2 ± 15.2
    -4.1 ± 17.5
        Cognitive function: Change at PS Visit (n=140,144)
    -3.1 ± 18.9
    -5.4 ± 16.8
        Constipation: Baseline (n=158,164)
    6.8 ± 15.9
    8.3 ± 18.2
        Constipation: Change at Week 5 (n=155,159)
    0.0 ± 16.1
    3.1 ± 22.1
        Constipation: Change at Week 9 (n=151,158)
    0.2 ± 17.0
    0.2 ± 18.6
        Constipation: Change at Week 13 (n=151,156)
    -0.4 ± 18.5
    -0.6 ± 19.5
        Constipation: Change at Week 16 (n=146,148)
    -1.1 ± 17.2
    1.6 ± 20.3
        Constipation: Change at PS Visit (n=140,145)
    4.8 ± 23.2
    1.1 ± 16.9
        Diarrhoea: Baseline (n=157,163)
    5.9 ± 14.9
    4.3 ± 11.8
        Diarrhoea: Change at Week 5 (n=154,155)
    6.7 ± 21.7
    -0.2 ± 13.4
        Diarrhoea: Change at Week 9 (n=150,157)
    6.4 ± 24.3
    0.8 ± 15.1
        Diarrhoea: Change at Week 13 (n=152,155)
    7.9 ± 22.3
    -0.4 ± 14.7
        Diarrhoea: Change at Week 16 (n=146,146)
    8.4 ± 23.1
    0.2 ± 16.4
        Diarrhoea: Change at PS Visit (n=140,144)
    0.2 ± 17.7
    -0.9 ± 15.7
        Dyspnoea: Baseline (n=157,165)
    7.4 ± 15.8
    8.5 ± 17.5
        Dyspnoea: Change at Week 5 (n=154,160)
    -0.2 ± 14.0
    0.6 ± 18.1
        Dyspnoea: Change at Week 9 (n=150,159)
    2.0 ± 17.4
    1.9 ± 19.9
        Dyspnoea: Change at Week 13 (n=151,157)
    3.5 ± 21.1
    1.7 ± 22.3
        Dyspnoea: Change at Week 16 (n=146,151)
    3.4 ± 20.2
    2.6 ± 22.6
        Dyspnoea: Change at PS Visit (n=138,146)
    3.1 ± 24.8
    2.1 ± 21.5
        Emotional function: Baseline (n=158,163)
    77.0 ± 20.4
    78.2 ± 19.9
        Emotional function: Change at Week 5 (n=154,157)
    4.2 ± 15.2
    2.4 ± 17.0
        Emotional function: Change at Week 9 (n=151,157)
    3.8 ± 14.7
    1.3 ± 20.7
        Emotional function: Change at Week 13 (n=153,156)
    2.5 ± 15.2
    -1.4 ± 18.6
        Emotional function: Change at Week 16 (n=147,147)
    1.0 ± 17.0
    -3.5 ± 20.2
        Emotional function: Change at PS Visit (n=140,144)
    -0.8 ± 19.0
    -3.6 ± 20.9
        Fatigue: Baseline (n=158,165)
    14.8 ± 18.7
    15.6 ± 18.5
        Fatigue: Change at Week 5 (n=155,161)
    4.7 ± 13.9
    4.9 ± 17.9
        Fatigue: Change at Week 9 (n=152,159)
    5.0 ± 15.9
    7.5 ± 20.3
        Fatigue: Change at Week 13 (n=151,158)
    7.9 ± 18.1
    8.8 ± 21.4
        Fatigue: Change at Week 16 (n=146,151)
    6.8 ± 17.5
    8.0 ± 20.4
        Fatigue: Change at PS Visit (n=140,146)
    12.3 ± 19.5
    12.4 ± 22.6
        Fin. difficulties: Baseline (n=156,160)
    9.0 ± 20.9
    10.0 ± 20.4
        Fin. difficulties: Change at Week 5 (n=152,154)
    -2.6 ± 14.6
    -0.4 ± 20.2
        Fin. difficulties: Change at Week 9 (n=151,153)
    -2.6 ± 17.9
    0.7 ± 20.4
        Fin. difficulties: Change at Week 13 (n=150,152)
    -1.1 ± 17.9
    0.0 ± 19.9
        Fin. difficulties: Change at Week 16 (n=145,144)
    -1.1 ± 15.9
    2.1 ± 24.4
        Fin. difficulties: Change at PS Visit (n=138,141)
    1.9 ± 20.0
    3.8 ± 23.6
        Global health status:Baseline(n=158,162)
    75.3 ± 19.7
    74.6 ± 21.2
        Global health status:Change at Week 5(n=153,156)
    1.5 ± 15.2
    -1.1 ± 18.5
        Global health status:Change at Week 9(n=150,155)
    -1.1 ± 15.9
    -3.2 ± 22.7
        Global health status:Change at Week 13(n=152,155)
    -2.4 ± 19.5
    -3.7 ± 20.7
        Global health status:Change at Week 16(n=147,146)
    -2.2 ± 18.4
    -2.9 ± 22.6
        Global health status:Change at PS Visit(n=139,143)
    -5.9 ± 19.7
    -7.0 ± 22.2
        Insomnia: Baseline (n=158,165)
    23.0 ± 27.1
    22.4 ± 28.1
        Insomnia: Change at Week 5 (n=155,161)
    -2.4 ± 24.1
    -0.4 ± 27.6
        Insomnia: Change at Week 9 (n=151,159)
    -1.8 ± 24.9
    -0.6 ± 26.9
        Insomnia: Change at Week 13 (n=153,158)
    -1.1 ± 27.7
    2.1 ± 29.5
        Insomnia: Change at Week 16 (n=146,149)
    -0.7 ± 26.1
    -2.2 ± 27.6
        Insomnia: Change at PS Visit (n=140,146)
    -1.4 ± 26.8
    3.2 ± 34.4
        Nausea / vomiting: Baseline (n=158,165)
    1.9 ± 7.5
    1.6 ± 6.2
        Nausea / vomiting: Change at Week 5 (n=155,161)
    3.7 ± 11.3
    1.9 ± 9.9
        Nausea / vomiting: Change at Week 9 (n=152,159)
    3.4 ± 10.9
    1.7 ± 10.3
        Nausea / vomiting: Change at Week 13 (n=153,158)
    3.7 ± 12.9
    0.7 ± 8.5
        Nausea / vomiting: Change at Week 16 (n=146,151)
    2.5 ± 14.0
    0.6 ± 8.0
        Nausea / vomiting: Change at PS Visit (n=140,146)
    2.1 ± 14.8
    1.0 ± 8.6
        Pain: Baseline (n=157,165)
    13.1 ± 20.4
    12.3 ± 19.6
        Pain: Change at Week 5 (n=155,161)
    -0.6 ± 18.8
    2.6 ± 17.5
        Pain: Change at Week 9 (n=152,159)
    -1.8 ± 16.5
    3.8 ± 22.9
        Pain: Change at Week 13 (n=152,158)
    -1.4 ± 18.4
    4.7 ± 23.4
        Pain: Change at Week 16 (n=147,151)
    -0.9 ± 19.1
    1.8 ± 22.0
        Pain: Change at PS Visit (n=140,146)
    11.1 ± 26.0
    13.8 ± 26.6
        Physical function: Baseline (n=158,165)
    89.6 ± 13.7
    90.8 ± 13.4
        Physical function: Change at Week 5 (n=155,161)
    0.5 ± 9.6
    -1.2 ± 11.5
        Physical function: Change at Week 9 (n=152,157)
    0.2 ± 10.1
    -2.0 ± 13.1
        Physical function: Change at Week 13 (n=152,158)
    -0.3 ± 12.4
    -1.9 ± 14.0
        Physical function: Change at Week 16 (n=146,150)
    -0.5 ± 10.9
    -3.4 ± 15.1
        Physical function: Change at PS Visit (n=140,146)
    -5.2 ± 16.0
    -7.5 ± 15.7
        Role function: Baseline (n=157,165)
    90.7 ± 20.1
    93.1 ± 16.5
        Role function: Change at Week 5 (n=155,160)
    1.3 ± 14.3
    -2.5 ± 17.1
        Role function: Change at Week 9 (n=150,159)
    -0.2 ± 12.8
    -4.9 ± 18.9
        Role function: Change at Week 13 (n=152,157)
    -2.3 ± 17.4
    -5.6 ± 19.8
        Role function: Change at Week 16 (n=146,151)
    -4.6 ± 16.3
    -4.4 ± 18.9
        Role function: Change at PS Visit (n=140,146)
    -15.1 ± 24.7
    -20.1 ± 28.1
        Social function: Baseline (n=155,161)
    91.2 ± 17.6
    94.9 ± 14.3
        Social function: Change at Week 5 (n=151,155)
    3.1 ± 12.8
    -2.0 ± 15.7
        Social function: Change at Week 9 (n=150,155)
    2.0 ± 13.4
    -4.0 ± 18.1
        Social function: Change at Week 13 (n=150,154)
    0.0 ± 13.7
    -4.0 ± 19.0
        Social function: Change at Week 16 (n=146,145)
    -0.5 ± 13.7
    -3.1 ± 19.3
        Social function: Change at PS Visit (n=139,142)
    -6.4 ± 20.3
    -10.1 ± 24.2
    No statistical analyses for this end point

    Secondary: Mean Score for Treatment of Cancer Quality of Life Questionnaire BR23 (QLQ-BR23)

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    End point title
    		 Mean Score for Treatment of Cancer Quality of Life Questionnaire BR23 (QLQ-BR23)
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systematic therapy side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Negative change from Baseline indicated deterioration in QOL and positive change from Baseline indicated an improvement in QOL. Here, Post surgery= PS. ITT population includes all randomised subjects regardless of whether they received any study drug (taselisib or placebo).
    End point type
    Secondary
    End point timeframe
    Weeks 1, 5, 9, 13, 16, 4-week Post-Surgery
    End point values
    		 Experimental: Taselisib + Letrozole Placebo Comparator: Placebo + Letrozole
    Number of subjects analysed
    166
    168
    Units: score on a scale
    arithmetic mean (standard deviation)
        Body image: Baseline (n=155,160)
    91.8 ± 15.7
    94.0 ± 14.6
        Body image: Change at Week 5 (n=152,151)
    2.8 ± 8.8
    0.6 ± 11.4
        Body image: Change at Week 9 (n=149,150)
    1.2 ± 9.8
    -0.2 ± 10.3
        Body image: Change at Week 13 (n=150,149)
    1.2 ± 11.6
    -1.6 ± 13.8
        Body image: Change at Week 16 (n=145,143)
    0.1 ± 10.8
    -1.2 ± 12.8
        Body image: Change at PS Visit (n=138,140)
    -6.5 ± 22.3
    -8.3 ± 19.2
        Breast symptoms: Baseline (n=154,160)
    5.3 ± 9.8
    6.9 ± 12.7
        Breast symptoms: Change at Week 5 (n=148,150)
    2.3 ± 14.6
    1.0 ± 13.0
        Breast symptoms: Change at Week 9 (n=148,151)
    4.5 ± 15.1
    1.8 ± 11.7
        Breast symptoms: Change at Week 13 (n=149,151)
    5.8 ± 16.0
    2.3 ± 13.3
        Breast symptoms: Change at Week 16 (n=146,146)
    7.9 ± 18.6
    3.9 ± 14.9
        Breast symptoms: Change at PS Visit (n=136,140)
    6.6 ± 17.9
    4.3 ± 14.2
        Future perspective: Baseline (n=157,159)
    57.7 ± 31.0
    58.7 ± 29.9
        Future perspective: Change at Week 5 (n=154,151)
    6.5 ± 26.7
    9.3 ± 28.1
        Future perspective: Change at Week 9 (n=150,151)
    10.2 ± 25.0
    9.7 ± 26.6
        Future perspective: Change at Week 13 (n=151,152)
    7.7 ± 28.4
    4.4 ± 29.1
        Future perspective: Change at Week 16 (n=147,145)
    10.2 ± 26.1
    5.1 ± 29.2
        Future perspective: Change at PS Visit (n=139,139)
    6.5 ± 29.7
    3.4 ± 34.8
        Sexual enjoyment: Baseline (n=48,29)
    41.7 ± 22.3
    47.1 ± 28.9
        Sexual enjoyment: Change at Week 5 (n=40,24)
    3.3 ± 18.2
    11.1 ± 23.4
        Sexual enjoyment: Change at Week 9 (n=40,22)
    8.3 ± 23.6
    10.6 ± 23.9
        Sexual enjoyment: Change at Week 13 (n=33,21)
    6.1 ± 19.5
    1.6 ± 22.3
        Sexual enjoyment: Change at Week 16 (n=34,22)
    9.8 ± 19.3
    7.6 ± 22.8
        Sexual enjoyment: Change at PS Visit (n=21,15)
    14.3 ± 27.0
    2.2 ± 23.5
        Sexual functioning: Baseline (n=149,147)
    81.2 ± 23.4
    85.1 ± 20.2
        Sexual functioning: Change at Week 5 (n=144,133)
    1.2 ± 13.6
    1.0 ± 15.0
        Sexual functioning: Change at Week 9 (n=136,131)
    1.3 ± 14.5
    0.3 ± 16.5
        Sexual functioning: Change at Week 13 (n=129,126)
    4.1 ± 16.1
    1.6 ± 17.7
        Sexual functioning: Change at Week 16 (n=128,124)
    4.8 ± 15.9
    1.1 ± 18.1
        Sexual functioning: Change at PS Visit (n=120,121)
    9.6 ± 19.2
    4.1 ± 21.8
        SE: Baseline (n=159,162)
    8.7 ± 10.8
    9.5 ± 11.5
        SE: Change at Week 5 (n=156,153)
    4.3 ± 10.0
    3.9 ± 10.5
        SE: Change at Week 9 (n=153,154)
    6.7 ± 10.8
    5.9 ± 12.1
        SE: Change at Week 13 (n=154,155)
    7.3 ± 11.0
    6.2 ± 13.1
        SE: Change at Week 16 (n=149,149)
    7.5 ± 12.9
    7.1 ± 12.6
        SE: Change at PS Visit (n=141,142)
    7.0 ± 12.0
    5.9 ± 12.1
        Upset by hair loss: Baseline (n=19,18)
    24.6 ± 26.9
    35.2 ± 31.3
        Upset by hair loss: Change at Week 5 (n=12,10)
    11.1 ± 32.8
    -3.3 ± 18.9
        Upset by hair loss: Change at Week 9 (n=11,11)
    9.1 ± 44.9
    -9.1 ± 26.2
        Upset by hair loss: Change at Week 13 (n=10,11)
    16.7 ± 36.0
    -3.0 ± 34.8
        Upset by hair loss: Change at Week 16 (n=11,14)
    21.2 ± 34.2
    -7.1 ± 23.3
        Upset by hair loss: Change at PS Visit (n=13,13)
    30.8 ± 37.2
    -2.6 ± 34.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The safety population includes all randomised subjects who received at least one dose of taselisib or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 22 weeks
    End point values
    		 Taselisib + Letrozole Placebo + Letrozole
    Number of subjects analysed
    167
    167
    Units: percentage of subjects
        number (not applicable)
    91.0
    83.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 22 weeks
    Adverse event reporting additional description
    The safety population includes all randomised subjects who received at least one dose of taselisib or placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19, 19.1
    Reporting groups
    Reporting group title
    Placebo Comparator: Placebo + Letrozole
    Reporting group description
    		 Subjects received 2.5 mg letrozole tablets orally QD along with placebo on a 5-days-on/2-days-off schedule for a total of 16 weeks.

    Reporting group title
    Experimental: Taselisib + Letrozole
    Reporting group description
    		 Subjects received 2.5 milligrams (mg) letrozole tablets orally once daily (QD) along with taselisib tablets at 4 mg (two 2 mg tablets) orally on a 5 days-on/2 days-off schedule for a total of 16 weeks.

    Serious adverse events
    		 Placebo Comparator: Placebo + Letrozole Experimental: Taselisib + Letrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 167 (2.40%)
    20 / 167 (11.98%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 167 (0.00%)
    5 / 167 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    1 / 167 (0.60%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 167 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Comparator: Placebo + Letrozole Experimental: Taselisib + Letrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 167 (75.45%)
    130 / 167 (77.84%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 167 (2.40%)
    9 / 167 (5.39%)
         occurrences all number
    4
    9
    Vascular disorders
    Hot flush
         subjects affected / exposed
    33 / 167 (19.76%)
    25 / 167 (14.97%)
         occurrences all number
    33
    25
    Hypertension
         subjects affected / exposed
    11 / 167 (6.59%)
    10 / 167 (5.99%)
         occurrences all number
    13
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 167 (10.78%)
    16 / 167 (9.58%)
         occurrences all number
    19
    18
    Dizziness
         subjects affected / exposed
    9 / 167 (5.39%)
    9 / 167 (5.39%)
         occurrences all number
    9
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    40 / 167 (23.95%)
    33 / 167 (19.76%)
         occurrences all number
    43
    34
    Asthenia
         subjects affected / exposed
    16 / 167 (9.58%)
    17 / 167 (10.18%)
         occurrences all number
    18
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 167 (11.98%)
    49 / 167 (29.34%)
         occurrences all number
    25
    68
    Nausea
         subjects affected / exposed
    19 / 167 (11.38%)
    35 / 167 (20.96%)
         occurrences all number
    21
    40
    Stomatitis
         subjects affected / exposed
    5 / 167 (2.99%)
    22 / 167 (13.17%)
         occurrences all number
    6
    26
    Dry mouth
         subjects affected / exposed
    14 / 167 (8.38%)
    6 / 167 (3.59%)
         occurrences all number
    14
    6
    Constipation
         subjects affected / exposed
    7 / 167 (4.19%)
    10 / 167 (5.99%)
         occurrences all number
    7
    10
    Vomiting
         subjects affected / exposed
    6 / 167 (3.59%)
    10 / 167 (5.99%)
         occurrences all number
    6
    10
    Dyspepsia
         subjects affected / exposed
    1 / 167 (0.60%)
    9 / 167 (5.39%)
         occurrences all number
    1
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 167 (4.79%)
    9 / 167 (5.39%)
         occurrences all number
    8
    11
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 167 (4.79%)
    14 / 167 (8.38%)
         occurrences all number
    8
    14
    Rash
         subjects affected / exposed
    5 / 167 (2.99%)
    15 / 167 (8.98%)
         occurrences all number
    6
    16
    Pruritus
         subjects affected / exposed
    9 / 167 (5.39%)
    6 / 167 (3.59%)
         occurrences all number
    10
    6
    Dry skin
         subjects affected / exposed
    3 / 167 (1.80%)
    10 / 167 (5.99%)
         occurrences all number
    3
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 167 (6.59%)
    6 / 167 (3.59%)
         occurrences all number
    11
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 167 (21.56%)
    19 / 167 (11.38%)
         occurrences all number
    39
    20
    Back pain
         subjects affected / exposed
    10 / 167 (5.99%)
    6 / 167 (3.59%)
         occurrences all number
    10
    6
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    13 / 167 (7.78%)
    6 / 167 (3.59%)
         occurrences all number
    13
    7
    Urinary tract infection
         subjects affected / exposed
    9 / 167 (5.39%)
    7 / 167 (4.19%)
         occurrences all number
    9
    7
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    12 / 167 (7.19%)
    26 / 167 (15.57%)
         occurrences all number
    12
    27
    Decreased appetite
         subjects affected / exposed
    6 / 167 (3.59%)
    11 / 167 (6.59%)
         occurrences all number
    6
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2014
    • To improve clarity: Language was added that the investigator had the sole responsibility to break the treatment code in emergency situations • To improve safety of subjects in respect to pneumonitis as a known taselisib toxicity: Additional screening and management of pulmonary function was added • To ensure enrollment of appropriate subjects: Exclusion criteria were added for subjects with immediate surgery indicated and chemotherapy judged to be the optimal neoadjuvant treatment • To improve safety of subjects in respect to letrozole being an estrogen-lowering agent: Additional assessments and adequate monitoring were added • Bisphosphonates were added as permitted concomitant therapy for osteoporosis • Potent CYP3A4 inducers were added as prohibited therapy
    22 May 2014
    • Taselisib 2 mg tablet formulation information and information on relative bioavailability of taselisib capsules and tablets were added • Requirement for taking taselisib on an empty stomach was removed • Adverse event of special interest (AESI) management guidelines were updated
    27 Jul 2015
    • To increase monitoring of diarrhea: AESI Grade ≥3 diarrhea was changed to Grade ≥2 diarrhea; Grade ≥1 diarrhea that persisted for more than 2 weeks despite antidiarrheals (e.g., loperamide) was added as an AESI; recommendation for management of Gastrointestinal (GI) toxicities that subjects experiencing Grade ≥1 diarrhea be contacted at least weekly was added; AE assessments at Weeks 7 and 11 by telephone were added • To enable correlation of response with biomarker analysis: Collection was added of an additional blood sample at 4-week post-surgical follow-up visit for Circulating Tumor Deoxyribonucleic Acid (ctDNA) and plasma protein biomarkers analysis
    27 Jul 2015
    • To prevent subjects with potential predisposition to gastrointestinal side effects from being enrolled: Additional restriction was added to the following exclusion criterion: “History of prior or currently active small or large intestine inflammation (such as Crohn’s disease or ulcerative colitis). Any subject with a baseline medical condition involving the GI tract or who may have a predisposition for GI toxicity requires prior approval from the Medical Monitor” • To improve clarity: Requirement was added for Target Lesion #2, if selected, to be ≥10 mm; “Investigational Agents” was added amongst prohibited concomitant therapies; specification that there was a 4-week “wash-out” period for any other investigational agent prior to initiation of taselisib treatment was added

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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