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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label, Two-Arm, Phase II, Neoadjuvant Study Evaluating the Efficacy, Safety, and Pharmacokinetics of GDC-9545 Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer

    Summary
    EudraCT number
    		 2020-001007-16
    Trial protocol
    		 HU   PL   DE  
    Global end of trial date
    24 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WO42133
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04436744
    WHO universal trial number (UTN)
    		 -
    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
    24 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2021
    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, safety, and pharmacokinetics of giredestrant versus anastrozole (in the window-of-opportunity phase) and giredestrant plus palbociclib compared with anastrozole plus palbociclib (in the neoadjuvant phase) in postmenopausal women with untreated, estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, early breast cancer.
    Protection of trial subjects
    All participants were required to sign the informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Sep 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 78
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Ukraine: 36
    Country: Number of subjects enrolled
    United States: 34
    Worldwide total number of subjects
    221
    EEA total number of subjects
    98
    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)
    135
    From 65 to 84 years
    86
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in this study at 64 investigative sites in Australia, Brazil, Germany, Hungary, Korea, Poland, Russia, Spain, Taiwan, the United States, and Ukraine, from 4 September 2020 to 24 November 2021.

    Pre-assignment
    Screening details
    		 A total of 264 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Giredestrant + Palbociclib
    Arm description
    		 Participants received giredestrant, 30 milligrams (mg), orally, once per day (QD), during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received giredestrant, 30 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Giredestrant
    Investigational medicinal product code
    Other name
    GDC-9545, RO7197597
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Window-of-opportunityphase: Giredestrant 30 mg, administered orally, QD, for two weeks. Neoadjuvant treatment phase: Giredestrant, 30 mg, administered orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles.

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Ibrance
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Arm title
    		 Anastrozole + Palbociclib
    Arm description
    		 Participants received anastrozole, 1 mg, orally, QD, during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received anastrozole, 1 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Ibrance
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Window-of-opportunity phase: Anastrozole, 1 mg, administered orally, QD, for two weeks. Neoadjuvant treatment phase: Anastrozole, 1 mg, administered orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles.

    Number of subjects in period 1
    		Giredestrant + Palbociclib Anastrozole + Palbociclib
    Started
    112
    109
    Completed
    108
    98
    Not completed
    4
    11
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    1
    1
         Protocol Deviation
    1
    1
         Progressive Disease
    -
    4
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Giredestrant + Palbociclib
    Reporting group description
    		 Participants received giredestrant, 30 milligrams (mg), orally, once per day (QD), during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received giredestrant, 30 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Reporting group title
    Anastrozole + Palbociclib
    Reporting group description
    		 Participants received anastrozole, 1 mg, orally, QD, during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received anastrozole, 1 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Reporting group values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib Total
    Number of subjects
    		 112 109 221
    Age categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ± 7.9 62.4 ± 9.3 -
    Sex: Female, Male
    Units: participants
        Female
    		 112 109 221
        Male
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 16 11 27
        Not Hispanic or Latino
    		 95 98 193
        Unknown or Not Reported
    		 1 0 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 9 15
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 1 3
        White
    		 100 94 194
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 5 9
    Ki67 Scores
    The Ki67 is a proliferation biomarker with prognostic value in estrogen receptor (ER)-positive breast cancer. Ki67 score was centrally assessed.
    Units: percent Ki67 scores
        arithmetic mean (full range (min-max))
    		 37.92 (6.6 to 96.3) 41.66 (7.8 to 98.9) -

    End points

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    End points reporting groups
    Reporting group title
    Giredestrant + Palbociclib
    Reporting group description
    		 Participants received giredestrant, 30 milligrams (mg), orally, once per day (QD), during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received giredestrant, 30 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Reporting group title
    Anastrozole + Palbociclib
    Reporting group description
    		 Participants received anastrozole, 1 mg, orally, QD, during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received anastrozole, 1 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Primary: Percent Reduction from Baseline in Ki67 Scores at Week 2

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    End point title
    		 Percent Reduction from Baseline in Ki67 Scores at Week 2
    End point description
    The Ki67 is a proliferation biomarker with prognostic value in estrogen receptor (ER)-positive breast cancer. Change in Ki67 score during the window-of-opportunity phase was defined as the mean change of Ki67 score from baseline to Week 2. Ki67 score was centrally assessed. Efficacy-evaluable population included participants with Ki67-evaluable tumor specimens at baseline and Week 2. Participants with missing central Ki67 scores at baseline and/or Week 2 were excluded from the analysis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 2
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    107
    94
    Units: percent reduction in Ki67 scores
        geometric mean (confidence interval 95%)
    75 (70 to 80)
    67 (59 to 73)
    Statistical analysis title
    		 GDC-9545+Palbociclib vs Anastrozole+Palbociclib
    Comparison groups
    Giredestrant + Palbociclib v Anastrozole + Palbociclib
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0433
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Overall Response Rate (ORR) by Ultrasound as Determined by the Investigator

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    End point title
    		 Overall Response Rate (ORR) by Ultrasound as Determined by the Investigator
    End point description
    ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR), as determined by the investigator according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST). Ultrasound and clinical exam were used to assess response. CR per mRECIST was defined as the disappearance of all target lesions. PR per mRECIST was defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. An estimate of ORR and its 95% confidence interval (CI) was calculated using the Clopper-Pearson method. ORR-evaluable population included all randomised participants with measurable disease at baseline. Participants not meeting the criteria for ORR, including participants without any post-baseline tumor assessment, were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 4 Day 1 (each cycle is 28 days)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    112
    108
    Units: percentage of participants
        number (confidence interval 95%)
    50.0 (40.40 to 59.60)
    49.1 (39.33 to 58.87)
    Statistical analysis title
    		 GDC-9545+Palbociclib vs Anastrozole+Palbociclib
    Statistical analysis description
    ORR was calculated using the stratified Cochran-Mantel-Haenszel test.
    Comparison groups
    Giredestrant + Palbociclib v Anastrozole + Palbociclib
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8272
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rates
    Point estimate
    -0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.66
         upper limit
    		 12.81

    Secondary: Complete Cell Cycle Arrest (CCCA) Rate at Week 2

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    End point title
    		 Complete Cell Cycle Arrest (CCCA) Rate at Week 2
    End point description
    CCCA was defined as the percentage of participants with centrally assessed Ki67 scores ≤2.7%. The CCCA rate at Week 2 was summarized. Efficacy-evaluable population included participants with Ki67-evaluable tumor specimens at baseline and Week 2. Participants with missing central Ki67 scores at baseline and/or Week 2 were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Week 2
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    107
    94
    Units: percentage of participants
        number (not applicable)
    19.6
    12.8
    Statistical analysis title
    		 GDC-9545+Palbociclib vs Anastrozole+Palbociclib
    Comparison groups
    Giredestrant + Palbociclib v Anastrozole + Palbociclib
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Rate
    Point estimate
    6.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.25
         upper limit
    		 17.97

    Secondary: Number of Participants with Adverse Events (AEs) with Severity Determined in Accordance With National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

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    End point title
    		 Number of Participants with Adverse Events (AEs) with Severity Determined in Accordance With National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
    End point description
    AE is any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product regardless of causal attribution. An AE can be any unfavorable & unintended sign, symptom/disease temporally related to use of medicinal product, whether/not related to medicinal product. Severity of AEs was determined per NCI CTCAE v5.0. Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living; Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care activities of daily living; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE. Safety-evaluable population included all participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    From baseline up to 28 days after the last dose (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    112
    109
    Units: participants
        AEs
    104
    98
        Grade 1
    19
    20
        Grade 2
    35
    31
        Grade 3
    45
    45
        Grade 4
    4
    2
        Grade 5
    1
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Respiratory Rate Over Time

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    End point title
    		 Change from Baseline in Respiratory Rate Over Time
    End point description
    Respiratory rate was measured while the participant was in a seated position. Safety-evaluable population included all participants who received any amount of study treatment. Overall number analysed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery and end of study (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    98
    102
    Units: breath/minute (min)
    arithmetic mean (standard deviation)
        Baseline (n=98,102)
    17.16 ± 2.27
    17.10 ± 2.05
        Change from Baseline at Cycle 1 Day 1 (n=91,91)
    0.30 ± 2.12
    0.26 ± 1.50
        Change from Baseline at Cycle 1 Day 15 (n=90,88)
    -0.01 ± 1.49
    -0.06 ± 1.36
        Change from Baseline at Cycle 2 Day 1 (n=89,92)
    -0.10 ± 1.83
    0.16 ± 1.34
        Change from Baseline at Cycle 2 Day 15 (n=89,91)
    -0.24 ± 1.71
    -0.03 ± 1.64
        Change from Baseline at Cycle 3 Day 1 (n=87,89)
    0.07 ± 1.58
    0.01 ± 1.61
        Change from Baseline at Cycle 4 Day 1 (n=91,83)
    -0.04 ± 1.71
    0.01 ± 1.53
        Change from Baseline at Day of Surgery (n=72,62)
    0.04 ± 1.72
    -0.02 ± 1.69
        Change from Baseline at End of Study (n=88,81)
    -0.26 ± 1.65
    0.01 ± 1.42
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pulse Rate Over Time

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    End point title
    		 Change from Baseline in Pulse Rate Over Time
    End point description
    Pulse rate was measured while the participant was in a seated position. Safety-evaluable population included all participants who received any amount of study treatment. Overall number analysed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery and end of study (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    98
    102
    Units: beats/min
    arithmetic mean (standard deviation)
        Baseline (n=98, 102)
    75.86 ± 10.67
    76.73 ± 9.85
        Change from Baseline at Cycle 1 Day 1 (n=90,92)
    -4.74 ± 9.07
    -1.96 ± 9.43
        Change from Baseline at Cycle 1 Day 15 (n=91,90)
    -6.02 ± 12.02
    -1.47 ± 8.15
        Change from Baseline at Cycle 2 Day 1 (n=90,92)
    -5.20 ± 10.26
    -1.11 ± 10.79
        Change from Baseline at Cycle 2 Day 15 (n=92,91)
    -7.68 ± 11.03
    -1.95 ± 8.64
        Change from Baseline at Cycle 3 Day 1 (n=88,90)
    -5.47 ± 11.61
    -0.81 ± 10.83
        Change from Baseline at Cycle 4 Day 1 (n=91,83)
    -5.67 ± 9.79
    -1.11 ± 10.62
        Change from Baseline at Day of Surgery (n=73,65)
    -4.14 ± 11.25
    -1.26 ± 10.46
        Change from Baseline at End of Study (n=88,81)
    -0.61 ± 10.74
    1.59 ± 10.44
    No statistical analyses for this end point

    Secondary: Change from Baseline in Systolic Blood Pressure Over Time

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    End point title
    		 Change from Baseline in Systolic Blood Pressure Over Time
    End point description
    Systolic blood pressure was measured while the participant was in a seated position. Safety-evaluable population included all participants who received any amount of study treatment. Overall number analysed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery and end of study (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    98
    102
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n=98,102)
    135.63 ± 14.13
    130.03 ± 16.43
        Change from Baseline at Cycle 1 Day 1 (n=91,92)
    -0.82 ± 11.11
    1.12 ± 13.65
        Change from Baseline at Cycle 1 Day 15 (n=91,90)
    -2.55 ± 14.01
    0.23 ± 15.85
        Change from Baseline at Cycle 2 Day 1 (n=90,92)
    -2.08 ± 14.13
    0.28 ± 14.43
        Change from Baseline at Cycle 2 Day 15 (n=92,90)
    -4.25 ± 15.37
    0.16 ± 16.49
        Change from Baseline at Cycle 3 Day 1 (n=88,90)
    -2.66 ± 16.95
    0.33 ± 15.81
        Change from Baseline at Cycle 4 Day 1 (n=91,83)
    -1.29 ± 15.30
    -0.25 ± 14.17
        Change from Baseline at Day of Surgery (n=74,65)
    -2.35 ± 13.79
    1.51 ± 15.24
        Change from Baseline at End of Study (n=88,81)
    -5.38 ± 13.98
    -1.67 ± 16.20
    No statistical analyses for this end point

    Secondary: Change from Baseline in Diastolic Blood Pressure Over Time

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    End point title
    		 Change from Baseline in Diastolic Blood Pressure Over Time
    End point description
    Diastolic blood pressure was measured while the participant was in a seated position. Safety-evaluable population included all participants who received any amount of study treatment. Overall number analysed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery and end of study (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    98
    102
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (n=98, 102)
    80.40 ± 8.84
    78.49 ± 9.55
        Change from Baseline at Cycle 1 Day 1 (n=91,92)
    -2.42 ± 7.77
    0.39 ± 8.13
        Change from Baseline at Cycle 1 Day 15 (n=91,90)
    -4.80 ± 8.58
    -2.42 ± 8.71
        Change from Baseline at Cycle 2 Day 1 (n=90,92)
    -4.79 ± 10.08
    -0.76 ± 8.80
        Change from Baseline at Cycle 2 Day 15 (n=92,90)
    -5.64 ± 9.24
    -1.32 ± 9.64
        Change from Baseline at Cycle 3 Day 1 (n=88,90)
    -5.25 ± 8.51
    -0.16 ± 9.52
        Change from Baseline at Cycle 4 Day 1 (n=91,83)
    -4.35 ± 9.31
    -2.57 ± 9.50
        Change from Baseline at Day of Surgery (n=74,65)
    -4.93 ± 8.72
    -2.15 ± 9.58
        Change from Baseline at End of Study (n=88,81)
    -2.73 ± 8.37
    -2.52 ± 12.11
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Temperature Over Time

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    End point title
    		 Change from Baseline in Body Temperature Over Time
    End point description
    Safety-evaluable population included all participants who received any amount of study treatment. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery and end of study (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    112
    109
    Units: Celsius (C)
    arithmetic mean (standard deviation)
        Baseline (n=112,109)
    36.35 ± 0.41
    36.45 ± 0.38
        Change from Baseline at Cycle 1 Day 1 (n=110,105)
    0.07 ± 0.39
    0.04 ± 0.36
        Change from Baseline at Cycle 1 Day 15 (n=107,103)
    0.01 ± 0.41
    -0.01 ± 0.43
        Change from Baseline at Cycle 2 Day 1 (n=108,105)
    0.03 ± 0.40
    -0.04 ± 0.52
        Change from Baseline at Cycle 2 Day 15 (n=110,102)
    -0.03 ± 0.37
    -0.12 ± 0.47
        Change from Baseline at Cycle 3 Day 1 (n=109,102)
    -0.04 ± 0.42
    0.01 ± 0.39
        Change from Baseline at Cycle 4 Day 1 (n=109,103)
    -0.03 ± 0.37
    -0.08 ± 0.38
        Change from Baseline at Day of Surgery (n=97,85)
    0.06 ± 0.39
    -0.01 ± 0.38
        Change from Baseline at End of Study (n=107,102)
    0.05 ± 0.39
    -0.04 ± 0.48
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts in Hematology Test Parameters from NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline

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    End point title
    		 Number of Participants With Shifts in Hematology Test Parameters from NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline
    End point description
    Haematology test parameters like hemoglobin, lymphocytes absolute (Abs), neutrophils, total, Abs, platelet, total leukocyte count were measured per NCI CTCAE v5.0. Number of participants with shift in the laboratory values from grade 0-2 at baseline to grade 3-4 at post-baseline were reported. Safety-evaluable population included all participants who received any amount of study treatment. Participants with at least 1 post-baseline assessment were included in the analysis. Overall number analysed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    From baseline up to 28 days after the last dose (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    112
    108
    Units: participants
        Hemoglobin: Low (n=101,103)
    3
    1
        Hemoglobin: High (n=111,105)
    0
    1
        Lymphocytes Abs: Low (n=95,91)
    9
    2
        Lymphocytes Abs: High (n=90,88)
    1
    2
        Neutrophils, Total, Abs: Low (n=98,96)
    43
    38
        Platelet: Low (n=112,108)
    0
    0
        Total Leukocyte Count: Low (n=112,108)
    15
    11
        Total Leukocyte Count: High (n=104,105)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts in Blood Chemistry Parameters from NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline

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    End point title
    		 Number of Participants With Shifts in Blood Chemistry Parameters from NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline
    End point description
    Blood chemistry parameters albumin, alkaline phosphatase, serum glutamic pyruvic transaminase (SGPT)/alanine transaminase (ALT), serum glutamic oxaloacetic transaminase (SGOT)/aspartate transaminase (AST), calcium, cholesterol, creatinine, glucose, potassium, sodium, bilirubin, triglycerides and uric acid were measured per NCI CTCAE v5.0. Number of participants with shift in the laboratory values from grade 0-2 at baseline to grade 3-4 at post-baseline were reported. Safety-evaluable population included all participants who received any amount of study treatment. Participants with at least 1 post-baseline assessment were included in the analysis. Overall number analysed is the number of participants with data available for analysis. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    From baseline up to 28 days after the last dose (up to approximately 24 weeks)
    End point values
    		 Giredestrant + Palbociclib Anastrozole + Palbociclib
    Number of subjects analysed
    112
    108
    Units: participants
        Albumin: low (n=111,108)
    1
    0
        Alkaline Phosphatase: High (n=112,108)
    0
    0
        SGPT/ALT: High (n=112,108)
    1
    5
        SGOT/AST: High (n=112,108)
    1
    3
        Calcium: Low (n=102,101)
    0
    3
        Calcium: High (n=109,103)
    0
    0
        Cholesterol: High (n=93,89)
    0
    0
        Creatinine: High (n=112,108)
    0
    1
        Glucose: Low (n=112,108)
    0
    0
        Potassium: Low (n=106,101)
    0
    0
        Potassium: High (n=112,107)
    0
    0
        Sodium: Low (n=111,107)
    0
    0
        Sodium: High (n=111,106)
    0
    0
        Bilirubin: High (n=112,108)
    0
    0
        Triglycerides: High (n=93,88)
    1
    0
        Uric Acid: High (n=87,86)
    21
    22
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Giredestrant at Specified Timepoints

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    End point title
    		 Plasma Concentration of Giredestrant at Specified Timepoints [1]
    End point description
    Pharmacokinetics (PK) evaluable population included all participants who received giredestrant and had at least one evaluable post-dose giredestrant plasma concentration. Number analysed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Cycle 0 Day 1, 3 hours Postdose; Cycle 0 Day 15, Predose; Cycle 2 Day 1, Predose
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive analysis was planned to be reported for this endpoint.
    End point values
    		 Giredestrant + Palbociclib
    Number of subjects analysed
    108
    Units: nanograms per milliliters (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 0 Day 1, 3-h Postdose (n=108)
    81.8 ± 284
        Cycle 0 Day 15, Predose (n=104)
    137 ± 61.1
        Cycle 2 Day 1, Predose (n=99)
    130 ± 122
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to 28 days after the last dose (up to approximately 24 weeks)
    Adverse event reporting additional description
    AEs are reported for the safety-evaluable population that was defined as all participants who received any amount of study treatment, grouped according to treatment received. All-cause mortality was also reported for the safety-evaluable population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Giredestrant + Palbociclib
    Reporting group description
    		 Participants received giredestrant, 30 mg, orally, QD, during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received giredestrant, 30 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Reporting group title
    Giredestrant + Palbociclib
    Reporting group description
    		 Participants received anastrozole, 1 mg, orally, QD, during the window-of-opportunity phase of two weeks. During the neoadjuvant treatment phase, participants received anastrozole, 1 mg, orally, QD on Days 1-28 of each 28-day cycle for a total of 4 cycles in combination with palbociclib, 125 mg, administered orally, QD on Days 1-21 of each 28-day cycle for a total of 4 cycles.

    Serious adverse events
    		 Giredestrant + Palbociclib Giredestrant + Palbociclib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 112 (4.46%)
    2 / 109 (1.83%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine perforation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 109 (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
    Hypoxia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Giredestrant + Palbociclib Giredestrant + Palbociclib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 112 (88.39%)
    93 / 109 (85.32%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 112 (0.89%)
    9 / 109 (8.26%)
         occurrences all number
    1
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 112 (0.89%)
    6 / 109 (5.50%)
         occurrences all number
    1
    6
    Neutrophil count decreased
         subjects affected / exposed
    26 / 112 (23.21%)
    24 / 109 (22.02%)
         occurrences all number
    39
    32
    White blood cell count decreased
         subjects affected / exposed
    14 / 112 (12.50%)
    10 / 109 (9.17%)
         occurrences all number
    19
    12
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 112 (1.79%)
    6 / 109 (5.50%)
         occurrences all number
    2
    6
    Vascular disorders
    Hot flush
         subjects affected / exposed
    16 / 112 (14.29%)
    16 / 109 (14.68%)
         occurrences all number
    16
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 112 (4.46%)
    9 / 109 (8.26%)
         occurrences all number
    5
    9
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    14 / 112 (12.50%)
    16 / 109 (14.68%)
         occurrences all number
    20
    29
    Anaemia
         subjects affected / exposed
    12 / 112 (10.71%)
    6 / 109 (5.50%)
         occurrences all number
    13
    7
    Neutropenia
         subjects affected / exposed
    46 / 112 (41.07%)
    44 / 109 (40.37%)
         occurrences all number
    77
    79
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    25 / 112 (22.32%)
    27 / 109 (24.77%)
         occurrences all number
    28
    31
    Fatigue
         subjects affected / exposed
    10 / 112 (8.93%)
    18 / 109 (16.51%)
         occurrences all number
    10
    19
    Mucosal inflammation
         subjects affected / exposed
    9 / 112 (8.04%)
    3 / 109 (2.75%)
         occurrences all number
    9
    3
    Pyrexia
         subjects affected / exposed
    1 / 112 (0.89%)
    6 / 109 (5.50%)
         occurrences all number
    1
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 112 (2.68%)
    6 / 109 (5.50%)
         occurrences all number
    3
    6
    Diarrhoea
         subjects affected / exposed
    8 / 112 (7.14%)
    18 / 109 (16.51%)
         occurrences all number
    11
    25
    Nausea
         subjects affected / exposed
    16 / 112 (14.29%)
    13 / 109 (11.93%)
         occurrences all number
    19
    15
    Vomiting
         subjects affected / exposed
    6 / 112 (5.36%)
    1 / 109 (0.92%)
         occurrences all number
    6
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 112 (5.36%)
    5 / 109 (4.59%)
         occurrences all number
    6
    5
    Rash
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 109 (1.83%)
         occurrences all number
    7
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 112 (10.71%)
    21 / 109 (19.27%)
         occurrences all number
    13
    22

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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