Trial Outcomes & Findings for A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Giredestrant Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer (coopERA Breast Cancer) (NCT NCT04436744)

Last Updated: 2023-02-02

Results Overview

Ki67 is a proliferation biomarker with prognostic value in ER-positive breast cancer. Ki67 scores were centrally assessed with immunohistochemistry and defined as a percentage of positively stained tumor cell nuclei among the total number of tumor cells assessed, with a potential range of 0-100%. A score of 0% indicates no tumor cell nuclei with Ki67 staining and a score of 100% indicates all tumor cell nuclei are positively stained with Ki67. The relative percentage change was calculated using Ki67 scores at Baseline and Week 2. Relative Percent Change was defined as Week 2 Ki67 percentage score/Baseline Ki67 percentage score\*100. A smaller value of relative percentage change indicates improvement.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

221 participants

Primary outcome timeframe

Baseline, Week 2

Results posted on

2023-02-02

Participant Flow

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.

A total of 264 participants were screened.

Participant milestones

Participant milestones
Measure	Giredestrant + Palbociclib 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.	Anastrozole + Palbociclib 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.
Overall Study STARTED	112	109
Overall Study COMPLETED	108	98
Overall Study NOT COMPLETED	4	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Giredestrant + Palbociclib 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.	Anastrozole + Palbociclib 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.
Overall Study Adverse Event	1	1
Overall Study Death	1	0
Overall Study Lost to Follow-up	0	2
Overall Study Physician Decision	0	1
Overall Study Progressive Disease	0	4
Overall Study Protocol Deviation	1	1
Overall Study Withdrawal by Subject	1	2

Baseline Characteristics

A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Giredestrant Plus Palbociclib Compared With Anastrozole Plus Palbociclib for Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Untreated Early Breast Cancer (coopERA Breast Cancer)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Giredestrant + Palbociclib n=112 Participants 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.	Anastrozole + Palbociclib n=109 Participants 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.	Total n=221 Participants Total of all reporting groups
Age, Continuous	63.1 years STANDARD_DEVIATION 7.9 • n=5 Participants	62.4 years STANDARD_DEVIATION 9.3 • n=7 Participants	62.8 years STANDARD_DEVIATION 8.6 • n=5 Participants
Sex: Female, Male Female	112 Participants n=5 Participants	109 Participants n=7 Participants	221 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	16 Participants n=5 Participants	11 Participants n=7 Participants	27 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	95 Participants n=5 Participants	98 Participants n=7 Participants	193 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	100 Participants n=5 Participants	94 Participants n=7 Participants	194 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Ki67 Scores	37.92 percent Ki67 score n=5 Participants	41.66 percent Ki67 score n=7 Participants	39.76 percent Ki67 score n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 2

Population: 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.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=107 Participants 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.	Anastrozole + Palbociclib n=94 Participants 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.
Relative Percent Change in Ki67 Scores From Baseline to Week 2	25 percent change Interval 20.0 to 30.0	33 percent change Interval 27.0 to 41.0

SECONDARY outcome

Timeframe: Baseline up to Cycle 4 Day 1 (each cycle is 28 days)

Population: ORR-evaluable population included all randomized 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.

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.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=112 Participants 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.	Anastrozole + Palbociclib n=108 Participants 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.
Overall Response Rate (ORR) by Ultrasound as Determined by the Investigator	50.0 percentage of participants Interval 40.4 to 59.6	49.1 percentage of participants Interval 39.33 to 58.87

SECONDARY outcome

Timeframe: Week 2

CCCA was defined as the percentage of participants with centrally assessed Ki67 scores ≤2.7%. The CCCA rate at Week 2 was summarized.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=107 Participants 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.	Anastrozole + Palbociclib n=94 Participants 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.
Complete Cell Cycle Arrest (CCCA) Rate at Week 2	19.6 percentage of participants	12.8 percentage of participants

SECONDARY outcome

Timeframe: From baseline up to 28 days after the last dose (up to approximately 24 weeks)

Population: Safety-evaluable population included all participants who received any amount of study treatment.

AE is any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable \& unintended sign, symptom/disease temporally associated with use of a medicinal product, whether or not related to medicinal product. Preexisting conditions which worsen during a study also considered as AEs. 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.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=112 Participants 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.	Anastrozole + Palbociclib n=109 Participants 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.
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) AEs	104 Participants	98 Participants
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) Grade 1	19 Participants	20 Participants
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) Grade 2	35 Participants	31 Participants
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) Grade 3	45 Participants	45 Participants
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) Grade 4	4 Participants	2 Participants
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) Grade 5	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline; Cycles 1-2: Day 1 and Day 15; Cycles 3-4: Day 1; day of surgery (up to 2 weeks after the final dose of study treatment [approximately Week 18]) and end of study (up to approximately 24 weeks)

Population: Safety-evaluable population included all participants who received any amount of study treatment. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.

Respiratory rate was measured while the participant was in a seated position.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=98 Participants 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.	Anastrozole + Palbociclib n=102 Participants 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.
Change From Baseline in Respiratory Rate Over Time Baseline	17.16 breath/minute (min) Standard Deviation 2.27	17.10 breath/minute (min) Standard Deviation 2.05
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Cycle 1 Day 1	0.30 breath/minute (min) Standard Deviation 2.12	0.26 breath/minute (min) Standard Deviation 1.50
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Cycle 1 Day 15	-0.01 breath/minute (min) Standard Deviation 1.49	-0.06 breath/minute (min) Standard Deviation 1.36
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Cycle 2 Day 1	-0.10 breath/minute (min) Standard Deviation 1.83	0.16 breath/minute (min) Standard Deviation 1.34
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Cycle 2 Day 15	-0.24 breath/minute (min) Standard Deviation 1.71	-0.03 breath/minute (min) Standard Deviation 1.64
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Cycle 3 Day 1	0.07 breath/minute (min) Standard Deviation 1.58	0.01 breath/minute (min) Standard Deviation 1.61
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Cycle 4 Day 1	-0.04 breath/minute (min) Standard Deviation 1.71	0.01 breath/minute (min) Standard Deviation 1.53
Change From Baseline in Respiratory Rate Over Time Change from Baseline at Day of Surgery	0.04 breath/minute (min) Standard Deviation 1.72	-0.02 breath/minute (min) Standard Deviation 1.69
Change From Baseline in Respiratory Rate Over Time Change from Baseline at End of Study	-0.26 breath/minute (min) Standard Deviation 1.65	0.01 breath/minute (min) Standard Deviation 1.42

SECONDARY outcome

Pulse rate was measured while the participant was in a seated position.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=98 Participants 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.	Anastrozole + Palbociclib n=102 Participants 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.
Change From Baseline in Pulse Rate Over Time Baseline	75.86 beats/min Standard Deviation 10.67	76.73 beats/min Standard Deviation 9.85
Change From Baseline in Pulse Rate Over Time Change from Baseline at Cycle 1 Day 1	-4.74 beats/min Standard Deviation 9.07	-1.96 beats/min Standard Deviation 9.43
Change From Baseline in Pulse Rate Over Time Change from Baseline at Cycle 1 Day 15	-6.02 beats/min Standard Deviation 12.02	-1.47 beats/min Standard Deviation 8.15
Change From Baseline in Pulse Rate Over Time Change from Baseline at Cycle 2 Day 1	-5.20 beats/min Standard Deviation 10.26	-1.11 beats/min Standard Deviation 10.79
Change From Baseline in Pulse Rate Over Time Change from Baseline at Cycle 2 Day 15	-7.68 beats/min Standard Deviation 11.03	-1.95 beats/min Standard Deviation 8.64
Change From Baseline in Pulse Rate Over Time Change from Baseline at Cycle 3 Day 1	-5.47 beats/min Standard Deviation 11.61	-0.81 beats/min Standard Deviation 10.83
Change From Baseline in Pulse Rate Over Time Change from Baseline at Cycle 4 Day 1	-5.67 beats/min Standard Deviation 9.79	-1.11 beats/min Standard Deviation 10.62
Change From Baseline in Pulse Rate Over Time Change from Baseline at Day of Surgery	-4.14 beats/min Standard Deviation 11.25	-1.26 beats/min Standard Deviation 10.46
Change From Baseline in Pulse Rate Over Time Change from Baseline at End of Study	-0.61 beats/min Standard Deviation 10.74	1.59 beats/min Standard Deviation 10.44

SECONDARY outcome

Systolic blood pressure was measured while the participant was in a seated position.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=98 Participants 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.	Anastrozole + Palbociclib n=102 Participants 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.
Change From Baseline in Systolic Blood Pressure Over Time Baseline	135.63 millimeters of mercury (mmHg) Standard Deviation 14.13	130.03 millimeters of mercury (mmHg) Standard Deviation 16.43
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Cycle 1 Day 1	-0.82 millimeters of mercury (mmHg) Standard Deviation 11.11	1.12 millimeters of mercury (mmHg) Standard Deviation 13.65
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Cycle 1 Day 15	-2.55 millimeters of mercury (mmHg) Standard Deviation 14.01	0.23 millimeters of mercury (mmHg) Standard Deviation 15.85
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Cycle 2 Day 1	-2.08 millimeters of mercury (mmHg) Standard Deviation 14.13	0.28 millimeters of mercury (mmHg) Standard Deviation 14.43
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Cycle 2 Day 15	-4.25 millimeters of mercury (mmHg) Standard Deviation 15.37	0.16 millimeters of mercury (mmHg) Standard Deviation 16.49
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Cycle 3 Day 1	-2.66 millimeters of mercury (mmHg) Standard Deviation 16.95	0.33 millimeters of mercury (mmHg) Standard Deviation 15.81
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Cycle 4 Day 1	-1.29 millimeters of mercury (mmHg) Standard Deviation 15.30	-0.25 millimeters of mercury (mmHg) Standard Deviation 14.17
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at Day of Surgery	-2.35 millimeters of mercury (mmHg) Standard Deviation 13.79	1.51 millimeters of mercury (mmHg) Standard Deviation 15.24
Change From Baseline in Systolic Blood Pressure Over Time Change from Baseline at End of Study	-5.38 millimeters of mercury (mmHg) Standard Deviation 13.98	-1.67 millimeters of mercury (mmHg) Standard Deviation 16.20

SECONDARY outcome

Diastolic blood pressure was measured while the participant was in a seated position.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=98 Participants 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.	Anastrozole + Palbociclib n=102 Participants 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.
Change From Baseline in Diastolic Blood Pressure Over Time Baseline	80.40 mmHg Standard Deviation 8.84	78.49 mmHg Standard Deviation 9.55
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Cycle 1 Day 1	-2.42 mmHg Standard Deviation 7.77	0.39 mmHg Standard Deviation 8.13
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Cycle 1 Day 15	-4.80 mmHg Standard Deviation 8.58	-2.42 mmHg Standard Deviation 8.71
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Cycle 2 Day 1	-4.79 mmHg Standard Deviation 10.08	-0.76 mmHg Standard Deviation 8.80
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Cycle 2 Day 15	-5.64 mmHg Standard Deviation 9.24	-1.32 mmHg Standard Deviation 9.64
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Cycle 3 Day 1	-5.25 mmHg Standard Deviation 8.51	-0.16 mmHg Standard Deviation 9.52
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Cycle 4 Day 1	-4.35 mmHg Standard Deviation 9.31	-2.57 mmHg Standard Deviation 9.50
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at Day of Surgery	-4.93 mmHg Standard Deviation 8.72	-2.15 mmHg Standard Deviation 9.58
Change From Baseline in Diastolic Blood Pressure Over Time Change from Baseline at End of Study	-2.73 mmHg Standard Deviation 8.37	-2.52 mmHg Standard Deviation 12.11

SECONDARY outcome

Population: Safety-evaluable population included all participants who received any amount of study treatment. Number analyzed is the number of participants with data available for analysis at the specified time point.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=112 Participants 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.	Anastrozole + Palbociclib n=109 Participants 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.
Change From Baseline in Body Temperature Over Time Baseline	36.35 Celsius (C) Standard Deviation 0.41	36.45 Celsius (C) Standard Deviation 0.38
Change From Baseline in Body Temperature Over Time Change from Baseline at Cycle 1 Day 1	0.07 Celsius (C) Standard Deviation 0.39	0.04 Celsius (C) Standard Deviation 0.36
Change From Baseline in Body Temperature Over Time Change from Baseline at Cycle 1 Day 15	0.01 Celsius (C) Standard Deviation 0.41	-0.01 Celsius (C) Standard Deviation 0.43
Change From Baseline in Body Temperature Over Time Change from Baseline at Cycle 2 Day 1	0.03 Celsius (C) Standard Deviation 0.40	-0.04 Celsius (C) Standard Deviation 0.52
Change From Baseline in Body Temperature Over Time Change from Baseline at Cycle 2 Day 15	-0.03 Celsius (C) Standard Deviation 0.37	-0.12 Celsius (C) Standard Deviation 0.47
Change From Baseline in Body Temperature Over Time Change from Baseline at Cycle 3 Day 1	-0.04 Celsius (C) Standard Deviation 0.42	0.01 Celsius (C) Standard Deviation 0.39
Change From Baseline in Body Temperature Over Time Change from Baseline at Cycle 4 Day 1	-0.03 Celsius (C) Standard Deviation 0.37	-0.08 Celsius (C) Standard Deviation 0.38
Change From Baseline in Body Temperature Over Time Change from Baseline at Day of Surgery	0.06 Celsius (C) Standard Deviation 0.39	-0.01 Celsius (C) Standard Deviation 0.38
Change From Baseline in Body Temperature Over Time Change from Baseline at End of Study	0.05 Celsius (C) Standard Deviation 0.39	-0.04 Celsius (C) Standard Deviation 0.48

SECONDARY outcome

Timeframe: From baseline up to 28 days after the last dose (up to approximately 24 weeks)

Population: 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 analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.

Hematology test parameters were measured per NCI CTCAE v5.0. Grade 0 is normal, and Grades 1 to 4 represent worsening levels of the parameter outside of the normal range in the specified direction of the abnormality (high and low are above and below the range, respectively). Number of participants with shift in the hematology values from grade 0-2 at baseline to grade 3-4 at post-baseline were reported. A marked reference range for hemoglobin 12.3-15.3 grams per deciliter (g/dL), lymphocytes absolute (Abs) 1.0-4.8 10\^3/microliters (uL), neutrophils total, Abs, 1.8-8.5 10\^3/uL, platelet 100-450 10\^9/liter (L), total leukocyte 4.4-11 10\^9/L.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=112 Participants 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.	Anastrozole + Palbociclib n=108 Participants 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.
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Hemoglobin: Low	3 Participants	1 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Hemoglobin: High	0 Participants	1 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Lymphocytes Abs: Low	9 Participants	2 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Lymphocytes Abs: High	1 Participants	2 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Neutrophils, Total, Abs: Low	43 Participants	38 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Platelet: Low	0 Participants	0 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Total Leukocyte Count: Low	15 Participants	11 Participants
Number of Participants With Shifts in Hematology Test Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Total Leukocyte Count: High	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline up to 28 days after the last dose (up to approximately 24 weeks)

Blood chemistry parameters were measured per NCI CTCAE v5.0. Grade 0=normal, and Grades 1 to 4 represent worsening levels of parameter outside of normal range in the specified direction of abnormality (high \& low are above \& below the range, respectively). Number of participants with shift in blood chemistry values from grade 0-2 at baseline to grade 3-4 at post-baseline were reported. Marked reference range for albumin 32-45 grams per liter (g/L), alkaline phosphatase 20-130 units per liter (U/L), serum glutamic pyruvic transaminase (SGPT)/ alanine transaminase (ALT) 4-36 U/L, serum glutamic oxaloacetic transaminase (SGOT)/ aspartate transaminase (AST) 8-33 U/L, calcium 2.3-2.74 millimoles per liter (mmol/L), cholesterol 3.88-6.47mmol/L, creatinine 6-12 milligrams per liter (mg/L), glucose 3.9-6.1 mmol/L, potassium 3.5-5.0 mmol/L, sodium 135-147 mmol/L, bilirubin 2-21 micromoles per liter (μmol/L), triglycerides 0.11-2.15 mmol/L, \& uric acid 2.7-7.3 milligrams per deciliter (mg/dL).

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=112 Participants 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.	Anastrozole + Palbociclib n=108 Participants 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.
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Albumin: low	1 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Alkaline Phosphatase: High	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline SGPT/ALT: High	1 Participants	5 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline SGOT/AST: High	1 Participants	3 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Calcium: Low	0 Participants	3 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Calcium: High	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Cholesterol: High	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Creatinine: High	0 Participants	1 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Glucose: Low	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Potassium: Low	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Potassium: High	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Sodium: Low	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Sodium: High	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Bilirubin: High	0 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Triglycerides: High	1 Participants	0 Participants
Number of Participants With Shifts in Blood Chemistry Parameters From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 at Post-baseline Uric Acid: High	21 Participants	22 Participants

SECONDARY outcome

Timeframe: Window of Opportunity Phase: Day 1 (3 hours Postdose) and Day 15 (Predose) during Cycle 0 (the 15-day period in Window of Opportunity Phase is called Cycle 0 for PK analysis); Neoadjuvant Phase: Cycle 2 Day 1, Predose

Population: Pharmacokinetics (PK) evaluable population included all participants who received giredestrant and had at least one evaluable post-dose giredestrant plasma concentration. Number analyzed is the number of participants with data available for analysis at the specified time point.

Outcome measures

Outcome measures
Measure	Giredestrant + Palbociclib n=108 Participants 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.	Anastrozole + Palbociclib 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.
Plasma Concentration of Giredestrant at Specified Timepoints Window of Opportunity Phase: Cycle 0 Day 1, 3-h Postdose	81.8 nanograms per milliliters (ng/mL) Geometric Coefficient of Variation 284	—
Plasma Concentration of Giredestrant at Specified Timepoints Window of Opportunity Phase: Cycle 0 Day 15, Predose	137 nanograms per milliliters (ng/mL) Geometric Coefficient of Variation 61.1	—
Plasma Concentration of Giredestrant at Specified Timepoints Neoadjuvant Phase: Cycle 2 Day 1, Predose	130 nanograms per milliliters (ng/mL) Geometric Coefficient of Variation 122	—

Adverse Events

Giredestrant + Palbociclib

Serious events: 5 serious events

Other events: 99 other events

Deaths: 1 deaths

Anastrozole + Palbociclib

Serious events: 2 serious events

Other events: 93 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Giredestrant + Palbociclib n=112 participants at risk 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.	Anastrozole + Palbociclib n=109 participants at risk 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.
Cardiac disorders Myocardial infarction	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.00% 0/109 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
General disorders Pyrexia	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.00% 0/109 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Infections and infestations COVID-19	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.00% 0/109 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Injury, poisoning and procedural complications Hip fracture	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.00% 0/109 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Injury, poisoning and procedural complications Procedural pain	0.00% 0/112 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.92% 1/109 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Injury, poisoning and procedural complications Uterine perforation	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.00% 0/109 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/112 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.92% 1/109 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Giredestrant + Palbociclib n=112 participants at risk 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.	Anastrozole + Palbociclib n=109 participants at risk 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.
Blood and lymphatic system disorders Anaemia	10.7% 12/112 • Number of events 13 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	5.5% 6/109 • Number of events 7 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Blood and lymphatic system disorders Leukopenia	12.5% 14/112 • Number of events 20 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	14.7% 16/109 • Number of events 29 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Blood and lymphatic system disorders Neutropenia	41.1% 46/112 • Number of events 77 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	40.4% 44/109 • Number of events 79 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Gastrointestinal disorders Constipation	2.7% 3/112 • Number of events 3 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	5.5% 6/109 • Number of events 6 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Gastrointestinal disorders Diarrhoea	7.1% 8/112 • Number of events 11 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	16.5% 18/109 • Number of events 25 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Gastrointestinal disorders Nausea	14.3% 16/112 • Number of events 19 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	11.9% 13/109 • Number of events 15 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Gastrointestinal disorders Vomiting	5.4% 6/112 • Number of events 6 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	0.92% 1/109 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
General disorders Asthenia	22.3% 25/112 • Number of events 28 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	24.8% 27/109 • Number of events 31 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
General disorders Fatigue	8.9% 10/112 • Number of events 10 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	16.5% 18/109 • Number of events 19 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
General disorders Mucosal inflammation	8.0% 9/112 • Number of events 9 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	2.8% 3/109 • Number of events 3 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
General disorders Pyrexia	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	5.5% 6/109 • Number of events 6 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Injury, poisoning and procedural complications Procedural pain	1.8% 2/112 • Number of events 2 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	5.5% 6/109 • Number of events 6 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Investigations Alanine aminotransferase increased	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	8.3% 9/109 • Number of events 9 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Investigations Aspartate aminotransferase increased	0.89% 1/112 • Number of events 1 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	5.5% 6/109 • Number of events 6 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Investigations Neutrophil count decreased	23.2% 26/112 • Number of events 39 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	22.0% 24/109 • Number of events 32 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Investigations White blood cell count decreased	12.5% 14/112 • Number of events 19 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	9.2% 10/109 • Number of events 12 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Musculoskeletal and connective tissue disorders Arthralgia	10.7% 12/112 • Number of events 13 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	19.3% 21/109 • Number of events 22 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Nervous system disorders Headache	4.5% 5/112 • Number of events 5 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	8.3% 9/109 • Number of events 9 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Skin and subcutaneous tissue disorders Alopecia	5.4% 6/112 • Number of events 6 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	4.6% 5/109 • Number of events 5 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Skin and subcutaneous tissue disorders Rash	5.4% 6/112 • Number of events 7 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	1.8% 2/109 • Number of events 2 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.
Vascular disorders Hot flush	14.3% 16/112 • Number of events 16 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.	14.7% 16/109 • Number of events 17 • From baseline up to 28 days after the last dose (up to approximately 24 weeks) 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.