A Study Evaluating the Efficacy and Safety of Giredestrant Compared With Physician's Choice of Endocrine Monotherapy in Participants With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (acelERA Breast Cancer)

PFS was defined as the Kaplan-Meier estimate of time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first). Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Kaplan-Meier methodology was used to estimate median PFS. The 95% confidence interval for the median was computed using the method of Brookmeyer and Crowley. Participants without the occurrence of disease progression or death as of the clinical cutoff were censored at the time of the last tumor assessment prior to the clinical cutoff or at the time of randomization plus 1 day for those without post-baseline assessment.

Time frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (duration of follow-up, median [range]: 7.9 [0.0-14.1] months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

The clinical benefit rate is defined as the percentage of participants with stable disease for ≥24 weeks or a CR or PR. Per RECIST v1.1, CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

Time frame: From randomization until disease progression or death (up to approximately 15 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

DOR is defined as the Kaplan-Meier estimate of time from the first occurrence of a documented objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). Objective response rate is defined as the percentage of participants with a CR or PR on two consecutive occasions at least 4 weeks apart. Per RECIST v1.1, CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.

Time frame: From first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 15 months)

PFS was defined as the Kaplan-Meier estimate of time from randomization to the first occurrence of disease progression determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). Disease progression was defined as ≥20% increase in in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Investigator-assessed PFS was analyzed in subgroups categorized by baseline ESR1 mutation status (i.e., with or without ESR1 mutation at baseline) from plasma circulating tumor deoxyribonucleic acid (ctDNA). Participants without the occurrence of disease progression or death as of the clinical cutoff were censored at the time of the last tumor assessment prior to the clinical cutoff or at the time of randomization plus 1 day for those without post-baseline assessment.

Time frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (duration of follow-up, median [range]: 7.9 [0.0-14.1] months)

Population: ctDNA-evaluable population included all FAS participants with evaluable plasma ctDNA at baseline. Number analyzed is the number of participants with data available for analysis at the specified time point. Participants without the occurrence of disease progression or death as of the clinical cutoff were censored at the time of last tumor assessment prior to the clinical cutoff or at the time of randomization plus 1 day for those without post-baseline assessment.

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; recurrence of an intermittent medical condition; any deterioration in a laboratory value or other clinical test; AEs that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment.

Time frame: From first dose until 30 days after final dose of study drug (up to approximately 55 months)

Biochemistry parameters include bicarbonate or total carbon dioxide, sodium, potassium, chloride, glucose, blood urea nitrogen (BUN) or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, alkaline phosphatase level test (ALP), Alanine transaminase (ALT), aspartate aminotransferase (AST), urate, and lactate dehydrogenase (LDH).

Time frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to approximately 55 months)

Hematology parameters include white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).

Time frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to approximately 55 months)

Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.

Time frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to approximately 55 months)

The objective response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart. Per RECIST v1.1, CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

Time frame: From randomization until disease progression or death (up to approximately 15 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

Overall survival (OS) is defined as the Kaplan-Meier estimate of time from randomization to death from any cause. Kaplan-Meier methodology was used to estimate median OS. The 95% confidence interval for the median was computed using the method of Brookmeyer and Crowley. Analysis strata are: Site of disease, Prior treatment with CDK4/6 inhibitor and Prior treatment with fulvestrant. Hazard ratios were estimated by Cox regression. Data for participants who were alive at the time of the analysis data cutoff were censored at the last date they were known to be alive. Data from participants without postbaseline information were censored at the date of randomization plus 1 day.

Time frame: From randomization to death from any cause (duration of follow-up, median [range]: 34.6 [0.0-41.8] months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

Time frame: Cycle 1 Day 1 3-hours postdose, Cycle 2 Day 1 predose, Cycle 2 Day 1 3-hour postdose, Cycle 3 Day 1 predose

Population: Pharmacokinetics (PK)-Evaluable Population: All randomized patients in the giredestrant arm who had at least one evaluable post-dose giredestrant plasma concentration. The overall number of participants analyzed is the total number of unique participants who had an evaluable PK sample for at least one timepoint. The number analyzed at a given timepoint indicates those with an evaluable sample for the specified timepoint.

TTD in pain severity is defined as time to first documented ≥2-point increase from Baseline in the Worst Pain item from the BPI-SF Questionnaire held for at least two consecutive cycles or an initial ≥2-point worsening followed by death or treatment discontinuation within 3 weeks from the last assessment. The BPI-SF is a self administered questionnaire developed to assess the severity of pain (the sensory dimension) as well as the degree to which pain interferes with function (the reactive dimension). The BPI-SF uses 10-point numeric rating scale, with 0=No pain, No interference to 10=Pain as bad as you can imagine, Highest imaginable interference. A lower score indicates improvement. 95% CI for median was computed using the method of Brookmeyer and Crowley. Strata are: Site of disease, Prior treatment with CDK4/6 inhibitor, and Prior treatment with fulvestrant. Hazard ratios were estimated by Cox regression.

Time frame: From Baseline until treatment discontinuation (up to approximately 41 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

TTD in GHS/QoL is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed RF scale score (0-100 scale) held for at least 2 consecutive cycles or an initial ≥10-point worsening followed by death or treatment discontinuation within 3 weeks from the last assessment. EORTC QLQ-C30 is a patient-reported measure with 30 questions assessing 5 aspects of functioning, 3 symptom scales, global health and quality of life, and 6 single items with a recall period of the previous week. The GHS/QoL scale has 7 possible scores of responses (1=very poor to 7=excellent); higher scores indicate better QoL. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Strata are: Site of disease, Prior treatment with CDK4/6 inhibitor, and Prior treatment with fulvestrant. Hazard ratios were estimated by Cox regression.

Time frame: From Baseline until treatment discontinuation (up to approximately 41 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

TTD in pain presence and interference is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed pain scale score (0-100 scale) held for at least 2 consecutive cycles or an initial ≥10-point worsening followed by death or treatment discontinuation within 3 weeks from the last assessment. EORTC QLQ-C30 is a patient-reported measure with 30 questions assessing 5 aspects of functioning, 3 symptom scales, global health and quality of life, and 6 single items with a recall period of the previous week. The pain scale is scored on a 4-point scale (1=Not at All to 4=Very Much); higher scores indicate worse pain symptoms. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Strata are: Site of disease, Prior treatment with CDK4/6 inhibitor, and Prior treatment with fulvestrant. Hazard ratios were estimated by Cox regression.

Time frame: From Baseline until treatment discontinuation (up to approximately 41 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

TTD in PF is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed PF scale score (0-100 scale) held for at least 2 consecutive cycles or an initial ≥10-point worsening followed by death or treatment discontinuation within 3 weeks from the last assessment. EORTC QLQ-C30 is a patient-reported measure with 30 questions assessing 5 aspects of functioning, 3 symptom scales, global health and quality of life, and 6 single items with a recall period of the previous week. The PF scale has 5 questions scored on a 4-point scale (1=Not at All to 4=Very Much); higher scores indicate better function. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Strata are: Site of disease, Prior treatment with CDK4/6 inhibitor, and Prior treatment with fulvestrant. Hazard ratios were estimated by Cox regression.

Time frame: From Baseline until treatment discontinuation (up to approximately 41 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.

TTD in RF is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed RF scale score (0-100 scale) held for at least 2 consecutive cycles or an initial ≥10-point worsening followed by death or treatment discontinuation within 3 weeks from the last assessment. EORTC QLQ-C30 is a patient-reported measure with 30 questions assessing 5 aspects of functioning, 3 symptom scales, global health and quality of life, and 6 single items with a recall period of the previous week. The RF is scored on a 4-point scale (1=Not at All to 4=Very Much); higher scores indicate better function. The 95% CI for median was computed using the method of Brookmeyer and Crowley. Strata are: Site of disease, Prior treatment with CDK4/6 inhibitor, and Prior treatment with fulvestrant. Hazard ratios were estimated by Cox regression.

Time frame: From Baseline until treatment discontinuation (up to approximately 41 months)

Population: FAS included all participants assigned to treatment groups as randomized by the IxRS.