Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant in Men and Postmenopausal Women With Advanced Breast Cancer Which Progressed on or After Aromatase Inhibitor Treatment.

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Progression was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Once approximately 243 PFS events in the PIK3CA mutant cohort had been observed, up to 33.3 months

Population: All subjects with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) who were randomized to study treatment

The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicated improvement. For each cohort, this analysis only included assessments up to the time point where there were at least 10 patients on each of the 2 treatment groups.

Time frame: Baseline, every 8 weeks after randomization during the first 18 months and thereafter every 12 weeks, up to 120 weeks.

Population: Randomized participants with baseline scores and at least one non-missing post-baseline assessment. Number analyzed refers to the number of participants with an evaluable value at the specified time point

Clinical benefit rate was defined as the percentage of patients with a best overall response of CR or PR or stable disease (SD) or Non-CR/Non-PD lasting more than 24 weeks based on local investigator assessment according to RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

Time frame: Up to 56.4 months

Population: All subjects who were randomized to study treatment.

OS was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive. The OS distribution was estimated using Kaplan-Meier methodology.

Time frame: Up to 56.4 months

Population: All subjects without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) who were randomized to study treatment

ORR was defined as the percentage of patients with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, any pathological lymph nodes assigned as target and non-target lesions must have a reduction in short axis to \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Time frame: Up to 56.4 months

Population: All subjects who were randomized to study treatment.

OS was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last known date patient alive. The OS distribution was estimated using Kaplan-Meier methodology.

Time frame: Once approximately 178 deaths in the PIK3CA mutant cohort had been observed, up to 55.7 months

Population: All subjects with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) who were randomized to study treatment

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Progression was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Up to 56.4 months

Population: All subjects without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) who were randomized to study treatment

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. Subjects were analyzed according to the PIK3CA mutation status (mutant or non-mutant) as identified using plasma ctDNA. Progression was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From baseline up to 56.4 months

Population: Subjects who were randomized to study treatment with an evaluable mutation status by ctDNA at baseline

The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as at least 10% relative to baseline worsening of the GHS/QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.

Time frame: From baseline up to 55.7 months

Population: All subjects who were randomized to study treatment

ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration of ECOG PS by one score was defined as the time from the date of randomization to the date of the event, defined as experiencing at least one score lower than the baseline. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.

Time frame: From baseline up to 56.4 months

Population: All subjects who were randomized to study treatment

Pre-dose plasma concentrations of alpelisib were assessed. Only participants randomized to the alpelisib + fulvestrant arm were included in this analysis.

Time frame: Day 8 and Day 15 of Cycle 1, then Day 1 of Cycles 2, 4, 6 and 8. Cycle = 28 days

Population: Participants who received at least one dose of alpelisib and provided at least one evaluable trough plasma concentration for alpelisib at the specified time points

Pre-dose plasma concentrations of fulvestrant were assessed.

Time frame: Day 15 of Cycle 1, then Day 1 of Cycles 2, 4, 6 and 8. Cycle = 28 days

Population: Participants who received at least one dose of fulvestrant and provided at least one evaluable trough plasma concentration for fulvestrant at the specified time points

Pre-treatment deaths were collected from randomization to the day before first dose of study medication. On-treatment deaths were collected from start of treatment to 30 days after last dose of study medication. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study treatment to end of study.

Time frame: Pre-treatment: Up to 35 days. On-treatment: Up to approx. 6.5 years. Post-treatment survival follow-up: Up to approx. 6.5 years

Population: All subjects who were randomized to study treatment.

PFS was defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS was assessed via a local radiology assessment according to RECIST 1.1. If a patient did not have an event, PFS was censored at the date of last adequate tumor assessment. The PFS distribution was estimated using Kaplan-Meier methodology. This analysis was conducted at the time of the final OS analysis (when approximately 178 deaths in the PIK3CA mutant cohort had been achieved) and includes a longer follow-up time. Progression was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: Up to 55.7 months

Population: All subjects with a PIK3CA mutation who were randomized to study treatment