Trial Outcomes & Findings for 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. (NCT NCT02437318)

Last Updated: 2025-02-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

572 participants

Primary outcome timeframe

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

Results posted on

2025-02-13

Participant Flow

Participants were enrolled in 198 centers across 31 countries

One subject in the PIK3CA mutant cohort, who was randomized to the placebo + fulvestrant arm, did not receive study treatment due to a protocol deviation.

Participant milestones

Participant milestones
Measure	Alpelisib + Fulvestrant Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	Placebo + Fulvestrant Subjects treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Overall Study STARTED	284	288
Overall Study Treated	284	287
Overall Study PIK3CA Mutant Cohort by Tumor Tissue	169	172
Overall Study PIK3CA Non-mutant Cohort by Tumor Tissue	115	116
Overall Study PIK3CA Mutant Cohort by ctDNA	92	94
Overall Study PIK3CA Non-mutant Cohort by ctDNA	181	182
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	284	288

Reasons for withdrawal

Reasons for withdrawal
Measure	Alpelisib + Fulvestrant Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	Placebo + Fulvestrant Subjects treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Overall Study Progressive disease	207	240
Overall Study Subject/guardian decision	24	11
Overall Study Physician Decision	29	22
Overall Study Adverse Event	14	4
Overall Study Death	4	4
Overall Study Protocol deviation	5	7
Overall Study Sponsor decision	1	0

Baseline Characteristics

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.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Alpelisib + Fulvestrant n=284 Participants Subjects treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	Placebo + Fulvestrant n=288 Participants Subjects treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	Total n=572 Participants Total of all reporting groups
Age, Continuous	62.6 Years STANDARD_DEVIATION 9.74 • n=5 Participants	63.3 Years STANDARD_DEVIATION 10.26 • n=7 Participants	63.0 Years STANDARD_DEVIATION 10.00 • n=5 Participants
Sex: Female, Male Female	283 Participants n=5 Participants	288 Participants n=7 Participants	571 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	199 Participants n=5 Participants	178 Participants n=7 Participants	377 Participants n=5 Participants
Race/Ethnicity, Customized Asian	59 Participants n=5 Participants	66 Participants n=7 Participants	125 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Other	9 Participants n=5 Participants	17 Participants n=7 Participants	26 Participants n=5 Participants
Race/Ethnicity, Customized Unknown	14 Participants n=5 Participants	17 Participants n=7 Participants	31 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Progression-free Survival (PFS) Per Investigator Assessment in the PIK3CA Mutant Cohort	11.0 Months Interval 7.49 to 14.52	5.7 Months Interval 3.65 to 7.36	—	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Overall Survival (OS) in the PIK3CA Mutant Cohort	39.3 Months Interval 34.1 to 44.85	31.4 Months Interval 26.78 to 41.3	—	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=115 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=116 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
PFS Per Investigator Assessment in the PIK3CA Non-mutant Cohort	7.43 Months Interval 5.55 to 10.84	7.23 Months Interval 5.06 to 9.17	—	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=115 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=116 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
OS in the PIK3CA Non-mutant Cohort	37.29 Months Interval 27.89 to 45.47	34.30 Months Interval 26.81 to 39.03	—	—

SECONDARY outcome

Timeframe: Up to 56.4 months

Population: All subjects 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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=115 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=116 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Overall Response Rate (ORR) Per Investigator Assessment	26.6 Percentage of participants Interval 20.1 to 34.0	13.4 Percentage of participants Interval 8.7 to 19.4	20.9 Percentage of participants Interval 13.9 to 29.4	12.9 Percentage of participants Interval 7.4 to 20.4

SECONDARY outcome

Timeframe: Up to 56.4 months

Population: All subjects who were randomized to study treatment.

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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=115 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=116 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Clinical Benefit Rate (CBR) Per Investigator Assessment	61.5 Percentage of participants Interval 53.8 to 68.9	44.8 Percentage of participants Interval 37.2 to 52.5	53.9 Percentage of participants Interval 44.4 to 63.2	49.1 Percentage of participants Interval 39.7 to 58.6

SECONDARY outcome

Timeframe: From baseline up to 56.4 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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=115 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=116 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Time to Definitive Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score From Baseline	34.07 Months Interval 26.32 to NA: Not estimable due to the insufficient number of participants with events	NA Months Interval 22.11 to NA: Not estimable due to the insufficient number of participants with events	NA Months Interval 13.83 to NA: Not estimable due to the insufficient number of participants with events	40.44 Months Interval 18.46 to 47.21

SECONDARY outcome

Timeframe: From baseline up to 55.7 months

Population: All subjects 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 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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=115 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=116 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Time to 10% Deterioration in the Global Health Status (GHS) /Quality of Life (QOL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)	18.14 Months Interval 14.55 to 28.68	19.98 Months Interval 11.5 to 25.59	7.39 Months Interval 5.62 to NA: not estimable due to the insufficient number of participants with events	9.23 Months Interval 3.94 to 13.17

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=142 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=140 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=98 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=92 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 8	-2.477 Score on a Scale Standard Error 2.286	-0.369 Score on a Scale Standard Error 2.324	1.524 Score on a Scale Standard Error 2.578	2.698 Score on a Scale Standard Error 2.601
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 16	-1.796 Score on a Scale Standard Error 2.349	-2.685 Score on a Scale Standard Error 2.455	2.866 Score on a Scale Standard Error 2.809	1.700 Score on a Scale Standard Error 2.835
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 24	-3.010 Score on a Scale Standard Error 2.415	-0.337 Score on a Scale Standard Error 2.587	1.383 Score on a Scale Standard Error 3.087	4.909 Score on a Scale Standard Error 3.385
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 32	-2.802 Score on a Scale Standard Error 2.519	-0.891 Score on a Scale Standard Error 2.646	1.063 Score on a Scale Standard Error 3.420	4.345 Score on a Scale Standard Error 3.731
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 40	-2.815 Score on a Scale Standard Error 2.581	-1.854 Score on a Scale Standard Error 2.739	13.232 Score on a Scale Standard Error 4.783	4.923 Score on a Scale Standard Error 4.003
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 48	-3.635 Score on a Scale Standard Error 2.621	-1.460 Score on a Scale Standard Error 2.853	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 56	-1.617 Score on a Scale Standard Error 2.701	0.248 Score on a Scale Standard Error 2.935	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 64	-1.937 Score on a Scale Standard Error 2.835	-1.979 Score on a Scale Standard Error 2.984	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 72	-2.525 Score on a Scale Standard Error 2.823	-1.526 Score on a Scale Standard Error 3.098	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 84	-1.135 Score on a Scale Standard Error 2.958	-1.495 Score on a Scale Standard Error 3.143	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 96	-3.869 Score on a Scale Standard Error 3.054	-3.581 Score on a Scale Standard Error 3.423	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 108	-2.158 Score on a Scale Standard Error 3.328	-2.068 Score on a Scale Standard Error 3.609	—	—
Change From Baseline in the GHS/QOL Scale Score of the EORTC QLQ-C30 Week 120	-2.928 Score on a Scale Standard Error 3.251	-2.593 Score on a Scale Standard Error 3.868	—	—

SECONDARY outcome

Timeframe: 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 alpelisib were assessed. Only participants randomized to the alpelisib + fulvestrant arm were included in this analysis.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=96 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Trough Plasma Concentration of Alpelisib Cycle 1 Day 8	424 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 41.1	—	—	—
Trough Plasma Concentration of Alpelisib Cycle 1 Day 15	468 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 57.6	—	—	—
Trough Plasma Concentration of Alpelisib Cycle 2 Day 1	436 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 53.4	—	—	—
Trough Plasma Concentration of Alpelisib Cycle 4 Day 1	458 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 69.4	—	—	—
Trough Plasma Concentration of Alpelisib Cycle 6 Day 1	418 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 57.1	—	—	—
Trough Plasma Concentration of Alpelisib Cycle 8 Day 1	469 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 58.3	—	—	—

SECONDARY outcome

Timeframe: 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-dose plasma concentrations of fulvestrant were assessed.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=124 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=124 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Trough Plasma Concentration of Fulvestrant Cycle 2 Day 1	14.0 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 39.7	14.7 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 41.2	—	—
Trough Plasma Concentration of Fulvestrant Cycle 1 Day 15	10.8 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 43.5	10.3 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 51.0	—	—
Trough Plasma Concentration of Fulvestrant Cycle 4 Day 1	11.5 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 32.2	12.2 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 29.8	—	—
Trough Plasma Concentration of Fulvestrant Cycle 6 Day 1	12.6 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 30.5	14.0 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 24.2	—	—
Trough Plasma Concentration of Fulvestrant Cycle 8 Day 1	13.5 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 35.2	14.7 nanogram (ng)/ milliliter (mL) Geometric Coefficient of Variation 23.2	—	—

SECONDARY outcome

Timeframe: From baseline up to 56.4 months

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

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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=92 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=94 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=181 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=182 Participants Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
PFS Per Investigator Criteria in Subjects With PIK3CA Mutation Status Measured in ctDNA at Baseline	10.9 Months Interval 7.03 to 15.28	3.7 Months Interval 2.27 to 6.11	9.0 Months Interval 7.23 to 11.01	7.4 Months Interval 5.55 to 9.2

POST_HOC outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=284 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=288 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
All Collected Deaths Pre-treatment	0 Participants	0 Participants	—	—
All Collected Deaths On-treatment	9 Participants	12 Participants	—	—
All Collected Deaths Post-treatment survival follow-up	151 Participants	156 Participants	—	—
All Collected Deaths All deaths	160 Participants	168 Participants	—	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 55.7 months

Population: All subjects with a PIK3CA mutation 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.

Outcome measures

Outcome measures
Measure	PIK3CA Mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant n=169 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Mutant Cohort by Tumor Tissue: Placebo + Fulvestrant n=172 Participants Subjects with advanced breast cancer with a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Alpelisib + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with alpelisib (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)	PIK3CA Non-mutant Cohort by Tumor Tissue: Placebo + Fulvestrant Subjects with advanced breast cancer without a PIK3CA mutation (based on central testing of hotspot-mutations in tumor tissue) treated with placebo (300 mg; oral; once daily) in combination with fulvestrant (500 mg; intramuscular injection on Day 1 and Day 15 of Cycle 1, and then Day 1 of each subsequent 28-day cycle)
Updated PFS Per Investigator Assessment in the PIK3CA Mutant Cohort (Longer Follow-up)	10.97 Months Interval 7.49 to 14.52	5.65 Months Interval 3.65 to 7.36	—	—

Adverse Events

Alpelisib + Fulvestrant

Serious events: 110 serious events

Other events: 280 other events

Deaths: 9 deaths

Placebo + Fulvestrant

Serious events: 54 serious events

Other events: 244 other events

Deaths: 12 deaths

Alpelisib + Fulvestrant (Post-treatment Survival Follow-up)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 151 deaths

Placebo + Fulvestrant (Post-treatment Survival Follow-up)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 156 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER