Trial Outcomes & Findings for Fulvestrant and Ipatasertib for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor (NCT NCT04650581)

Last Updated: 2026-01-28

Results Overview

Progression-free survival (PFS) defined as time from randomization to disease progression or death from any cause, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

250 participants

Primary outcome timeframe

4 years

Results posted on

2026-01-28

Participant Flow

Dates of the recruitment period: January 27, 2021 to May 08, 2024

Participant milestones

Participant milestones
Measure	Ipatasertib + Fulvestrant Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Placebo + Flvestrant Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
Overall Study STARTED	125	125
Overall Study COMPLETED	124	124
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Ipatasertib + Fulvestrant Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Placebo + Flvestrant Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
Overall Study No treated	1	1

Baseline Characteristics

Intent to treat

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ipatasertib + Fulvestrant n=125 Participants Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Placebo + Flvestrant n=125 Participants Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Total n=250 Participants Total of all reporting groups
Race (NIH/OMB) Asian	16 Participants n=158 Participants	12 Participants n=157 Participants	28 Participants n=315 Participants
Age, Continuous	60 Years n=158 Participants	59 Years n=157 Participants	60 Years n=315 Participants
Sex: Female, Male Female	123 Participants n=158 Participants	124 Participants n=157 Participants	247 Participants n=315 Participants
Sex: Female, Male Male	2 Participants n=158 Participants	1 Participants n=157 Participants	3 Participants n=315 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=158 Participants	0 Participants n=157 Participants	2 Participants n=315 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=158 Participants	0 Participants n=157 Participants	1 Participants n=315 Participants
Race (NIH/OMB) Black or African American	4 Participants n=158 Participants	1 Participants n=157 Participants	5 Participants n=315 Participants
Race (NIH/OMB) White	98 Participants n=158 Participants	107 Participants n=157 Participants	205 Participants n=315 Participants
Race (NIH/OMB) More than one race	0 Participants n=158 Participants	0 Participants n=157 Participants	0 Participants n=315 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=158 Participants	5 Participants n=157 Participants	9 Participants n=315 Participants
Region of Enrollment Canada	89 Participants n=158 Participants	91 Participants n=157 Participants	180 Participants n=315 Participants
Region of Enrollment Australia	29 Participants n=158 Participants	29 Participants n=157 Participants	58 Participants n=315 Participants
Region of Enrollment New Zealand	7 Participants n=158 Participants	5 Participants n=157 Participants	12 Participants n=315 Participants
Body Mass Index	27.72 Kg per meter square (kg/(m*m)) STANDARD_DEVIATION 5.68 • n=158 Participants • Intent to treat	27.26 Kg per meter square (kg/(m*m)) STANDARD_DEVIATION 5.29 • n=157 Participants • Intent to treat	27.49 Kg per meter square (kg/(m*m)) STANDARD_DEVIATION 5.48 • n=315 Participants • Intent to treat

PRIMARY outcome

Timeframe: 4 years

Population: Intention-to-treat population

Outcome measures

Outcome measures
Measure	Placebo + Flvestrant n=125 Participants Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Ipatasertib + Fulvestrant n=125 Participants Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
Number of Participants With Progression-free Survival (PFS) Using RECIST 1.1	103 Participants	94 Participants

SECONDARY outcome

Timeframe: 4 years

Population: Subset of patients in the PIK3CA/AKT1/PTEN altered cohort

The PFS is tested in the PIK3CA/PTEN/AKT1 altered status subset under the same 0.05 significance level among the 111 subjects in the PIK3CA/PTEN/AKT1 altered status subset

Outcome measures

Outcome measures
Measure	Placebo + Flvestrant n=54 Participants Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Ipatasertib + Fulvestrant n=57 Participants Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
To Compare the Two Treatment Arms With Respect to Investigator Assessed PFS (Per RECIST 1.1) in the PIK3CA/AKT1/PTEN Altered Cohort	50 Participants	43 Participants

SECONDARY outcome

Timeframe: 4 years

Population: Intention-to-treat population

Number of patients with commencement of subsequent line of systemic therapy or death between enrollment and the end of study

Outcome measures

Outcome measures
Measure	Placebo + Flvestrant n=125 Participants Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Ipatasertib + Fulvestrant n=125 Participants Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
Commencement of Subsequent Line of Systemic Therapy or Death (TSST)	98 Participants	95 Participants

Adverse Events

Ipatasertib + Fulvestrant

Serious events: 18 serious events

Other events: 124 other events

Deaths: 42 deaths

Placebo + Flvestrant

Serious events: 18 serious events

Other events: 120 other events

Deaths: 36 deaths

Serious adverse events

Other adverse events

Additional Information

Bingshu Chen, Ph. D.

Canadian Cancer Trials Group

Phone: 613-533-6000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Ipatasertib + Fulvestrant n=124 participants at risk Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Placebo + Flvestrant n=124 participants at risk Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Cardiac disorders Chest pain - cardiac	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Cardiac disorders Myocardial infarction	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Abdominal pain	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Ascites	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Diarrhea	3.2% 4/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Enterocolitis	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Gastric hemorrhage	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Gastritis	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Mucositis oral	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Nausea	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Vomiting	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Death NOS	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Fever	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Pain	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Hepatobiliary disorders Hepatic failure	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Biliary tract infection	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Kidney infection	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Skin infection	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Urinary tract infection	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Injury, poisoning and procedural complications Fracture	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Injury, poisoning and procedural complications Hip fracture	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Injury, poisoning and procedural complications Uterine perforation	4.0% 5/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	2.4% 3/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Investigations Alanine aminotransferase increased	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Investigations Aspartate aminotransferase increased	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Investigations Blood bilirubin increased	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Metabolism and nutrition disorders Hyperglycemia	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Bone pain	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Reversible posterior leukoencephalopathy syndrome	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Stroke	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Syncope	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Renal and urinary disorders Urinary tract obstruction	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.81% 1/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.

Other adverse events
Measure	Ipatasertib + Fulvestrant n=124 participants at risk Ipatasertib will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.	Placebo + Flvestrant n=124 participants at risk Placebo will be administered orally at a dose of 400 mg once daily from Day 1 to Day 21 of each cycle. Fulvestrant will be administered intramuscularly at a dose of 500 mg. For the first cycle only, fulvestrant will be given on both Day 1 and Day 15. In all subsequent cycles, fulvestrant will be administered on Day 1 only. The duration of each cycle is 28 days.
Cardiac disorders Palpitations	2.4% 3/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Abdominal pain	24.2% 30/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	16.9% 21/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Bloating	12.1% 15/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	12.9% 16/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Constipation	36.3% 45/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	49.2% 61/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Diarrhea	90.3% 112/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	35.5% 44/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Dry mouth	11.3% 14/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	8.1% 10/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Dyspepsia	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	3.2% 4/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Gastroesophageal reflux disease	8.9% 11/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	10.5% 13/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Mucositis oral	20.2% 25/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	8.9% 11/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Nausea	77.4% 96/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	46.0% 57/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Gastrointestinal disorders Vomiting	45.2% 56/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	21.0% 26/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Edema limbs	8.9% 11/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	9.7% 12/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Fatigue	66.9% 83/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	62.1% 77/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Fever	8.1% 10/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	8.9% 11/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Flu like symptoms	4.8% 6/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Injection site reaction	3.2% 4/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	9.7% 12/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Non-cardiac chest pain	8.1% 10/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	8.9% 11/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
General disorders Pain	18.5% 23/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	16.1% 20/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Other infections and infestations	12.1% 15/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	9.7% 12/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Upper respiratory infection	7.3% 9/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	6.5% 8/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Infections and infestations Urinary tract infection	7.3% 9/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Metabolism and nutrition disorders Anorexia	30.6% 38/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	19.4% 24/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Metabolism and nutrition disorders Dehydration	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	0.00% 0/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Arthralgia	20.2% 25/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	21.0% 26/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Back pain	31.5% 39/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	39.5% 49/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Bone pain	36.3% 45/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	34.7% 43/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Buttock pain	7.3% 9/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	8.1% 10/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Chest wall pain	4.0% 5/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Flank pain	1.6% 2/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	3.2% 4/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	7.3% 9/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Myalgia	16.1% 20/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	25.0% 31/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Neck pain	8.9% 11/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	21.8% 27/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	19.4% 24/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Dizziness	14.5% 18/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	13.7% 17/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Dysgeusia	10.5% 13/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	4.8% 6/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Headache	38.7% 48/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	33.1% 41/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Neuralgia	5.6% 7/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	4.0% 5/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Paresthesia	8.1% 10/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	6.5% 8/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Nervous system disorders Peripheral sensory neuropathy	11.3% 14/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	15.3% 19/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.
Psychiatric disorders Anxiety	17.7% 22/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.	13.7% 17/124 • From enrollment until end of follow-up, up to 4 years All-cause mortality was analyzed based on all 250 randomized patients. Serious Adverse Events and Other Adverse Events were analyzed based on 248 patients who received protocol treatment.