Trial Outcomes & Findings for A Phase II Study Comparing The Efficacy Of Venetoclax + Fulvestrant Vs. Fulvestrant In Women With Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy (NCT NCT03584009)

Last Updated: 2022-06-28

Results Overview

Clinical Benefit was defined as CR, PR, or SD lasting more than equal to 24 weeks from randomization in participants with measurable disease at baseline, as determined by the investigator according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. Per RECIST v1.1 for target lesions assessed by CT or MRI: CR, Disappearance of all target lesions; PR, PR \>= 30% decrease in the sum of diameters of target lesions (TL) taking as reference the baseline sum of diameters; SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Disease Progression (PD), PD\>= 20% increase in the sum of diameters of TL taking as reference the smallest sum on study(Nadir). In addition to the relative increase of 20% sum must have demonstrate an absolute increase of at least 5mm.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

103 participants

Primary outcome timeframe

Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Results posted on

2022-06-28

Participant Flow

The study was conducted at 38 centers in 5 countries.

A total of 103 participants were randomized in this study. Of these, 101 participants received at least one dose of any study drug.

Participant milestones

Participant milestones
Measure	Venetoclax + Fulvestrant Participants were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Overall Study STARTED	51	52
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	51	52

Reasons for withdrawal

Reasons for withdrawal
Measure	Venetoclax + Fulvestrant Participants were administered Venetoclax 800mg orally once daily (QD) and Fulvestrant 500mg intramuscularly (IM) on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Overall Study Death	25	18
Overall Study Lost to Follow-up	0	1
Overall Study Physician Decision	1	1
Overall Study Study Terminated by Sponsor	22	30
Overall Study Withdrawal by Subject	3	2

Baseline Characteristics

A Phase II Study Comparing The Efficacy Of Venetoclax + Fulvestrant Vs. Fulvestrant In Women With Estrogen Receptor-Positive, Her2-Negative Locally Advanced Or Metastatic Breast Cancer Who Experienced Disease Recurrence Or Progression During Or After CDK4/6 Inhibitor Therapy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Venetoclax + Fulvestrant n=51 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=52 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Total n=103 Participants Total of all reporting groups
Age, Continuous	57.4 years STANDARD_DEVIATION 10.6 • n=93 Participants	58.8 years STANDARD_DEVIATION 11.7 • n=4 Participants	58.1 years STANDARD_DEVIATION 11.1 • n=27 Participants
Sex: Female, Male Female	51 Participants n=93 Participants	52 Participants n=4 Participants	103 Participants n=27 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants	3 Participants n=4 Participants	4 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	47 Participants n=93 Participants	46 Participants n=4 Participants	93 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=93 Participants	3 Participants n=4 Participants	6 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	6 Participants n=93 Participants	3 Participants n=4 Participants	9 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	3 Participants n=93 Participants	2 Participants n=4 Participants	5 Participants n=27 Participants
Race (NIH/OMB) White	40 Participants n=93 Participants	46 Participants n=4 Participants	86 Participants n=27 Participants
Race (NIH/OMB) More than one race	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants

PRIMARY outcome

Timeframe: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Population: The Baseline Measurable Disease Population represented all randomized participants with measurable disease at baseline.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=51 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=51 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Clinical Benefit Defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) Lasting >= 24 Weeks, as Determined by the Investigator According to RECIST v1.1	11.8 Percentage of Participants Interval 4.44 to 23.87	13.7 Percentage of Participants Interval 5.7 to 26.26

SECONDARY outcome

Timeframe: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Population: ITT population included all randomized participants whether or not they were assigned to the arm where the study treatment was administered.

PFS was defined as the time from randomization to the first occurrence of disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=51 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=52 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Progression Free Survival (PFS)	2.69 Months Interval 1.94 to 3.71	1.94 Months Interval 1.84 to 3.55

SECONDARY outcome

Timeframe: Randomization through till 6 months after the last participant is enrolled into the study (up to approximately 23 months)

Population: The Baseline Measurable Disease Population represented all randomized participants with measurable disease at baseline.

OR was defined as CR or PR, in participants with measurable disease at baseline as determined by the investigator according to RECIST v1.1.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=51 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=51 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Objective Response (OR)	3.9 Percentage of Participants Interval 0.48 to 13.46	5.9 Percentage of Participants Interval 1.23 to 16.24

SECONDARY outcome

Timeframe: Time from first occurrence of a documented objective response to the first documented disease progression or death from any cause, whichever occurs first, until 6 months after the last participant is enrolled in the study (up to approximately 23 months)

Population: Only participants with a documented objective response were analysed for this Outcome Measure.

DOR was defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression (as determined by the investigator according to RECIST v1.1) or death from any cause, whichever occurs first.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=2 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=3 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Duration of Response (DOR)	NA Months Insufficient number of participants meant that Median, Lower Limit and Upper Limit values could not be estimated.	3.61 Months Interval 1.94 to Insufficient number of participants meant that Upper Limit value could not be estimated.

SECONDARY outcome

Timeframe: Randomization to death from any cause, through till the end of the study (up to approximately 32 months)

Population: ITT population included all randomized participants whether or not they were assigned to the arm where the study treatment was administered.

OS was defined as the time from randomization to death due to any cause.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=51 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=52 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Overall Survival (OS)	19.71 Months Interval 13.73 to Data for upper limit of CI was not estimable due to fewer number of participants with events.	NA Months Interval 20.93 to Data for median and upper limit of CI was not estimable due to fewer number of participants with events

SECONDARY outcome

Timeframe: Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months

Population: Safety-evaluable population which included all participants who received any amount of any component of the investigational or non-investigational study treatments.

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study were also considered as AEs.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=50 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=51 Participants Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Percentage of Participants With Adverse Events (AEs)	94.0 Percentage of Participants	76.5 Percentage of Participants

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 4 hours (hrs) post-dose; Cycle 2 Day 1: pre-dose (within 1 hr) and 2, 4, 6, 8 hrs post-dose; any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)

Population: Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. Number analyzed is the number of participants with data available for analyses at the given time-point.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=47 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Plasma Concentrations of Venetoclax Cycle 1 Day 1: 4 hrs post-dose	1.78 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation 61.8	—
Plasma Concentrations of Venetoclax Cycle 2 Day 1: pre-dose	1.04 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation 85.4	—
Plasma Concentrations of Venetoclax Cycle 2 Day 1: 2 hrs post-dose	1.45 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation 74.1	—
Plasma Concentrations of Venetoclax Cycle 2 Day 1: 4 hrs post-dose	2.51 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation 57.2	—
Plasma Concentrations of Venetoclax Cycle 2 Day 1: 6 hrs post-dose	3.32 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation 56.4	—
Plasma Concentrations of Venetoclax Cycle 2 Day 1: 8 hrs post-dose	3.55 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation 57.8	—
Plasma Concentrations of Venetoclax Treatment discontinuation visit	0.0112 Micrograms per Milliliters (μg/mL) Geometric Coefficient of Variation NA Data for Geometric Coefficient of Variation was not reportable as more than one-third values were lower than reportable.	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1: pre-dose (within 1 hr); Cycle 6 Day 1: pre-dose (within 1 hr); any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)

Population: PK evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. Number analyzed is the number of participants with data available for analyses at the given time-point.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=42 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Plasma Concentrations of Fulvestrant (in Presence of Venetoclax) Cycle 2 Day 1: pre-dose	0.0129 μg/mL Geometric Coefficient of Variation 37.1	—
Plasma Concentrations of Fulvestrant (in Presence of Venetoclax) Cycle 6 Day 1: pre-dose	0.0145 μg/mL Geometric Coefficient of Variation 31.8	—
Plasma Concentrations of Fulvestrant (in Presence of Venetoclax) Treatment discontinuation visit	0.00985 μg/mL Geometric Coefficient of Variation 29.1	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1: pre-dose (within 1 hr); any time during visits up to study drug discontinuation/Early Termination (up to approximately 32 months)

Population: PK evaluable population included all participants who received at least one dose of the study drugs (either venetoclax or fulvestrant) and had evaluable PK data. Number of participants analyzed is the number of participants analyzed for this outcome measure. Number analyzed is the number of participants with data available for analyses at the given time-point.

Outcome measures

Outcome measures
Measure	Venetoclax + Fulvestrant n=5 Participants Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
Plasma Concentrations of Fulvestrant (in Absence of Venetoclax) Cycle 2 Day 1: pre-dose	0.0103 μg/mL Geometric Coefficient of Variation 29.4	—
Plasma Concentrations of Fulvestrant (in Absence of Venetoclax) Treatment discontinuation visit	0.0139 μg/mL Geometric Coefficient of Variation NA Data for Geometric Coefficient of Variation was not estimable due to lower number of participants at given timepoint.	—

Adverse Events

Venetoclax + Fulvestrant

Serious events: 4 serious events

Other events: 45 other events

Deaths: 26 deaths

Fulvestrant

Serious events: 2 serious events

Other events: 34 other events

Deaths: 18 deaths

Serious adverse events

Serious adverse events
Measure	Venetoclax + Fulvestrant n=50 participants at risk Participants were administered Venetoclax 800mg orally QD and Fulvestrant 500mg IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).	Fulvestrant n=51 participants at risk Participants were administered Fulvestrant 500mg only IM on Day 1 and 15 of Cycle 1 and Day 1 of subsequent cycles (Cycle length = 28 days).
General disorders Pyrexia	2.0% 1/50 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	0.00% 0/51 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Infections and infestations Lower respiratory tract infection	2.0% 1/50 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	0.00% 0/51 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Infections and infestations Urosepsis	2.0% 1/50 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	0.00% 0/51 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Investigations Ejection fraction decreased	2.0% 1/50 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	0.00% 0/51 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/50 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	2.0% 1/51 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/50 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	2.0% 1/51 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/50 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.	2.0% 1/51 • Number of events 1 • Baseline up until 28 days after the last dose of study drug (venetoclax or fulvestrant, whichever is later) up to approximately 32 months. The 1 additional death in the Venetoclax + Fulvestrant arm compared to in the Participant Flow section, relates to a participant who had withdrawn consent from the study and later died. Their death was reported in public records (reported as a post study reporting death). All-cause mortality is for ITT population and serious and other AEs are reported for safety population.

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER