Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3)

• ClinicalTrials.gov Identifier: NCT01942135
• Recruitment Status: Active, not recruiting
• First Posted: September 13, 2013
• Results First Posted: May 23, 2016
• Last Update Posted: November 27, 2019
• Sponsor: Pfizer
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer
• Interventions: Drug: Palbociclib; Drug: Fulvestrant; Drug: Placebo
• Enrollment: 521

Participant Flow

Recruitment Details	The study was conducted at 144 sites in 17 countries that randomized 521 participants. Eligible participants were to have histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of recurrent (local or metastatic) disease.
Pre-assignment Details	The study consisted of a screening visit within 28 days before randomization, an active treatment phase, divided in cycles of 28 days each, and a post-treatment follow-up period during which survival and new anti-cancer therapy information was collected every 3 months for the first 9 months, then every 6 months from the last dose of study drug.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Period Title: Overall Study
Started	347	174
Completed	0	0
Not Completed	347	174
Reason Not Completed
Adverse Event	9	3
Global deterioration of health status	8	3
Randomized Not Treated	2	2
Death	0	1
ObjectiveProgression+Progressive Disease	85	87
Participant Refused toContinue Treatment	1	1
Withdrawal by Subject	4	2
Ongoing at date of cut-off (05 Dec 2014)	238	75

Baseline Characteristics

Arm/Group Title		Palbociclib + Fulvestrant	Placebo + Fulvestrant	Total
Arm/Group Description		Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Total of all reporting groups
Overall Number of Baseline Participants		347	174	521
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	347 participants	174 participants	521 participants
		56.9 (11.7)	56.8 (10.4)	56.9 (11.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	347 participants	174 participants	521 participants
	Female	347 100.0%	174 100.0%	521 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) as Assessed by the Investigator
Description	PFS is the time from the date of randomization to the date of the first documentation of objective progression of disease (PD)or death due to any cause in absence of documented PD. Participants lacking an evaluation of tumor response after randomization had their PFS time censored on the date of randomization with the duration of a day. Participants with documentation of PD or death after a long interval (2 or more incomplete or non-evaluable assessments) since the last tumor assessment were censored at the time of last objective assessment that did not show PD. The length of PFS was calculated as PFS time (months) =[progression/death date(censor date) - randomization date + 1]/30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors(RECIST v1.1) a 20% increase in the sum of diameters of target lesions and the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of existing non-target lesions or the appearance of new lesions.
Time Frame	From randomization date to date of first documentation of progression or death (assessed up to 12 months)

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received the study medication or received a different drug from that to which they were randomized.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	347	174
Median (95% Confidence Interval); Unit of Measure: Months
	9.2 [1]; (7.5 to NA)	3.8; (3.5 to 5.5)

[1]

This parameter is not estimable when the Kaplan Meier-based curve representing the upper confidence limits for survival function lies above 50%, which suggested that this arm was performing well in terms of PFS prolongation at the data cutoff date.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	The primary hypothesis to be tested was H0: λ≥1 versus. HA: λ<1, where λ was the palbociclib plus fulvestrant: placebo plus fulvestrant hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Fulvestrant. The study was planned to have 90% power and control the type-I error rate at 0.025.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.000001
	Comments	The overall Type-I error rate was persevered at 1-sided 0.025 level for the analysis of the primary endpoint PFS by the Haybittle-Peto efficacy boundary. The priori threshold for statistical significance at the interim analysis was 0.00135.
	Method	Stratified Log Rank Test (1-sided)
	Comments	The log rank test stratified by sensitivity to prior hormonal therapy and the presence of visceral metastases based on the randomization information.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.422
	Confidence Interval	(2-Sided) 95%; 0.318 to 0.560
	Estimation Comments	Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of the palbociclib plus fulvestrant arm.

2. Secondary Outcome

Title	Overall Survival (OS) - Number of Participants Who Died
Description	OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. For participants lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Participants lacking survival data beyond randomization were to have their OS times be censored at randomization. The length of OS was calculated as OS time (months) = [death date (censor date) – randomization date + 1]/30.4. No inferential statistical analysis were done because of the immaturity of the OS data.
Time Frame	From randomization until death (up to approximately 36 months)

Outcome Measure Data

Analysis Population Description

The ITT population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received the study medication or received a different drug from that to which they were randomized.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	347	174
Measure Type: Number; Unit of Measure: deaths
	19	9

3. Secondary Outcome

Title	Objective Response (OR)
Description	OR is defined as the overall complete response (CR) or partial response (PR) according to the RECIST version 1.1 Objective Response Rate (ORR) is defined as the proportion of participants with CR or PR relative to all randomized participants and randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR. Per response evaluation criteria in solid tumors criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), ≥30% decrease in the sum of the longest diameter of target lesions (longest for non-nodal and short axis for nodal target lesions); Overall Response (OR) = CR + PR.
Time Frame	From randomization until end of treatment (assessed up to 12 months)

Outcome Measure Data

Analysis Population Description

The ITT population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received the study medication or received a different drug from that to which they were randomized. Randomized participants with measurable disease at baseline was also included.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	347	174
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	10.4; (7.4 to 14.1)	6.3; (3.2 to 11.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	The exact test is testing the null hypothesis that the odds ratio of objective response rate is less than or equal to 1 vs. the alternative hypothesis that the odds ratio of objective response rate is greater than 1. An Odds Ratio >1 means better response in favor of palbociclib plus fulvestrant arm.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0791
	Comments	The p-value was not adjusted for multiple comparisons. The priori threshold for statistical significance is 1-sided, alpha=0.025.
	Method	Exact test (1-sided)
	Comments	The 1-sided p-value is from the stratified exact test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.725
	Confidence Interval	(2-Sided) 95%; 0.835 to 3.896
	Estimation Comments	An Odds Ratio >1 means better response in favor of the palbociclib plus fulvestrant arm.

4. Secondary Outcome

Title	Duration of Response (DR)
Description	DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as [the date response ended (ie, date of PD or death) – first CR or PR date + 1)]/30.4. Kaplan-Meier estimate of median of the DR is provided below. No inferential statistical analysis were done for DR. The DR was only calculated for the participants with a CR or PR.
Time Frame	From randomization until end of treatment (assessed up to 12 months)

Outcome Measure Data

Analysis Population Description

The ITT population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received the study medication or received a different drug from that to which they were randomized.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	347	174
Median (95% Confidence Interval); Unit of Measure: Months
	9.3 [1]; (4.0 to NA)	5.7; (3.7 to 5.7)

[1]

Due to less follow-up time and insufficient number of participants having Duration Response.

5. Secondary Outcome

Title	Clinical Benefit Response (CBR)
Description	CBR is defined as the overall complete response (CR), partial response (PR) , or stable disease (SD) ≥24 weeks according to the RECIST version 1.1. Clinical Benefit Response Rate (CBRR) is defined as the proportion of participants with CR, PR, or SD ≥24 weeks relative to all randomized participants and randomized participants with measurable disease at baseline. Participants who do not have on-study radiographic tumor re-evaluation, who received antitumor treatment other than the study medication prior to reaching a CR or PR, a best response of SD ≥24 weeks, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR and a best response of SD ≥24 weeks was counted as non-responders in the assessment of CBR. Per RECIST v1.1 for target lesions and assessed by MRI: CR, disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions; OR = CR + PR.
Time Frame	From randomization until end of treatment (assessed up to 12 months)

Outcome Measure Data

Analysis Population Description

The ITT population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received the study medication or received a different drug from that to which they were randomized. Randomized participants with measurable disease at baseline was also included.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	347	174
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	34.0; (29.0 to 39.3)	19.0; (13.4 to 25.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	The exact test is testing the null hypothesis that the odds ratio of objective response rate is less than or equal to 1 vs. the alternative hypothesis that the odds ratio of objective response rate is greater than 1. An Odds Ratio >1 means better response in favor of palbociclib plus fulvestrant arm.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	The p-value was not adjusted for multiple comparisons. The priori threshold for statistical significance is 1-sided, alpha=0.025.
	Method	Exact test (1-sided)
	Comments	The 1-sided p-value is from the stratified exact test.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.189
	Confidence Interval	(2-Sided) 95%; 1.391 to 3.523
	Estimation Comments	An odds ratio > 1 means better clinical benefit response in favor of palbociclib plus fulvestrant arm.

6. Secondary Outcome

Title	Survival Probabilities at Months 12, 24 and 36
Description	One-, Two- or Three-year Survival Probability is defined as the probability of survival 1 year, 2 or 3 years after the date of randomization based on the Kaplan-Meier estimate. Survival time was censored to last date the participant is known to be alive.
Time Frame	From randomization until death (assessed up to 36 months)

Outcome Measure Data

Analysis Population Description

The ITT population or full analysis set included all participants who were randomized, with study medication, regardless of whether participants received the study medication or received a different drug from that to which they were randomized.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	347	174
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Survival Probability at Month 12	89.3; (78.1 to 95.0)	89.3; (77.8 to 95.0)
Survival Probability at Month 24	NA [1]; (NA to NA)	NA [1]; (NA to NA)
Survival Probability at Month 36	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Due to less follow-up time and insufficient number of participants with events.

7. Secondary Outcome

Title	Observed Plasma Trough Concentration (Ctrough) for Palbociclib
Description	Ctrough for palbociclib (if applicable). The method of dispersion applied here is "percent coefficient of variation" (%CV).
Time Frame	Cycle 1/Day 15 and Cycle 2/Day 15

Outcome Measure Data

Analysis Population Description

All participants who had PK blood samples collected for palbociclib and had at least one measured plasma drug concentration.

Arm/Group Title	Palbociclib + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	325
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Cycle 1/Day 15 (N= 165)	70.70; (44%)
Cycle 2/Day 15 (N= 160)	75.29; (44%)

8. Secondary Outcome

Title	Ctrough for Fulvestrant
Description	Ctrough for Fulvestrant (if applicable). The method of dispersion applied here is "percent coefficient of variation" (%CV).
Time Frame	Cycles 2/Day 1 and Cycle 3/Day 1

Outcome Measure Data

Analysis Population Description

All participants who had PK blood samples collected for palbociclib and had at least one measured plasma drug concentration.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	64	33
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Cycle 2/Day 1 (N= 35, 19)	11.75; (41%)	9.31; (52%)
Cycle 3/Day 1 (N= 29, 14)	9.90; (42%)	7.60; (72%)

9. Secondary Outcome

Title	Ctrough for Goserelin
Description	Cmin for goserelin (if applicable). The method of dispersion applied here is "percent coefficient of variation" (%CV).
Time Frame	Cycles 2/ Day 1 and Cycle 3/ Day 1

Outcome Measure Data

Analysis Population Description

All participants who had PK blood samples collected for palbociclib and had at least one measured plasma drug concentration.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	16	8
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: pg/mL
Cycle 2/Day 1 (N= 9, 5)	295.1; (153%)	302.5; (74%)
Cycle 3/Day 1 (N= 7, 3)	344.8; (64%)	288.5; (40%)

10. Secondary Outcome

Title	Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores
Description	The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from “not at all” to “very much” and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.
Time Frame	From Cycle 1 to 14, as of 05 December 2014.

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Global health status / QoL	-0.9; (-2.5 to 0.7)	-4.0; (-6.3 to -1.7)
Physical functioning	-0.7; (-2.1 to 0.7)	-1.7; (-3.7 to 0.2)
Role functioning	-1.8; (-3.7 to 0.1)	-3.7; (-6.5 to -0.9)
Emotional functioning	2.7; (1.1 to 4.3)	-1.9; (-4.2 to 0.5)
Cognitive functioning	-1.7; (-3.1 to -0.2)	-2.9; (-5.0 to -0.7)
Social functioning	-0.5; (-2.5 to 1.5)	-0.6; (-3.4 to 2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for Global health status/ QoL
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0313
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; 0.3 to 6.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for physical functioning
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4000
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -1.4 to 3.5
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for role functioning
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2615
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -1.5 to 5.3
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for emotional functioning
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0016
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95%; 1.7 to 7.4
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for cognitive functioning
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3650
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -1.4 to 3.8
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for social functioning
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9615
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -3.4 to 3.5
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores
Description	The EORTC-QLQ-C30 is a 30-item questionnaire composed of five multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and six single item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and the financial impact of cancer). The questionnaire employs 28 4-point Likert scales with responses from “not at all” to “very much” and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. A 10-point or higher change in scores from baseline is considered clinically significant.
Time Frame	From Cycle 1 to 14, as of 05 December 2014.

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Fatigue	1.8; (0.1 to 3.5)	3.3; (0.9 to 5.8)
Nausea and vomiting	1.7; (0.4 to 3.0)	4.2; (2.3 to 6.1)
Pain	-3.3; (-5.1 to -1.5)	2.0; (-0.6 to 4.6)
Dyspnoea	2.8; (1.0 to 4.7)	3.3; (0.6 to 6.0)
Insomnia	-2.4; (-4.4 to -0.4)	-0.4; (-3.3 to 2.5)
Appetite loss	1.1; (-0.8 to 3.1)	1.7; (-1.1 to 4.6)
Constipation	3.5; (1.7 to 5.3)	2.8; (0.1 to 5.4)
Diarrhoea	1.9; (0.6 to 3.1)	2.4; (0.5 to 4.3)
Financial difficulties	-3.7; (-5.6 to -1.9)	-4.0; (-6.7 to -1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for fatigue
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3200
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -4.5 to 1.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for nausea and vomiting
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0369
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -4.8 to -0.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for pain
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0011
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.3
	Confidence Interval	(2-Sided) 95%; -8.5 to -2.1
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for dyspnoea
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7699
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -3.7 to 2.8
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for insomnia
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2721
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.0
	Confidence Interval	(2-Sided) 95%; -5.5 to 1.6
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for appetite loss
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7334
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -4.1 to 2.9
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for constipation
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6491
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -2.5 to 3.9
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for diarrhoea
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6293
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -2.8 to 1.7
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for financial difficulties
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8812
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -3.1 to 3.6
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores
Description	The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from ’not at all’ to ’very much’. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning.
Time Frame	From Cycle 1 to 14, as of 05 December 2014.

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Body image	1.9; (0.2 to 3.6)	-0.3; (-2.8 to 2.1)
Sexual functioning	-1.1; (-2.5 to 0.2)	-0.4; (-2.3 to 1.5)
Sexual enjoyment	-5.2; (-8.3 to -2.1)	-6.6; (-11.6 to -1.7)
Future perspective	8.1; (5.8 to 10.4)	4.5; (1.2 to 7.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for body image
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1386
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -0.7 to 5.2
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for sexual functioning
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5235
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -3.1 to 1.6
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for sexual enjoyment
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6271
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -4.4 to 7.3
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for future perspective
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0845
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.6
	Confidence Interval	(2-Sided) 95%; -0.5 to 7.6
	Estimation Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores
Description	The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from ’not at all’ to ’very much’. All scores are converted to a 0 to 100 scale. For symptom-oriented scales, a higher score represent more severe symptoms.
Time Frame	From Cycle 1 to 14, as of 05 December 2014.

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
Systemic therapy side effects	3.8; (2.6 to 4.9)	3.4; (1.8 to 5.0)
Breast symptoms	-2.2; (-3.2 to -1.3)	-1.3; (-2.7 to 0.0)
Arm symptoms	-2.2; (-3.6 to -0.9)	-2.0; (-4.0 to -0.1)
Upset by hair loss	2.9; (-1.7 to 7.4)	-6.0; (-12.3 to 0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for systemic therapy side effects
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7273
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -1.6 to 2.3
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for breast symptoms
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2671
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -2.6 to 0.7
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for arm symptoms
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8750
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -2.6 to 2.2
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Statistical significance for palbociclib plus fulvestrant vs placebo plus fulvestrant for upset by hair loss
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0255
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.9
	Confidence Interval	(2-Sided) 95%; 1.1 to 16.6
	Estimation Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D)- Health Index Scores
Description	The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The first part consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/ depression); a participant is asked to rate each state on a three level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/ impairment Published weights are available that allow for the creation of a single summary score called the EQ-5D index, which basically ranges from 0 to 1 with low scores representing a higher level of dysfunction and 1 as perfect health. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).
Time Frame	From Cycle 1 to 14, as of 05 December 2014.

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
	0.006; (-0.01 to 0.03)	-0.031; (-0.06 to 0.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0308
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.037
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.07
	Estimation Comments	[Not Specified]

15. Secondary Outcome

Title	Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale
Description	The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).
Time Frame	From Cycle 1 to 14, as of 05 December 2014.

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment. Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Mean (95% Confidence Interval); Unit of Measure: Units on a scale
	-1.8; (-3.3 to -0.3)	-2.6; (-4.8 to -0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5523
	Comments	The priori threshold for statistical significance is 2-sided alpha=0.05. The p-value was not adjusted for multiple comparisons.
	Method	Mixed Model Analysis (2-sided)
	Comments	Analysis based on repeated measures mixed-effects model with an intercept term, treatment, time, treatment-by-time, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -1.9 to 3.5
	Estimation Comments	[Not Specified]

16. Secondary Outcome

Title	Time to Deterioration (TTD)
Description	A time to event analysis was pre-specified for pain. An analysis of TTD in pain defined as time between baseline and first occurrence of increase of ≥10 points in pain. Deterioration will be defined increase in score of 10 points or greater from baseline. The Kaplan-Meier estimates of quartiles (time to deterioration) with 95% CI is mentioned below.
Time Frame	Baseline, Day 1 of Cycles 2 to 4, Day 1 of every alternate cycle after that until the end of treatment

Outcome Measure Data

Analysis Population Description

The PRO –evaluable population is defined as a subset of ITT participants, who have completed a baseline and at least one post –baseline PRO assessment prior to end of study treatment.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	335	166
Median (95% Confidence Interval); Unit of Measure: Months
25% quartile	1.9; (1.2 to 2.2)	1.0; (1.0 to 1.9)
50% quartile	8.0 [1]; (5.6 to NA)	2.8; (2.3 to 5.4)

[1]

Due to less follow-up time and insufficient number of participants with events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Palbociclib + Fulvestrant, Placebo + Fulvestrant
	Comments	Treatment with palbociclib plus fulvestrant significantly delayed TTD in pain symptom compared with placebo plus fulvestrant for unstratified analysis.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	The priori threshold for statistical significance is 1-sided alpha=0.025. The p-value was not adjusted for multiple comparisons.
	Method	Unstratified log-rank test (1-sided)
	Comments	1-sided p-value from the unstratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.642
	Confidence Interval	(2-Sided) 95%; 0.487 to 0.846
	Estimation Comments	Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of the palbociclib plus fulvestrant arm.

17. Secondary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities)
Description	An AE is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death; is life-threatening; requires hospitalization; results in persistent or significant disability or in congenital anomaly/birth defect. Severity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.
Time Frame	From the signing of the informed consent until 28 days after the last dose of study medication up to 14 months

Outcome Measure Data

Analysis Population Description

The as-treated (AT) population or safety analysis set included all participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description:	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
Overall Number of Participants Analyzed	345	172
Measure Type: Number; Unit of Measure: Percentage of Participants
With AEs	97.7	89.0
With SAEs	9.6	14.0
With Grade 3 or 4 AEs	70.1	18.0
With Grade 5 AEs	0.9	1.2
Discontinued palbociclib/placebo due to AEs	3.8	4.1

Adverse Events

Time Frame	From the date of randomization up to 28 calendar days (±7 days) after last dose of study medication up to 14 months.
Adverse Event Reporting Description	The safety analysis set included participants who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.
Arm/Group Title	Palbociclib + Fulvestrant	Placebo + Fulvestrant
Arm/Group Description	Participants were administered an initial dose of 125 mg per day orally continuously for 3 weeks followed by 1 week off that can be reduced to 100 mg or 75 mg in case of toxicity; repeated at each subsequent cycle and fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.	Participants were administered placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle and Fulvestrant 500 mg intramuscularly on Days 1 and 15 of cycle 1 and then every 28 days. Pre- and perimenopausal women received goserelin at least 4 weeks before study treatment start and continued receiving concurrent ovarian function suppression with goserelin administered subcutaneously every 28 days during the active treatment phase.
All-Cause Mortality
	Palbociclib + Fulvestrant	Placebo + Fulvestrant
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Palbociclib + Fulvestrant	Placebo + Fulvestrant
	Affected / at Risk (%)	Affected / at Risk (%)
Total	33/345 (9.57%)	24/172 (13.95%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation * 1	1/345 (0.29%)	0/172 (0.00%)
Febrile neutropenia * 1	1/345 (0.29%)	1/172 (0.58%)
Neutropenia * 1	1/345 (0.29%)	0/172 (0.00%)
Cardiac disorders
Atrial fibrillation * 1	1/345 (0.29%)	0/172 (0.00%)
Pericarditis * 1	1/345 (0.29%)	0/172 (0.00%)
Endocrine disorders
Hyperthyroidism * 1	1/345 (0.29%)	0/172 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	1/345 (0.29%)	0/172 (0.00%)
Ascites * 1	0/345 (0.00%)	2/172 (1.16%)
Duodenogastric reflux * 1	1/345 (0.29%)	0/172 (0.00%)
Intestinal obstruction * 1	1/345 (0.29%)	0/172 (0.00%)
Nausea * 1	0/345 (0.00%)	1/172 (0.58%)
Pancreatitis * 1	0/345 (0.00%)	1/172 (0.58%)
Vomiting * 1	1/345 (0.29%)	1/172 (0.58%)
General disorders
Chest pain * 1	0/345 (0.00%)	1/172 (0.58%)
Device occlusion * 1	1/345 (0.29%)	0/172 (0.00%)
Disease progression * 1	2/345 (0.58%)	0/172 (0.00%)
General physical health deterioration * 1	1/345 (0.29%)	0/172 (0.00%)
Non-cardiac chest pain * 1	0/345 (0.00%)	1/172 (0.58%)
Oedema peripheral * 1	1/345 (0.29%)	1/172 (0.58%)
Pain * 1	1/345 (0.29%)	0/172 (0.00%)
Pyrexia * 1	3/345 (0.87%)	1/172 (0.58%)
Hepatobiliary disorders
Cholecystitis * 1	0/345 (0.00%)	1/172 (0.58%)
Cholelithiasis * 1	1/345 (0.29%)	0/172 (0.00%)
Hepatic failure * 1	1/345 (0.29%)	0/172 (0.00%)
Infections and infestations
Bacteraemia * 1	1/345 (0.29%)	0/172 (0.00%)
Cellulitis * 1	1/345 (0.29%)	0/172 (0.00%)
Erysipelas * 1	1/345 (0.29%)	0/172 (0.00%)
Gastrointestinal infection * 1	0/345 (0.00%)	1/172 (0.58%)
Otitis media acute * 1	1/345 (0.29%)	0/172 (0.00%)
Pharyngitis * 1	1/345 (0.29%)	0/172 (0.00%)
Pneumonia * 1	1/345 (0.29%)	2/172 (1.16%)
Pyelonephritis * 1	0/345 (0.00%)	1/172 (0.58%)
Upper respiratory tract infection * 1	1/345 (0.29%)	0/172 (0.00%)
Urinary tract infection * 1	1/345 (0.29%)	0/172 (0.00%)
Injury, poisoning and procedural complications
Femur fracture * 1	0/345 (0.00%)	1/172 (0.58%)
Fracture * 1	0/345 (0.00%)	1/172 (0.58%)
Humerus fracture * 1	0/345 (0.00%)	1/172 (0.58%)
Road traffic accident * 1	0/345 (0.00%)	1/172 (0.58%)
Investigations
Alanine aminotransferase increased * 1	1/345 (0.29%)	0/172 (0.00%)
Electrocardiogram QT prolonged * 1	1/345 (0.29%)	0/172 (0.00%)
Neutrophil count * 1	1/345 (0.29%)	0/172 (0.00%)
Troponin increased * 1	1/345 (0.29%)	0/172 (0.00%)
Metabolism and nutrition disorders
Dehydration * 1	1/345 (0.29%)	0/172 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain * 1	1/345 (0.29%)	2/172 (1.16%)
Osteonecrosis of jaw * 1	0/345 (0.00%)	1/172 (0.58%)
Pain in extremity * 1	1/345 (0.29%)	0/172 (0.00%)
Pathological fracture * 1	0/345 (0.00%)	1/172 (0.58%)
Nervous system disorders
Aphasia * 1	0/345 (0.00%)	1/172 (0.58%)
Cerebral haemorrhage * 1	0/345 (0.00%)	1/172 (0.58%)
Cerebrovascular accident * 1	0/345 (0.00%)	1/172 (0.58%)
Dysarthria * 1	0/345 (0.00%)	1/172 (0.58%)
Facial paresis * 1	0/345 (0.00%)	1/172 (0.58%)
Migraine * 1	1/345 (0.29%)	0/172 (0.00%)
Sedation * 1	1/345 (0.29%)	0/172 (0.00%)
Somnolence * 1	1/345 (0.29%)	0/172 (0.00%)
Psychiatric disorders
Depression * 1	1/345 (0.29%)	0/172 (0.00%)
Psychotic disorder * 1	1/345 (0.29%)	0/172 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome * 1	0/345 (0.00%)	1/172 (0.58%)
Chronic obstructive pulmonary disease * 1	1/345 (0.29%)	1/172 (0.58%)
Dyspnoea * 1	1/345 (0.29%)	1/172 (0.58%)
Pleural effusion * 1	1/345 (0.29%)	3/172 (1.74%)
Pulmonary embolism * 1	3/345 (0.87%)	0/172 (0.00%)
Pulmonary hypertension * 1	0/345 (0.00%)	1/172 (0.58%)
Skin and subcutaneous tissue disorders
Rash maculo-papular * 1	1/345 (0.29%)	0/172 (0.00%)
Vascular disorders
Deep vein thrombosis * 1	1/345 (0.29%)	0/172 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 17.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Palbociclib + Fulvestrant	Placebo + Fulvestrant
	Affected / at Risk (%)	Affected / at Risk (%)
Total	333/345 (96.52%)	147/172 (85.47%)
Blood and lymphatic system disorders
Anaemia * 1	88/345 (25.51%)	17/172 (9.88%)
Leukopenia * 1	70/345 (20.29%)	2/172 (1.16%)
Neutropenia * 1	212/345 (61.45%)	3/172 (1.74%)
Thrombocytopenia * 1	40/345 (11.59%)	0/172 (0.00%)
Gastrointestinal disorders
Abdominal pain * 1	21/345 (6.09%)	9/172 (5.23%)
Abdominal pain upper * 1	12/345 (3.48%)	11/172 (6.40%)
Constipation * 1	58/345 (16.81%)	24/172 (13.95%)
Diarrhoea * 1	66/345 (19.13%)	30/172 (17.44%)
Dry mouth * 1	22/345 (6.38%)	14/172 (8.14%)
Dyspepsia * 1	25/345 (7.25%)	7/172 (4.07%)
Nausea * 1	100/345 (28.99%)	44/172 (25.58%)
Stomatitis * 1	40/345 (11.59%)	4/172 (2.33%)
Vomiting * 1	50/345 (14.49%)	20/172 (11.63%)
General disorders
Asthenia * 1	23/345 (6.67%)	8/172 (4.65%)
Chest pain * 1	6/345 (1.74%)	9/172 (5.23%)
Fatigue * 1	131/345 (37.97%)	46/172 (26.74%)
Injection site pain * 1	19/345 (5.51%)	16/172 (9.30%)
Oedema peripheral * 1	25/345 (7.25%)	8/172 (4.65%)
Pain * 1	15/345 (4.35%)	12/172 (6.98%)
Pyrexia * 1	27/345 (7.83%)	6/172 (3.49%)
Infections and infestations
Nasopharyngitis * 1	25/345 (7.25%)	9/172 (5.23%)
Upper respiratory tract infection * 1	20/345 (5.80%)	7/172 (4.07%)
Investigations
Aspartate aminotransferase increased * 1	19/345 (5.51%)	8/172 (4.65%)
Neutrophil count decreased * 1	73/345 (21.16%)	3/172 (1.74%)
Platelet count decreased * 1	27/345 (7.83%)	0/172 (0.00%)
White blood cell count decreased * 1	92/345 (26.67%)	5/172 (2.91%)
Metabolism and nutrition disorders
Decreased appetite * 1	44/345 (12.75%)	13/172 (7.56%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	45/345 (13.04%)	28/172 (16.28%)
Back pain * 1	38/345 (11.01%)	25/172 (14.53%)
Muscle spasms * 1	21/345 (6.09%)	11/172 (6.40%)
Musculoskeletal chest pain * 1	9/345 (2.61%)	9/172 (5.23%)
Musculoskeletal pain * 1	20/345 (5.80%)	11/172 (6.40%)
Myalgia * 1	23/345 (6.67%)	12/172 (6.98%)
Pain in extremity * 1	33/345 (9.57%)	19/172 (11.05%)
Nervous system disorders
Dizziness * 1	37/345 (10.72%)	16/172 (9.30%)
Dysgeusia * 1	22/345 (6.38%)	3/172 (1.74%)
Headache * 1	73/345 (21.16%)	30/172 (17.44%)
Psychiatric disorders
Anxiety * 1	14/345 (4.06%)	9/172 (5.23%)
Depression * 1	16/345 (4.64%)	10/172 (5.81%)
Insomnia * 1	27/345 (7.83%)	12/172 (6.98%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	45/345 (13.04%)	18/172 (10.47%)
Dyspnoea * 1	37/345 (10.72%)	10/172 (5.81%)
Epistaxis * 1	19/345 (5.51%)	2/172 (1.16%)
Oropharyngeal pain * 1	32/345 (9.28%)	9/172 (5.23%)
Skin and subcutaneous tissue disorders
Alopecia * 1	51/345 (14.78%)	10/172 (5.81%)
Pruritus * 1	19/345 (5.51%)	10/172 (5.81%)
Rash * 1	31/345 (8.99%)	7/172 (4.07%)
Vascular disorders
Hot flush * 1	51/345 (14.78%)	28/172 (16.28%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 17.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Masuda N, Mukai H, Inoue K, Rai Y, Ohno S, Mori Y, Hashigaki S, Muramatsu Y, Umeyama Y, Iwata H, Toi M. Neutropenia management with palbociclib in Japanese patients with advanced breast cancer. Breast Cancer. 2019 Sep;26(5):637-650. doi: 10.1007/s12282-019-00970-7. Epub 2019 May 24. Erratum in: Breast Cancer. 2019 Jun 5;:.

Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S, DeMichele A, Harbeck N, André F, Bayar MA, Michiels S, Zhang Z, Giorgetti C, Arnedos M, Huang Bartlett C, Cristofanilli M. Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 2019 May 10;37(14):1169-1178. doi: 10.1200/JCO.18.00925. Epub 2019 Feb 26. Erratum in: J Clin Oncol. 2019 Nov 1;37(31):2956.

Masuda N, Inoue K, Nakamura R, Rai Y, Mukai H, Ohno S, Hara F, Mori Y, Hashigaki S, Muramatsu Y, Nagasawa T, Umeyama Y, Huang X, Iwata H. Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients. Int J Clin Oncol. 2019 Mar;24(3):262-273. doi: 10.1007/s10147-018-1359-3. Epub 2018 Nov 3.

Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, André F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. doi: 10.1056/NEJMoa1810527. Epub 2018 Oct 20.

Cristofanilli M, DeMichele A, Giorgetti C, Turner NC, Slamon DJ, Im SA, Masuda N, Verma S, Loi S, Colleoni M, Theall KP, Huang X, Liu Y, Bartlett CH. Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. Eur J Cancer. 2018 Nov;104:21-31. doi: 10.1016/j.ejca.2018.08.011. Epub 2018 Oct 8.

Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N, Masuda N, Im SA, Huang X, Kim S, Sun W, Iyer S, Schnell P, Bartlett CH, Johnston S. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018 Sep;101:123-133. doi: 10.1016/j.ejca.2018.05.017. Epub 2018 Jul 25.

Diéras V, Rugo HS, Schnell P, Gelmon K, Cristofanilli M, Loi S, Colleoni M, Lu DR, Mori A, Gauthier E, Huang Bartlett C, Slamon DJ, Turner NC, Finn RS. Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer. J Natl Cancer Inst. 2019 Apr 1;111(4):419-430. doi: 10.1093/jnci/djy109.

Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.

Turner NC, Finn RS, Martin M, Im SA, DeMichele A, Ettl J, Diéras V, Moulder S, Lipatov O, Colleoni M, Cristofanilli M, Lu DR, Mori A, Giorgetti C, Iyer S, Bartlett CH, Gelmon KA. Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases. Ann Oncol. 2018 Mar 1;29(3):669-680. doi: 10.1093/annonc/mdx797.

Loibl S, Turner NC, Ro J, Cristofanilli M, Iwata H, Im SA, Masuda N, Loi S, André F, Harbeck N, Verma S, Folkerd E, Puyana Theall K, Hoffman J, Zhang K, Bartlett CH, Dowsett M. Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results. Oncologist. 2017 Sep;22(9):1028-1038. doi: 10.1634/theoncologist.2017-0072. Epub 2017 Jun 26.

Verma S, Bartlett CH, Schnell P, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Cristofanilli M, Zhang K, Thiele A, Turner NC, Rugo HS. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3). Oncologist. 2016 Oct;21(10):1165-1175. Epub 2016 Jul 1.

Fribbens C, O'Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S, Jiang J, Bartlett CH, Koehler M, Dowsett M, Bliss JM, Johnston SR, Turner NC. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. J Clin Oncol. 2016 Sep 1;34(25):2961-8. doi: 10.1200/JCO.2016.67.3061. Epub 2016 Jun 6.

Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, André F, Loi S, Verma S, Iwata H, Bhattacharyya H, Puyana Theall K, Bartlett CH, Loibl S. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016 Jun;27(6):1047-54. doi: 10.1093/annonc/mdw139. Epub 2016 Mar 30.

Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. Epub 2016 Mar 3. Erratum in: Lancet Oncol. 2016 Apr;17 (4):e136. Lancet Oncol. 2016 Jul;17 (7):e270.

Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01942135 History of Changes
• Other Study ID Numbers: A5481023; 2013-002580-26 ( EudraCT Number )
• First Submitted: September 10, 2013
• First Posted: September 13, 2013
• Results First Submitted: December 3, 2015
• Results First Posted: May 23, 2016
• Last Update Posted: November 27, 2019