A Study Evaluating the Efficacy and Safety of Giredestrant Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Participants With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (persevERA Breast Cancer)

Study Overview
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Brief Summary
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This Phase III, randomized, double-blind, placebo-controlled, multicenter study will evaluate the efficacy and safety of giredestrant combined with palbociclib compared with letrozole combined with palbociclib in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative locally advanced (recurrent or progressed) or metastatic breast cancer.

Official Title
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A Phase III Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of GDC-9545 Combined With Palbociclib Compared With Letrozole Combined With Palbociclib in Patients With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer

Conditions
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Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Giredestrant
* Drug: Giredestrant-matched Placebo
* Drug: Letrozole
* Drug: Letrozole-matched Placebo
* Drug: Palbociclib
* Drug: LHRH Agonist


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For women who are premenopausal or perimenopausal and for men: treatment with approved LHRH agonist therapy for the duration of study treatment Locally advanced (recurrent or progressed) or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent Documented ER-positive tumor and HER2-negative tumor, assessed locally Patients who have bilateral breast cancers which are both ER-positive and HER2-negative can be included in the study because the metastases are suitably targeted by the study treatments. If patients have bilateral tumors which are of different biomarker status, then proof of the ER and HER2 status of the metastases is required for study entry No history of systemic anti-cancer therapy for locally advanced (recurrent or progressed) or metastatic disease Disease recurrence from early-stage breast cancer after standard adjuvant endocrine therapy meeting the protocol-defined criteria of having received at least 24 months of treatment without disease progression during treatment and a disease-free interval since the completion of treatment that was greater than 12 months Measurable disease as defined per RECIST v.1.1 or bone only disease which must have at least one predominantly lytic bone lesion confirmed by CT or MRI which can be followed Eastern Cooperative Oncology Group Performance Status 0-1 Adequate organ function Exclusion Criteria: Disease recurrence during or within 12 months of completing prior neoadjuvant or adjuvant treatment with any CDK4/6 inhibitor Prior treatment with a selective estrogen receptor degrader (SERD) Treatment with any investigational therapy within 28 days prior to study treatment Treatment with strong CYP3A inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to randomization Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease Active cardiac disease or history of cardiac dysfunction, as defined in the protocol Pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Giredestrant + Letrozole-matched Placebo + Palbociclib<br> | Drug: Giredestrant<br>* Giredestrant is taken orally once per day on Days 1-28 of each 28-day treatment cycle.<br>* Other names: RG6171;Drug: Letrozole-matched Placebo<br>* Letrozole-matched placebo is taken orally once per day on Days 1-28 of each 28-day treatment cycle.<br>Drug: Palbociclib<br>* Palbociclib 125 mg is taken orally once per day on Days 1-21 of each 28-day treatment cycle.<br>Drug: LHRH Agonist<br>* Only premenopausal/perimenopausal and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist on Day 1 of each 28-day treatment cycle. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer.<br>|
| Active Comparator: Letrozole + Giredestrant-matched Placebo + Palbociclib<br> | Drug: Giredestrant-matched Placebo<br>* Giredestrant-matched placebo is taken orally once per day on Days 1-28 of each 28-day treatment cycle.<br>Drug: Letrozole<br>* Letrozole 2.5 milligrams (mg) is taken orally once per day on Days 1-28 of each 28-day treatment cycle.<br>Drug: Palbociclib<br>* Palbociclib 125 mg is taken orally once per day on Days 1-21 of each 28-day treatment cycle.<br>Drug: LHRH Agonist<br>* Only premenopausal/perimenopausal and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist on Day 1 of each 28-day treatment cycle. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS), as Determined by the Investigator According to RECIST v1.1 |  | From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 78 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | From randomization to death from any cause (up to 78 months) | 
| Objective Response Rate, as Determined by the Investigator According to RECIST v1.1 | The objective response rate is defined as the percentage of participants with a complete response or partial response on two consecutive occasions at least (≥)4 weeks apart. | From randomization until disease progression or death (up to 78 months) | 
| Duration of Response, as Determined by the Investigator According to RECIST v1.1 |  | From first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first (up to 78 months) | 
| Clinical Benefit Rate, as Determined by the Investigator According to RECIST v1.1 | The clinical benefit rate is defined as the percentage of participants with stable disease for ≥24 weeks or a complete response or partial response. | From randomization until disease progression or death (up to 78 months) | 
| Time to Confirmed Deterioration in Pain Level, Defined as the Time to First Documented ≥2-Point Increase from Baseline in the 'Worst Pain' Item from the Brief Pain Inventory-Short Form (BPI-SF) Questionnaire |  | From Baseline until treatment discontinuation (up to 78 months) | 
| Time to Confirmed Deterioration in Pain Presence and Interference, Defined as the Time to First Documented ≥10-Point Increase from Baseline in the EORTC QLQ-C30 Linearly Transformed Pain Scale Score | EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire | From Baseline until treatment discontinuation (up to 78 months) | 
| Time to Confirmed Deterioration in Physical Functioning, Defined as the Time to First Documented ≥10-Point Decrease from Baseline in the EORTC QLQ-C30 Linearly Transformed Physical Functioning Scale Score |  | From Baseline until treatment discontinuation (up to 78 months) | 
| Time to Confirmed Deterioration in Role Functioning, Defined as the Time to First Documented ≥10-Point Decrease from Baseline in the EORTC QLQ-C30 Linearly Transformed Role Functioning Scale Score |  | From Baseline until treatment discontinuation (up to 78 months) | 
| Time to Confirmed Deterioration in Global Health Status and Quality of Life (GHS/QoL), Defined as the Time to First Documented ≥10-Point Decrease from Baseline in the EORTC QLQ-C30 Linearly Transformed GHS/QoL Scale Score |  | From Baseline until treatment discontinuation (up to 78 months) | 
| Number of Participants with Adverse Events, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE v5.0) |  | From treatment initiation until 30 days after the final dose of study treatment (up to 78 months) | 
| Number of Participants with Vital Sign Abnormalities Over the Course of the Study | Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the participant is in a seated position, and temperature. | Baseline, Days 1 and 15 of Cycles 1 and 2, and Day 1 of each cycle thereafter until treatment discontinuation (1 cycle is 28 days) | 
| Plasma Concentration of Giredestrant at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 8, and 16 (1 cycle is 28 days) | 
| Plasma Concentration of Palbociclib at Specified Timepoints |  | Days 1 and 15 of Cycle 1 (1 cycle is 28 days) |