A Study to Evaluate the Efficacy and Safety of Giredestrant in Combination With Phesgo (Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf) Versus Phesgo in Participants With Locally Advanced or Metastatic Breast Cancer (heredERA Breast Cancer)

Study Overview
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Brief Summary
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This Phase III, randomized, two-arm, open-label, multicenter study will evaluate the efficacy and safety of giredestrant plus Phesgo compared with Phesgo after induction therapy with Phesgo plus taxane in participants with human epidermal growth factor receptor 2 (HER2)-positive, estrogen receptor (ER)-positive advanced breast cancer (metastatic or locally advanced disease not amenable to curative treatment) who have not previously received a systemic non-hormonal anti-cancer therapy in the advanced setting.

Official Title
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A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Giredestrant in Combination With Phesgo Versus Phesgo After Induction Therapy With Phesgo + Taxane in Patients With Previously Untreated HER2-Positive, Estrogen Receptor-Positive Locally-Advanced or Metastatic Breast Cancer

Conditions
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Locally Advanced or Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Phesgo
* Drug: Giredestrant
* Drug: Docetaxel
* Drug: Paclitaxel
* Drug: LHRH Agonist
* Drug: Optional Endocrine Therapy of Investigator's Choice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed and documented human epidermal growth factor receptor 2 (HER2)-positive/estrogen receptor (ER)-positive adenocarcinoma of the breast with metastatic or locally-advanced disease not amenable to curative resection At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence of ≥6 months Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 Left ventricular ejection fraction (LVEF) of at least (≥)50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) Adequate hematologic and end-organ function For women of childbearing potential: Participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agree to refrain from donating eggs, during the treatment period and for 7 months after the final dose of Phesgo For men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, during the treatment period and for 7 months after the final dose of Phesgo to avoid exposing the embryo Maintenance Phase Inclusion Criteria Complete a minimum of four cycles of induction therapy Achieve a minimum of stable disease (SD) (or Non-complete response [CR]/Non-progressive disease [PD] for participants with non-measurable disease) (i.e., did not experience PD) according to RECIST v1.1 at the last tumor assessment during the induction therapy phase LVEF of ≥50% at the last assessment during the induction therapy phase Exclusion Criteria: Previous systemic non-hormonal anti-cancer therapy in the metastatic breast cancer (MBC) or advanced breast cancer (ABC) setting. Note: Up to one line of single-agent endocrine therapy given in the metastatic or locally advanced setting will be allowed. Prior treatment with a selective estrogen receptor degrader (SERD) Previous treatment with approved or investigative anti-HER2 agents in any breast cancer treatment setting, except Phesgo (or trastuzumab SC with pertuzumab IV, or pertuzumab and trastuzumab IV), single-agent trastuzumab IV or SC, ado-trastuzumab emtansine, lapatinib, and neratinib in the neoadjuvant or adjuvant setting Disease progression within 6 months of receiving adjuvant anti-HER2 therapy (such as trastuzumab, with or without pertuzumab [IV, SC, or fixed-dose combination], or ado-trastuzumab emtansine, or neratinib) Non-resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade 1 or better History of persistent Grade ≥2 (NCI-CTC, Version 5.0) hematological toxicity resulting from previous adjuvant or neo-adjuvant therapy History of exposure to the following cumulative doses of anthracyclines; Doxorubicin >360 mg/m2; Liposomal doxorubicin >500 mg/m2; Epirubucin >720 mg/m2; Mitoxantrone >120 mg/m2; Idarubicin >90 mg/m2. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the final dose of Phesgo (Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of induction therapy). Treated with investigational therapy within 28 days prior to initiation of induction therapy Treated with localized palliative radiotherapy within 14 days prior to initiation of induction therapy Concurrent participation in any other therapeutic clinical trial Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone or equivalent) Poorly controlled hypertension Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, active liver disease including active viral or other hepatitis virus, autoimmune hepatic disorders, or sclerosing cholangitis, current alcohol abuse, or cirrhosis Active cardiac disease or history of cardiac dysfunction Major surgical procedure or significant traumatic injury within 14 days prior to enrollment or anticipation of need for major surgery during induction therapy Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery Concurrent, serious, uncontrolled infections, or known infection with HIV with the following exception: Individuals who are HIV positive are eligible provided they are stable on anti-retroviral therapy for ≥4 weeks, have a CD4 count ≥350 cells/uL, and have an undetectable viral load and no history of AIDS-defining opportunistic infections within 12 months prior to enrollment. Serious COVID-19 infection within 14 days prior to enrollment; however, no screening testing for SARS-CoV-2 is required Serious infection requiring oral or IV antibiotics within 7 days prior to screening Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in the study History of malignancy within 5 years prior to screening with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death For pre- and perimenopausal women, and men: Known hypersensitivity to luteinizing hormone-releasing hormone agonist (LHRHa); Not willing to undergo and maintain treatment with approved LHRHa therapy for the duration of endocrine therapy that requires gonadal function suppression Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of giredestrant treatment in Arm B A documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism, including deep vein thrombosis, unless the condition is adequately treated and under control

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Induction Therapy: Phesgo plus Taxane-Based Chemotherapy<br> | Drug: Phesgo<br>* Phesgo will be administered subcutaneously (SC) at a fixed non-weight-based dose. In the induction therapy phase, a loading dose (1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase [rHuPH20]) will be administered in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses (600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20) will be administered once every 3 weeks (Q3W).<br>* Other names: RG6264;Drug: Docetaxel<br>* During the induction therapy phase, the investigator's choice of taxane-based chemotherapy (i.e., docetaxel or paclitaxel) will be administered after Phesgo. Docetaxel will be administered at 75 milligrams per metre squared of body surface area (mg/m2) intravenously over 60 (±10) minutes on Day 1 of each cycle for 4 to 8 cycles (a cycle is 21 days); this dose may be escalated to 100 mg/m2 if the initial dose was well tolerated.<br>Drug: Paclitaxel<br>* During the induction therapy phase, the investigator's choice of taxane-based chemotherapy (i.e., docetaxel or paclitaxel) will be administered after Phesgo. Paclitaxel will be administered at 80 milligrams per metre squared of body surface area (mg/m2) intravenously over a minimum of 1 hour on Days 1, 8, and 15 of each cycle for 4 to 8 cycles (a cycle is 21 days); this weekly regimen is considered as one complete cycle whenever 3 weekly doses are given.<br>|
| Active Comparator: Arm A, Maintenance Therapy: Phesgo<br> | Drug: Phesgo<br>* Phesgo will be administered subcutaneously (SC) at a fixed non-weight-based dose. In the induction therapy phase, a loading dose (1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase [rHuPH20]) will be administered in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses (600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20) will be administered once every 3 weeks (Q3W).<br>* Other names: RG6264;Drug: LHRH Agonist<br>* A luteinizing hormone-releasing hormone (LHRH) agonist will be administered every 28 days to pre- and peri-menopausal women and all male participants while receiving giredestrant in Arm B. An LHRH agonist may be administered to male participants and pre- and peri-menopausal female participants receiving tamoxifen in Arm A, and should be administered to those receiving an aromatase inhibitor in Arm A. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer. The LHRH agonist will be administered according to local prescribing information.<br>Drug: Optional Endocrine Therapy of Investigator's Choice<br>* For participants in Arm A, optional endocrine therapy of investigator's choice is allowed based on the standard of care, and it can include an aromatase inhibitor or tamoxifen with or without an LHRH agonist, or gonadal ablation. The decision to include or exclude this option must be made prior to randomization.<br>|
| Experimental: Arm B, Maintenance Therapy: Giredestrant plus Phesgo<br> | Drug: Phesgo<br>* Phesgo will be administered subcutaneously (SC) at a fixed non-weight-based dose. In the induction therapy phase, a loading dose (1200 milligram (mg) pertuzumab, 600 mg trastuzumab, and 30,000 units of recombinant human PH20 hyaluronidase [rHuPH20]) will be administered in the first cycle (1 cycle is 21 days). In subsequent cycles, maintenance doses (600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units rHuPH20) will be administered once every 3 weeks (Q3W).<br>* Other names: RG6264;Drug: Giredestrant<br>* A 30 milligram (mg) capsule of giredestrant will be taken orally once a day on Days 1 to 21 of each 21-day cycle.<br>* Other names: RG6171;Drug: LHRH Agonist<br>* A luteinizing hormone-releasing hormone (LHRH) agonist will be administered every 28 days to pre- and peri-menopausal women and all male participants while receiving giredestrant in Arm B. An LHRH agonist may be administered to male participants and pre- and peri-menopausal female participants receiving tamoxifen in Arm A, and should be administered to those receiving an aromatase inhibitor in Arm A. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer. The LHRH agonist will be administered according to local prescribing information.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1 |  | From randomization for maintenance therapy to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 50 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | From randomization for maintenance therapy to death from any cause (up to 122 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 (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart. | From randomization for maintenance therapy to disease progression or death (up to 50 months) | 
| Duration of Response, as Determined by the Investigator According to RECIST v1.1 |  | From first occurrence of documented objective response after randomization for maintenance therapy to disease progression or death from any cause, whichever occurs first (up to 50 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 (CR) or partial response (PR). | From randomization for maintenance therapy to disease progression or death (up to 50 months) | 
| Mean Role Functioning Score Over Time, as Assessed Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire |  | Maintenance Cycles 1 (Baseline), 3, 6, 9, 12, 15, 18, once every 6 cycles from Cycles 24 to 90 (1 cycle is 21 days), treatment discontinuation, every 6 months and every year for Follow-up Years 1-2 and 3-5, respectively (up to 10 years) | 
| Mean Change from Baseline in the Role Functioning Score Over Time, as Assessed Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire |  | Maintenance Cycles 1 (Baseline), 3, 6, 9, 12, 15, 18, once every 6 cycles from Cycles 24 to 90 (1 cycle is 21 days), treatment discontinuation, every 6 months and every year for Follow-up Years 1-2 and 3-5, respectively (up to 10 years) | 
| Mean Physical Functioning Score Over Time, as Assessed Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire |  | Maintenance Cycles 1 (Baseline), 3, 6, 9, 12, 15, 18, once every 6 cycles from Cycles 24 to 90 (1 cycle is 21 days), treatment discontinuation, every 6 months and every year for Follow-up Years 1-2 and 3-5, respectively (up to 10 years) | 
| Mean Change from Baseline in the Physical Functioning Score Over Time, as Assessed Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire |  | Maintenance Cycles 1 (Baseline), 3, 6, 9, 12, 15, 18, once every 6 cycles from Cycles 24 to 90 (1 cycle is 21 days), treatment discontinuation, every 6 months and every year for Follow-up Years 1-2 and 3-5, respectively (up to 10 years) | 
| Mean Global Health Status/Quality of Life Score Over Time, as Assessed Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire |  | Maintenance Cycles 1 (Baseline), 3, 6, 9, 12, 15, 18, once every 6 cycles from Cycles 24 to 90 (1 cycle is 21 days), treatment discontinuation, every 6 months and every year for Follow-up Years 1-2 and 3-5, respectively (up to 10 years) | 
| Mean Change from Baseline in the Global Health Status/Quality of Life Score Over Time, as Assessed Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire |  | Maintenance Cycles 1 (Baseline), 3, 6, 9, 12, 15, 18, once every 6 cycles from Cycles 24 to 90 (1 cycle is 21 days), treatment discontinuation, every 6 months and every year for Follow-up Years 1-2 and 3-5, respectively (up to 10 years) | 
| Number of Participants with at Least One Adverse Event, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0) |  | From Baseline until 28 days after the final dose of study treatment (up to 10 years, 3 months) | 
| Number of Participants with Abnormalities in Clinical Laboratory Test Results |  | From Baseline until 28 days after the final dose of study treatment (up to 10 years, 3 months) |