Second Opinion: A Case-Based Exploration of Clinical Investigator Best Practices Related to the Use of Oral SERDs for HR-Positive Breast Cancer

Faculty

Aditya Bardia

MD, MPH

UCLA Health Jonsson Comprehensive Cancer Center, Los Angeles, California

Program Director, Breast Medical Oncology, Assistant Chief (Translational Research), Division of Hematology-Oncology, Director of Translational Research Integration

Geffen School of Medicine, University of California Los Angeles, Los Angeles, California

Professor of Medicine

Faculty

Erica Mayer

MD, MPH, FASCO

Dana-Farber Cancer Institute, Boston, Massachusetts

Director of Breast Cancer Clinical Research, Breast Oncology Center

Harvard Medical School, Boston, Massachusetts

Associate Professor of Medicine

Faculty

Joyce O’Shaughnessy

MD

Baylor University Medical Center, Dallas, Texas

Celebrating Women Chair in Breast Cancer Research

Texas Oncology, Dallas, Texas

Director, Breast Cancer Research Program

Sarah Cannon Research Institute, Dallas, Texas

Moderator

Seth Wander

MD, PhD

Massachusetts General Hospital, Boston, Massachusetts

Director of Precision Medicine, Termeer Center for Targeted Therapies, Director of Translational Research, Breast Oncology Program

Harvard Medical School, Boston, Massachusetts

Assistant Professor of Medicine

Additional faculty to be announced.

Join us on Thursday, December 10^th from 7:00 PM to 9:00 PM central time (8:00 PM to 10:00 PM eastern time).

Current Role of Oral Selective Estrogen Degrader (SERD) Monotherapy in the Treatment of Hormone Receptor (HR)-Positive Metastatic Breast Cancer (mBC)

• Key factors affecting the selection of therapy for patients with HR-positive, HER2-negative mBC progressing on treatment with a CDK4/6 inhibitor and endocrine therapy (ET)
• Known mechanisms of resistance to ET in patients with HR-positive mBC; incidence of ESR1 mutations in endocrine-resistant mBC
• Optimal methodology and timing of assessment for ESR1 mutations in patients with progressive HR-positive, HER2-negative mBC
• Pharmacologic, structural and mechanistic similarities and differences between available (eg, elacestrant, imlunestrant) and investigational (eg, giredestrant, camizestrant) oral SERDs; implications for antitumor activity and tolerability
• Available results from the pivotal Phase III EMERALD trial evaluating elacestrant for pretreated HR-positive, HER2-negative mBC
• Updated efficacy results from the Phase III EMBER-3 study evaluating imlunestrant alone or in combination with abemaciclib for patients with pretreated HR-positive, HER2-negative mBC; recent FDA approval of the combination regimen and clinical implications
• FDA approvals of elacestrant and imlunestrant for previously treated HR-positive, HER2-negative, ESR1-mutated mBC; optimal incorporation into management algorithms
• Other available datasets and real-world analyses examining the role of oral SERD monotherapy in clinical management
• Incidence, severity and optimal approaches to monitoring for and management of toxicities associated with oral SERD therapy

Combination Approaches with Oral SERDs for HR-Positive Relapsed/Refractory mBC

• Biological rationale for combining oral SERDs with other systemic therapies for HR-positive mBC
• Efficacy and safety outcomes documented in the imlunestrant/abemaciclib arm of EMBER-3 among previously treated breast cancer with and without ESR1 mutations; recent FDA approval of and optimal candidates for this combination therapy
• NCCN guideline inclusion of imlunestrant/abemaciclib and potential clinical role
• Available findings from the Phase Ib/II ELEVATE trial evaluating elacestrant in combination with various therapeutic partners, such as abemaciclib, everolimus and capivasertib
• Design, eligibility criteria and key efficacy and safety endpoints of the Phase III evERA study assessing giredestrant with everolimus versus standard ET with everolimus for pretreated, HR-positive, HER2-negative mBC
• Demonstration of improved progression-free survival with giredestrant in combination with everolimus in the intention-to-treat and ESR1-mutated populations in the evERA study
• Ongoing FDA review and potential role of giredestrant/everolimus in the management of ET-pretreated, HR-positive, HER2-negative mBC; optimal candidates for combination therapy
• Spectrum, frequency and severity of side effects observed with various oral SERD-based combination regimens; optimal monitoring for and management of treatment-related adverse events (TRAEs)
• Ongoing clinical trials evaluating other SERD-based combinations, such as the ADELA and EvoPAR-BR01 studies

Available Evidence with Oral SERDs as a Component of First-Line Treatment

• Conceptual rationale for early therapeutic switching for patients with molecular progression in the absence of clinical or radiographic progression
• Key efficacy findings from the Phase III PADA-1 proof-of-concept trial evaluating a switch to fulvestrant and palbociclib versus no switch for patients with HR-positive, HER2-negative mBC found to harbor an ESR1 mutation during aromatase inhibitor (AI) and palbociclib therapy
• Published findings from the Phase III SERENA-6 study evaluating a switch from an AI to camizestrant after detection of an emergent ESR1 mutation during first-line therapy for HR-positive, HER2-negative mBC; recent FDA approval and optimal incorporation into the treatment paradigm
• Published findings from SERENA-6 with early therapeutic switching to camizestrant for patients with molecular progression; impact on patient-reported outcomes, including deterioration in global health status and quality of life and time to deterioration in pain
• Design, eligibility criteria and emerging efficacy results from the Phase III persevERA trial evaluating giredestrant/palbociclib as first-line treatment
• Other ongoing clinical trials evaluating oral SERDs in combination with CDK4/6 inhibitors as first-line treatment, such as the SERENA-4 and pionERA studies

Potential Role of SERDs in the Localized Disease Setting

• Rationale for the evaluation of oral SERDs as adjuvant therapy for localized HR-positive, HER2-negative breast cancer
• Available findings from the Phase III lidERA Breast Cancer study evaluating adjuvant giredestrant versus physician’s choice of adjuvant endocrine monotherapy for patients with HR-positive, HER2-negative localized breast cancer
• Improvement in invasive disease-free survival and other key efficacy outcomes documented with adjuvant giredestrant in the lidERA Breast Cancer study
• Spectrum, frequency and severity of toxicities with giredestrant in the lidERA Breast Cancer study; comparative tolerability of giredestrant versus standard adjuvant ET
• Potential clinical role of adjuvant giredestrant for patients with HR-positive, HER2-negative localized breast cancer; implications for treatment sequencing in the metastatic setting
• Ongoing Phase III trials, such as ELEGANT, TREAT ctDNA, EMBER-4, CAMBRIA-1 and CAMBRIA-2, attempting to further define the optimal role of oral SERDs in the adjuvant setting; estimated completion dates

Target Audience
This activity is intended for medical oncologists, breast surgeons, radiation oncologists and other healthcare professionals involved in the diagnosis and treatment of breast cancer.

Learning Objectives
Upon completion of this activity, participants should be able to

• Appreciate the incidence and clinical implications of ESR1 mutations for endocrine-resistant metastatic breast cancer (mBC) and determine optimal strategies to effectively identify patients harboring these abnormalities.
• Understand the biological rationale for, mechanism of action of, and pharmacologic similarities and differences between available and investigational oral selective estrogen receptor degraders (SERDs).
• Interrogate published research documenting the efficacy of oral SERD monotherapy for hormone receptor (HR)-positive, HER2-negative, ESR1-mutated mBC progressing on standard endocrine therapy in combination with a CDK4/6 inhibitor to optimally integrate these agents into the care of appropriately selected patients.
• Review available research data evaluating the role of serial ESR1 testing using circulating tumor DNA as a means to identify molecular progression and inform early therapeutic switching for patients with HR-positive mBC receiving CDK4/6 inhibitor-based first-line therapy, and consider the potential role of this novel strategy.
• Evaluate available clinical trial data with oral SERDs in combination with other systemic therapies, such as CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors, and consider the potential role of these regimens.
• Appraise the scientific justification for, available data with and potential clinical role of oral SERDs as adjuvant treatment for patients with localized HR-positive, HER2-negative breast cancer.
• Appreciate side effects associated with available and investigational oral SERDs alone and in combination with other therapies, and use this information to develop supportive management plans for patients undergoing treatment with these approaches.
• Assess ongoing clinical research studies evaluating novel applications of oral SERDs for HR-positive breast cancer, and counsel patients regarding the potential benefits of trial participation.

CE Credit
CME credit information will be given to each participant as part of the meeting course materials.

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FACULTY — Dr Mayer has no relevant financial relationships to disclose. The following faculty reported relevant financial relationships with ineligible entities:

Dr Bardia — Consulting Agreements: Alyssum Therapeutics, AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Lilly, Menarini Group, Merck, Novartis, Pfizer Inc, Vyome; Contracted Research (Support to Institution): AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Lilly, Menarini Group, Merck, Novartis, OnKure Therapeutics, Pfizer Inc. Dr O’Shaughnessy — Advisory Committees and Consulting Agreements: Aadi Bioscience, Agendia Inc, Amgen Inc, Aptitude Health, AstraZeneca Pharmaceuticals LP, BioNTech SE, Bristol Myers Squibb, Daiichi Sankyo Inc, Duality Biologics, Eisai Inc, Ellipses Pharma, Exact Sciences Corporation, G1 Therapeutics Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Guardant Health, HiberCell, Jazz Pharmaceuticals Inc, Johnson & Johnson, Lilly, Menarini Group, Merck, Mersana Therapeutics Inc, Natera Inc, Novartis, Pfizer Inc, Pierre Fabre, Puma Biotechnology Inc, RayzeBio, Roche Laboratories Inc, Sanofi, Seagen Inc, Stemline Therapeutics Inc, Summit Therapeutics, Tempus, TerSera Therapeutics LLC. Additional faculty to be announced.

MODERATOR
Dr Wander — Advisory Committees: AstraZeneca Pharmaceuticals LP, Celcuity, Genentech, a member of the Roche Group, Lilly, Menarini Group, Puma Biotechnology Inc, Regor Therapeutics, Stemline Therapeutics Inc; Consulting Agreements: 2nd.MD, Arvinas, Biovica International AB, Boundless Bio, Daiichi Sankyo Inc, Delcath Systems Inc, Foundation Medicine, Gilead Sciences Inc, Halda Therapeutics, Novartis, Pfizer Inc, Precede Biosciences, TerSera Therapeutics LLC, Veracyte Inc; Contracted Research: Arvinas, Boundless Bio, Genentech, a member of the Roche Group, Halda Therapeutics, Lilly, Menarini Group, Pfizer Inc, Phoenix Molecular Designs, Puma Biotechnology Inc, Regor Therapeutics, Sermonix Pharmaceuticals, Stemline Therapeutics Inc. 

Research To Practice CME Planning Committee Members, Staff and Reviewers
Planners, scientific staff and independent reviewers for Research To Practice have no relevant financial relationships to disclose.

Supporters
This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, and Stemline Therapeutics Inc.

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