Alexis LeVee, MD, is chief Hematology & Medical Oncology fellow at City of Hope

Kelly E. McCann, MD, PhD, is an assistant professor and breast medical oncologist at UCLA.

Efficacy and Safety of Next-Generation Oral SERDs for HR+/HER2– mBC

Combination Therapy Development and Oral SERD Pipeline

The Elevate study represents a comprehensive phase 1b/2 umbrella trial investigating elacestrant combinations with various targeted therapies, including CDK4/6 inhibitors and PI3K pathway inhibitors. Recent 2025 American Society of Clinical Oncology Annual Meeting updates demonstrated promising early efficacy with elacestrant plus ribociclib and elacestrant plus everolimus combinations, showing median progression-free survival in the range of 7 to 8 months. The safety profiles remained consistent with individual agent toxicities, with increased neutropenia from ribociclib and stomatitis from everolimus as expected.

The oral SERD landscape is expanding rapidly, with multiple agents in clinical development, including capivasertib, imlunestrant, and giredestrant, all demonstrating superior efficacy compared with fulvestrant, specifically in populations with 

-mutant disease. These agents share common characteristics of being well-tolerated oral medications that provide modest but clinically meaningful improvements over standard fulvestrant therapy. The consistency of efficacy across different oral SERDs suggests a class effect in hormone-sensitive, 

Proteolysis-targeting chimera technology adds another dimension to the oral SERD pipeline, with agents showing benefit across all patients with hormone receptor–positive disease while maintaining superior efficacy in populations with 

-mutant disease. The abundance of effective oral SERD options will likely provide clinicians with multiple therapeutic choices, allowing selection based on individual patient factors, combination potential, and specific toxicity profiles rather than efficacy differences alone.

Videos

Panelists discuss how upcoming oral selective estrogen receptor degraders (SERDs; eg, camasertinib, imlunestrant, and giredestrant) are showing efficacy primarily in populations with ESR1 mutations and are all well-tolerated oral agents that will likely receive approvals.

The Role of Elacestrant in the Treatment of HR+/HER2– mBC

Elacestrant Implementation and Biomarker-Driven Treatment Decisions

The Emerald trial established elacestrant as an important oral selective estrogen receptor degrader (SERD) option for patients with hormone receptor–positive metastatic breast cancer who have progressed on CDK4/6 inhibitor therapy. This phase 3 study enrolled over 400 patients who had received prior endocrine therapy and CDK4/6 inhibitors, with approximately 20% to 25% having received chemotherapy. The trial results demonstrated a modest progression-free survival advantage in the overall population, with the benefit primarily driven by patients harboring 

Subgroup analysis reveals that duration of prior CDK4/6 inhibitor therapy serves as a valuable biomarker for predicting elacestrant efficacy. Patients who received CDK4/6 inhibitor therapy for 12 months or longer achieved approximately 8.6 months of progression-free survival compared with 4 months for those with shorter durations of 6 months or less. This biomarker helps clinicians identify patients with endocrine-sensitive disease who are most likely to benefit from continued endocrine-based therapy.

Clinical implementation focuses on patients with 

 mutations who demonstrated prolonged benefit from prior CDK4/6 inhibitor therapy, regardless of comutations or 

 variant types. The data support using elacestrant in combination with other targeted therapies, with ongoing trials exploring various combination strategies. This approach allows clinicians to maximize the benefit of oral SERD therapy while maintaining quality of life through oral administration rather than intramuscular fulvestrant injections.

Panelists discuss how elacestrant from the EMERALD trial is being incorporated into practice based on ESR1 mutation status and duration of prior CDK4/6 inhibitor therapy, with combination approaches being explored in the ELEVATE trial.

Camizestrant in HR+/HER2– mBC: Emerging Data From the SERENA-6 Trial

SERENA-6 Trial Discussion and Clinical Implementation

The SERENA-6 trial represents a significant advancement in personalized breast cancer treatment through ctDNA monitoring for 

 mutations. In this innovative trial design, patients initially received an aromatase inhibitor plus CDK4/6 inhibitor in first-line treatment, with regular ctDNA testing to detect the emergence of 

 mutations develop specifically as resistance mechanisms to estrogen deprivation therapy, making their detection crucial for treatment optimization.

 mutations were detected, patients were randomly assigned to either continue their current aromatase inhibitor plus CDK4/6 inhibitor regimen or switch to oral SERD capivasertib while maintaining the same CDK4/6 inhibitor. The results showed median progression-free survival of approximately 16 months for patients who switched to capivasertib vs 9 months for those who remained on the aromatase inhibitor combination. This represents a clinically meaningful improvement in outcomes for patients with emergent 

Current clinical practice varies among oncologists regarding immediate implementation of these findings. Although some experts view the data as practice changing and have begun incorporating 

 mutation testing with treatment switches, others maintain their established second-line approach using fulvestrant plus PI3K pathway inhibitors. The consensus emphasizes the importance of secondary end points, including time to chemotherapy and overall survival data, to fully evaluate the clinical impact of this biomarker-driven strategy.

Panelists discuss how the SERENA-6 trial design uses circulating tumor DNA (ctDNA) monitoring to detect ESR1 mutations and switch patients from aromatase inhibitors to oral selective estrogen receptor degraders (SERDs) such as camasertinib while continuing CDK4/6 inhibitors.

Biomarker Testing Strategies in Metastatic Breast Cancer

This OncLive Peer Exchange® from ASCO 2025 in Chicago focuses on hormone receptor–positive breast cancer treatment advances and highlights from the conference. The panel brings together leading breast oncology experts from major academic institutions, including the University of Chicago, UCLA, University of California San Diego, Washington University, and City of Hope. The discussion centers on the latest developments in hormone receptor–positive, HER2-negative, and HER2-low metastatic breast cancer treatment.

The experts introduce the session’s comprehensive agenda covering oral SERDs, targeted therapies, and antibody-drug conjugates that are transforming the breast cancer treatment landscape. Key topics include reviewing critical trial data presented at ASCO 2025, particularly the SERENA-6 trial for capivasertib, and exploring how these emerging therapies are being integrated into clinical practice. The panel aims to provide practical insights for oncologists treating patients with hormone receptor–positive metastatic breast cancer.

This peer exchange represents a timely discussion of cutting-edge developments in breast cancer treatment, offering evidence-based perspectives on the rapidly evolving therapeutic options available to patients with hormone receptor–positive disease. The session promises to deliver actionable insights for improving patient outcomes in this specific breast cancer subtype.

Panelists discuss how they will review the latest updates in hormone receptor–positive, HER2-negative, and HER2-low metastatic breast cancer, focusing on oral selective estrogen receptor degraders (SERDs), targeted therapies, and antibody-drug conjugates presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Dr LeVee on ADC Trials That May Inform the Evolution of Breast Cancer Management

Alexis LeVee, MD, chief Hematology & Medical Oncology fellow at City of Hope, discussed highly-anticipated readouts of clinical trials investigating antibody-drug conjugates (ADCs) in patients with HER2-positive metastatic breast cancer and triple-negative breast cancer (TNBC) that will be presented at the 

One trial generating substantial interest is the phase 3 DESTINY-Breast09 trial (NCT04784715), which compared fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) with the current standard first-line regimen of docetaxel, trastuzumab (Herceptin), and pertuzumab in HER2-positive metastatic breast cancer, LeVee began. 

 shared that treatment with T-DXd plus pertuzumab improved progression-free survival (PFS) compared with the standard of care; this benefit was observed across all prespecified patient subgroups. These findings may have important implications for the first-line treatment paradigm in this breast cancer subtype, she explained.

Similarly, the phase 3 ASCENT-04 trial (NCT05382286), which evaluated sacituzumab govitecan-hziy (Trodelvy) in combination with pembrolizumab (Keytruda) vs physician’s choice of chemotherapy plus pembrolizumab in patients with PD-L1–positive metastatic TNBC, reported improved PFS with the investigational combination in a separate 

. The safety profile of the investigational combination was consistent with the known toxicities of each individual agent, supporting the potential clinical utility of this regimen, LeVee highlighted.

Several phase 2 studies of ADCs in breast cancer will also be presented at the meeting, LeVee stated. The phase 2 NeoSTAR trial (NCT04230109) evaluated neoadjuvant sacituzumab govitecan plus pembrolizumab in patients with early-stage TNBC. Additionally, the phase 2 OptiTROP-Breast05 study (NCT05445908) investigated a novel ADC, sacituzumab tirumotecan (formerly SKB264/MK-2870), as a first-line treatment for patients with metastatic TNBC. Both studies may provide valuable insights into evolving treatment strategies for TNBC, LeVee concluded.

Supported in part by Daiichi Sankyo. Content produced and independently developed by OncLive.

Alexis LeVee, MD, discusses clinical trials investigating ADCs that may change treatment standards for patients with various subtypes of breast cancer.

Dr LeVee on Ongoing Research With Immunotherapy and ADCs in TNBC

“There are a lot of exciting ongoing trials in TNBC, and because TNBC is more immunogenic compared with the other breast cancer subtypes, immunotherapy works [for this subtype].”

Alexis LeVee, MD, the chief fellow of Hematology & Medical Oncology at City of Hope, discussed ongoing research with immunotherapy agents and chemotherapy-free treatment strategies in patients with triple-negative breast cancer (TNBC).

TNBC is characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which precludes the use of targeted therapies directed at these receptors, LeVee began. Despite this limitation, TNBC demonstrates a heightened level of immunogenicity relative to other breast cancer subtypes, which makes it more responsive to immune checkpoint blockade, she explained. This increased immunogenic potential is evidenced by higher levels of PD-L1 expression, greater infiltration by tumor-infiltrating lymphocytes (TILs), and elevated tumor mutational burden, all of which are biomarkers associated with responses to immunotherapy, she stated.

Currently, immune checkpoint inhibitors have received regulatory approval for use in both early-stage and metastatic TNBC, LeVee noted. Numerous ongoing clinical trials are investigating the optimal use of immunotherapy in TNBC, including combination regimens and novel therapeutic targets, according to LeVee. Moreover, multiple phase 3 trials are underway in the neoadjuvant setting, she reported. Notable among these is the phase 3 SCARLET trial (NCT05929768), which is comparing an anthracycline-free neoadjuvant regimen with the standard-of-care phase 3 KEYNOTE-522 trial (NCT03036488) regimen of pembrolizumab (Keytruda) plus chemotherapy in patients with early-stage TNBC, LeVee said.

Another significant study is the phase 3 TROPION-Breast04 trial (NCT06112379), which is assessing neoadjuvant datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) in combination with durvalumab compared with the KEYNOTE-522 regimen in patients with early-stage disease, LeVee reported. Several other trials are investigating chemotherapy-free regimens to potentially reduce toxicity, she continued. For instance, the phase 3 BELLINI study (NCT03815890) of ipilimumab (Yervoy) plus nivolumab (Opdivo) has shown promising results in patients with early-stage TNBC with high TIL levels, suggesting a potential role for less toxic therapeutic backbones in this patient population, she added.

In the adjuvant setting, trials are being conducted for patients who achieve a pathologic complete response (pCR), as well as for those with residual disease, LeVee emphasized. The phase 3 OptimICE-pCR trial (NCT05812807) is examining the possibility of de-escalating adjuvant therapy by omitting pembrolizumab in patients who achieve pCR after neoadjuvant therapy. Conversely, for patients with residual disease following neoadjuvant therapy, combination strategies involving antibody-drug conjugates like Dato-DXd or sacituzumab govitecan-hziy (Trodelvy) with or without immunotherapy, are under active investigation. One such trial is the phase 3 TroFuse-012 study (NCT06393374), which is evaluating sacituzumab tirumotecan (SKB264/MK-2870) in combination with pembrolizumab.

Alexis LeVee, MD, discusses ongoing trials investigating immunotherapy agents and antibody-drug conjugates that may challenge the current SOC for TNBC.

Alexis LeVee, MD, discusses immune-related adverse effects in patients with early breast cancer treated with immune checkpoint inhibitors. 

Dr LeVee on Immune-Related AEs Associated With ICIs in Early Breast Cancer

“We found a much higher rate of immune-related adverse [effects] than what has been previously published based on the [phase 3] KEYNOTE-522 trial.”

Alexis LeVee, MD, chief hematology/oncology fellow, City of Hope, discusses findings from a multi-institutional study investigating the rates of and risk factors for immune-related adverse effects (iRAEs) in patients with early-stage breast cancer treated with immune checkpoint inhibitors.

2024 San Antonio Breast Cancer Symposium (SABCS)

. The multi-institutional study included 423 real-world patients who previously received immune checkpoint inhibitors for early-stage breast cancer, LeVee explains. The study included patients with stage I to III breast cancer who were treated with ICIs at 1 of 4 academic institutions between 2014 and 2024. An irAE was defined as a toxicity that was determined via an oncologist to be potentially or definitely related to immune checkpoint inhibitors or high dose steroids after the causative agent was not identified.

Of note, LeVee and colleagues found a higher rate of irAEs in their multi-institutional study compared with previous findings from the phase 3 KEYNOTE-522 trial (NCT03036488). The trial investigated the combination of pembrolizumab (Keytruda) and chemotherapy in previously untreated patients with stage II or III triple-negative breast cancer. Among patients from the multi-institutional study, 72.6% of patients experienced any-grade irAEs, LeVee says, and 18.9% experienced high-grade irAEs. She emphasizes that these findings were derived from patients treated in a real-world setting who were not selected for clinical trials because of comorbidities, which may be the reason for increased rates of irAEs.

LeVee notes that the association between comorbidities and increased rates of irAEs led them to focus on specific risk factors that may cause increased rates of irAEs. Based on their multivariate analysis, they found that patients older than age 50 and patients who had chronic kidney disease experienced higher rates of irAEs, she says. Therefore, it is crucial to identify patients at higher risk of irAEs to make informed treatment choices, she concludes.

Alexis LeVee, MD

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