Drs Mayer and Kalinsky conclude their discussion with a look at agents in development and unmet needs for patients with breast cancer and ESR1 mutations.

Ongoing Research and Unmet Needs in Patients With Breast Cancer and ESR1 Mutations

This is a synopsis of an Insights series featuring Kevin Kalinsky, MD, MS, of Winship Cancer Institute of Emory University, and Erica L. Mayer, MD, MPH, of Dana-Farber Cancer Institute.

As the discussion concluded, Dr Erica Mayer highlighted several promising novel agents for hormone receptor-positive breast cancer beyond selective estrogen receptor degraders [SERDs]. These include proteolysis-targeting chimeras [PROTACs] like ARV-471 [vepdegestrant] and selective estrogen receptor covalent antagonists [SERCAs] like H3B-6527 which may more potently inhibit estrogen receptor signaling.

Early phase clinical data presented at recent conferences suggests meaningful single-agent activity from both investigational drug classes despite heavily pretreated populations, with manageable toxicity. Combinations also appear feasible, though some unique drug-drug interactions may require consideration, as Dr Kevin Kalinsky noted a PROTAC/CDK4/6 inhibitor regimen showed heightened neutropenia.

Dr Kalinsky was also intrigued by phase III results for the selective estrogen receptor modulator lasofoxifene from the ELAINE studies, which improved progression-free survival over endocrine options when combined with abemaciclib. The ongoing phase III ELAINE-3 trial is evaluating lasofoxifene plus abemaciclib compared with fulvestrant plus abemaciclib specifically in patients harboring 

 mutations who progressed on prior CDK4/6 blockade. Demonstrating efficacy in this post-CDK4/6 setting could support a differentiated approval.

In closing, Dr Mayer emphasized practical challenges to integrating comprehensive genomic profiling for targetable alterations like 

 mutations into real-world practice. Overcoming barriers to accessible, serial ctDNA testing is imperative to realize the full potential of emerging biomarker-driven breast cancer therapies. Drs Kalinsky and Mayer urge focused education and implementation efforts surrounding ctDNA analysis to evolve the standard of care.

*Video synopsis is AI-generated and reviewed by OncLive editorial staff.

Videos

Medical oncologists discuss oral SERDs, with a focus on the SERENA-2 trial looking at camizestrant in patients with advanced ER+/HER2- breast cancer.

SERENA-2: Camizestrant vs Fulvestrant in Advanced ER+/HER2- Breast Cancer

Dr Erica Mayer discussed recent phase II data on the investigational oral selective estrogen receptor degrader [SERD] camizestrant from the SERENA-2 trial. Camizestrant was compared to the injectable fulvestrant in patients previously treated with endocrine therapy, about half having prior CDK4/6 inhibitors. Crossover was allowed on progression.

The primary endpoint of progression-free survival significantly improved with camizestrant over fulvestrant in the intention-to-treat population. A preplanned analysis of the 40% of patients with baseline 

 mutations showed an even greater progression-free survival difference favoring camizestrant arms over fulvestrant. No meaningful efficacy differences were evident in 

 wild-type disease. These results aligned with prior studies suggesting SERDs may provide preferential benefit in 

Camizestrant was reasonably well tolerated. Like other oral SERDs, low grade nausea and vomiting occurred. Unique but rare adverse effects included visual changes called phosphenes and asymptomatic bradycardia, both dose-dependent. Encouragingly, the 75-mg selected phase III dose showed lowest rates of these unusual toxicities vs higher camizestrant doses.

Dr Kevin Kalinsky concurred the SERENA-2 efficacy and safety data support further camizestrant development, noting several ongoing trials in both metastatic and adjuvant settings. He raised the future challenge of selecting among multiple approved oral SERDs. Beyond 

 mutation status predicting enhanced SERD activity, factors like tolerability differences and specificity for certain 

 mutations may ultimately guide choice. Early camizestrant analyses did not suggest efficacy variations by exact mutation type, but this warrants further study as precision targeting continues progressing.

Overall, Drs Mayer and Kalinsky are optimistic about the expanding oral SERD class. Multiple agents with distinct toxicity profiles are progressing through pivotal evaluation as monotherapy or combinations for HR+ breast cancer. Defining optimal treatment sequencing and patient selection biomarkers, potentially including specific 

 mutation variants, will be key to maximizing these next-generation endocrine agents’ impact across disease settings.

Erica L. Mayer, MD, MPH, discusses the role of elacestrant in the breast cancer treatment landscape and provides clinical insights on its safety profile.

The Role of Elacestrant in Breast Cancer

Dr Erica Mayer shares she utilizes the oral selective estrogen receptor degrader [SERD] elacestrant in practice per data suggesting longer duration of prior CDK4/6 inhibitor therapy predicts enhanced efficacy. This aligns with interpreting extended CDK4/6 duration as a marker of retained endocrine sensitivity rather than imminent resistance, supporting subsequent intensified estrogen pathway blockade.

In the phase III EMERALD trial, elacestrant improved progression-free survival over physician’s choice endocrine therapy specifically in patients on prior CDK4/6 inhibitors for ≥12 months. Dr Mayer often applies elacestrant in long-term CDK4/6 responders progressing after years of therapy, where further endocrine options are preferred based on the clinical context.

Additional EMERALD analyses highlighted elacestrant’s favorable toxicity profile with primarily low-grade nausea and no concerning safety signals, enabling flexible sequencing with other therapies. For instance, in patients harboring co-occurring 

 mutations, both actionable alterations, Dr Mayer utilizes elacestrant first considering its more favorable toxicity over PI3K inhibitors before subsequently deploying 

Dr Kevin Kalinsky noted that with expanding targeted therapy options in metastatic HR+ disease, including PI3K and AKT inhibition, treatment selection requires balancing efficacy and quality of life. He similarly prioritizes elacestrant in lower burden clinical scenarios where leveraging endocrine activity remains suitable, while utilizing more intensive regimens like fulvestrant/alpelisib for patients requiring rapid disease control.

Overall, Drs Mayer and Kalinsky believe elacestrant’s emergence helps fill a major unmet need in HR+ metastatic breast cancer. Its oral administration and tolerability provide a long-awaited endocrine sequencing option. Subpopulation analyses continue to refine appropriate patient selection, with duration of prior CDK4/6 response strongly indicating retained sensitivity to endocrine mechanisms.

Kevin Kalinsky, MD, MS, gives an overview of recent data from the EMERALD trial investigating elacestrant in patients with ER+/HER2- advanced breast cancer.

EMERALD: Elacestrant in ER+/HER2- Advanced Breast Cancer

Dr Erica Mayer discussed emerging data on elacestrant, the first oral selective estrogen receptor degrader (SERD) approved in breast cancer. The phase III EMERALD trial compared elacestrant to physician’s choice of endocrine therapy in patients previously treated with CDK4/6 inhibitors, about 20% also having prior fulvestrant exposure.

Elacestrant improved progression-free survival over endocrine therapy specifically in the 30% to 40% of patients with baseline 

 mutations. Additional EMERALD analyses suggest duration of prior CDK4/6 inhibitor therapy may predict elacestrant benefit. No significant difference was seen between arms for patients on CDK4/6 inhibitor <6 months. However, those remaining on CDK4/6 inhibitor ≥12 months derived substantial incremental progression-free survival from elacestrant over endocrine options.

Dr Kevin Kalinsky shared that in practice, he utilizes elacestrant monotherapy per its indication. The ≥12-month CDK4/6 duration analysis suggests retained endocrine sensitivity, supporting preferential efficacy of subsequent SERD therapy. Additional EMERALD analyses reinforced this CDK4/6 duration effect persisted across patient subgroups including co-occurring 

Drs. Mayer and Kalinsky believe these data collectively suggest CDK4/6 inhibitor duration may emerge as a clinical marker informing optimal SERD sequencing. Elacestrant appears particularly effective in patients retaining sufficient endocrine sensitivity as evidenced by sustained prior CDK4/6 response over 12 months. More intensive therapy may be reserved for those exhibiting earlier primary resistance. Defining molecular determinants of response and resistance will further optimize HR+ breast cancer therapy sequencing.

Drs Mayer and Kalinsky provide insights and offer their impressions of the PADA-1 trial, focusing on ESR1 mutation monitoring with circulating tumor DNA.

PADA-1 Trial: ctDNA Monitoring for Acquired ESR1 Mutations in Advanced Breast Cancer

Dr Erica Mayer noted that estrogen receptor [ER] mutations are uncommon at hormone receptor-positive [HR+] metastatic breast cancer diagnosis but emerge in about 40% of patients after 6 months of aromatase inhibitor plus CDK4/6 inhibitor therapy. This prompted discussion of the PADA-1 trial evaluating early intervention at detection of endocrine resistance mutations.

Dr Kevin Kalinsky outlined the PADA-1 study design in which patients received an aromatase inhibitor plus palbociclib as initial metastatic treatment. Circulating tumor DNA [ctDNA] was monitored for evolving 

 detection without radiographic progression, patients were randomized to continue aromatase inhibitor plus palbociclib or switch to fulvestrant plus palbociclib. Crossover was allowed at progression. The co-primary endpoints were progression-free survival from randomization (PFS1) and from subsequent therapy after progression (PFS2).

 emergence improved PFS1. Overall, the switching strategy increased duration of clinical benefit across treatment lines. However, Dr Mayer noted PADA-1 enrollment was small without survival data. Larger validation is needed before changing practice based on early ctDNA changes, despite the provocative signal.

This led to discussion of the ongoing phase III SERENA-6 trial, influenced by the PADA-1 paradigm. ER+ metastatic breast cancer patients on stable first-line aromatase inhibitor plus CDK4/6 inhibitor for ≥6 months enter a screening phase with liquid biopsy monitoring for 

 detection triggers randomization to continue current therapy or switch endocrine therapy to the oral selective ER degrader [SERD] camizestrant, assessing impact on progression-free survival.

Dr Mayer shared that SERENA-6’s clinical and genomic screening approach resonates with patients. Beyond evaluating specific interventions, these innovative trials may transform monitoring and decision algorithms in HR+ disease. Key open questions persist around optimal duration of therapy lines guided by molecular changes versus standard radiographic progression. Studies must balance maximizing benefit within lines while preserving options for later. Drs Kalinsky and Mayer believe engaging patients in research is imperative to define new paradigms in HR+ metastatic breast cancer care.

Drs Mayer and Kalinsky provide insights and offer their impressions of the PADA-1 trial, focusing on ESR1 mutation monitoring with circulating tumor DNA (ctDNA).

Experts on breast cancer discuss challenges encountered in biomarker testing for patients with breast cancer.

Overcoming Challenges in Biomarker Testing in Breast Cancer

Dr Erica Mayer and Dr. Kevin Kalinsky continued their discussion on evolving genomic profiling and treatment selection in hormone receptor-positive (HR+) metastatic breast cancer.

Dr Mayer highlighted challenges in circulating tumor DNA (ctDNA) testing, including low yield in minimal disease states like bone-only metastases. In such cases, she reflexes back to tumor tissue testing to evaluate targetable mutations like PIK3CA. Tumor biopsy is not always feasible, however, underscoring the utility of blood-based assays. Timing and logistics also pose challenges, as the multi-week turnaround for results does not align perfectly with clinical decision points about next treatment lines. However, Dr Mayer anticipates disease progression to mitigate these limitations.

Both speakers emphasized the value of recent ASCO [American Society of Clinical Oncology] guidelines recommending genomic profiling in HR+ metastatic breast cancer progressing on endocrine therapy. These evidence-based recommendations help establish testing as standard of care and facilitate insurance coverage.

Dr Mayer highlighted technical considerations in ctDNA assay selection, noting most assays used in metastatic disease evaluation take an agnostic approach detecting genome-wide alterations rather than tracking prespecified mutation panels informed by tumor tissue testing. This contrasts with ctDNA analysis in minimal residual disease assessment in early-stage patients, which often uses more personalized, tumor-informed assays. However, agnostic assays are emerging in this space as well.

Finally, the speakers concurred that serial ctDNA profiling over time is ideal given cancer genomic evolution with treatment pressure, which may uncover new targetable alterations not present earlier. As one example, Dr Mayer will evaluate for 

 mutations in patients who progress after multiple prior endocrine therapy lines, even with initially negative testing. Identifying late-arising 

 mutations may expand treatment options like selective estrogen receptor degraders.

Overall, Drs Kalinsky and Mayer advocate integrating plasma-based genomic cancer profiling into the continuum of HR+ metastatic breast cancer care. Serial liquid biopsy testing enables tracking of an adapting cancer genome, allowing for more timely, personalized therapeutic decisions as the disease landscape shifts.

Kevin Kalinsky, MD, MS, and Erica L. Mayer, MD, MPH, discuss testing practices for ESR1 mutations in patients with breast cancer.

Testing for ESR1 Mutations in Breast Cancer

Dr Kevin Kalinsky, director of the Glenn Family Breast Center at Winship Cancer Institute, and Dr Erica Mayer, director of Breast Cancer Clinical Research at Dana-Farber Cancer Institute, discussed evolving treatment approaches for hormone receptor-positive (HR+) metastatic breast cancer, focusing on the impact of estrogen receptor (ER) mutations.

Dr Mayer outlined current standards for genomic profiling in metastatic HR+ breast cancer, including tumor tissue-based testing and cell-free DNA (cfDNA) analysis from liquid biopsies. Liquid biopsies can provide a comprehensive snapshot of cancer genetics and allow for serial monitoring of mutations over time, especially at progression. She obtains baseline tissue testing but prefers serial cfDNA analysis to track genomic evolution.

 mutations, which confer endocrine therapy resistance. Unlike trunk mutations present at diagnosis, 

 mutations often emerge later, so tissue testing may underestimate prevalence. Dr. Mayer does not routinely order cfDNA testing for endocrine-sensitive disease but finds it valuable in certain contexts: patients on extended adjuvant aromatase inhibitor therapy approaching metastasis, and patients progressing rapidly on aromatase inhibitors, indicating probable resistance. In the latter case, 

 mutations would prompt use of non-aromatase inhibitor therapies like fulvestrant rather than continuing aromatase inhibitors plus CDK4/6 inhibitors.

 mutation testing is most relevant in deciding between endocrine therapies versus more targeted options when resistance emerges. He often orders testing around the time of clinical progression, scheduling a few weeks in advance to inform next-line decisions at the patient visit. Having real-time mutation data enables personalized therapy selection.

Overall, Drs Mayer and Kalinsky emphasized that advancing genomic profiling capabilities allow deeper understanding of the heterogeneity and evolution of HR+ metastatic breast cancer. Serial liquid biopsy testing for mutations like 

 that mediate endocrine resistance at progression enables more informed, personalized therapy selection to overcome tumor adaptation. Their discussion highlights how genomic information is transforming real-time clinical decision-making in this disease.

Dr Mayer on the Use of CDK4/6 Inhibitors in HR+/HER2– Breast Cancer

Erica L. Mayer, MD, MPH, director, Breast Cancer Clinical Research, Dana-Farber and Brigham and Women’s Hospital, institute physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses findings from research investigating CDK4/6 inhibitors in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

CDK4/6 inhibitors are integral to the management of HR-positive breast cancer, Mayer says. These agents, which were first used in breast cancer approximately 10 years ago, are widely used for patients with advanced or metastatic disease, Mayer explains. Four large, randomized trials have evaluated the efficacy and safety of this drug class in the adjuvant setting: the phase 3 PALLAS (NCT02513394) and Penelope-B (NCT01864746) trials with palbociclib (Ibrance); the phase 3 monarchE trial (NCT03155997) with abemaciclib (Verzenio); and the phase 3 NATALEE trial (NCT03701334) with ribociclib (Kisqali).

PALLAS randomly assigned patients with HR-positive HER2-negative early breast cancer to receive 2 years of adjuvant endocrine therapy with or without palbociclib. At a median follow-up of 31 months, invasive disease–free survival (IDFS) events occurred in 8.8% of patients in the ribociclib arm vs 9.1% of patients in the arm that received endocrine therapy alone.

Penelope-B enrolled patients with HR-positive HER2-negative primary breast cancer who did not achieve a pathological complete response after taxane-containing neoadjuvant chemotherapy and were at high risk of relapse to receive endocrine therapy. Patients were randomly assigned to receive either palbociclib or placebo. At a median follow-up of 42.8 months, palbociclib did not improve IDFS vs placebo when added to endocrine therapy (stratified hazard ratio, 0.93; 95% CI, 0.74-1.17; 

The monarchE trial investigated standard-of-care endocrine therapy with or without abemaciclib in patients with HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence. At a median follow-up of 42 months (interquartile range, 37-47), the median DFS was not reached in either arm, and investigators reported a sustained IDFS benefit with abemaciclib (hazard ratio, 0.664; 95% CI, 0.578-0.762; nominal 

NATALEE evaluated adjuvant ribociclib plus endocrine therapy vs endocrine therapy alone in patients with stage II or III HR-positive HER2-negative early breast cancer at risk for recurrence, including patients with no nodal involvement. At a median follow-up of 34 months, the 3-year IDFS rates were 90.4% with ribociclib vs 87.1% with endocrine therapy alone (hazard ratio, 0.748; 95% CI, 0.618-0.906; 

Although the PALLAS and Penelope-B trials did not meet their respective primary end points, positive findings from the NATALEE and monarchE trials indicate the benefit of adding CDK4/6 inhibitors to adjuvant endocrine therapy for patients with higher-risk, HR-positive, HER2-negative breast cancer, Mayer concludes.

Erica L. Mayer, MD, MPH, discusses findings from research investigating CDK4/6 inhibitors in patients with hormone receptor (HR)–positive, HER2-negative breast cancer.

Erica L. Mayer, MD, MPH, director, Clinical Research Institute, physician, Dana-Farber Cancer Institute, associate professor of Medicine, Harvard Medical School, discusses findings from the phase 2 PACE trial (NCT03147287) in patients with hormone receptor (HR)–positive/HER2-negative metastatic breast cancer.

Investigators examined the combination of palbociclib (Ibrance) plus fulvestrant (Faslodex) vs fulvestrant alone. The trial enrolled 220 patients with HR-positive/HER2-negative metastatic breast cancer who progressed on a CDK4/6 inhibitor and endocrine therapy with at least 6 months of stable disease. Patients were not permitted to have more than 2 prior lines of endocrine therapy, and prior exposure to fulvestrant was not allowed. Patients were randomly assigned 1:2:1 to receive fulvestrant alone, palbociclib plus fulvestrant, or palbociclib plus fulvestrant and avelumab (Bavencio).

Data presented at the 2022 San Antonio Breast Cancer Symposium showed that palbociclib plus fulvestrant beyond progression on a prior CDK4/6 inhibitor did not significantly improve progression-free survival (PFS) compared with fulvestrant alone. At median follow-up of 23.6 months, findings showed that patients treated with palbociclib plus fulvestrant experienced a median PFS of 4.6 months, compared with 4.8 months for those given fulvestrant alone. Mayer notes that the majority of enrolled patients received palbociclib as their prior CDK4/6 inhibitor and had been on that regimen for more than 1 year.

Although the primary end point for the superiority of palbociclib plus fulvestrant vs fulvestrant alone was negative, findings for the secondary end point for the superiority of palbociclib plus fulvestrant and avelumab vs fulvestrant alone were hypothesis generating, Mayer says. Patients administered the triplet achieved a median PFS of 8.1 months.

The findings from the addition of the PD-L1 inhibitor avelumab presented investigators with the potential benefit of immune-oncology (IO) therapy for patients with HR-positive breast cancer, Mayer says. The ongoing evaluation of serial circulating tumor DNA and circulating tumor cell samples will allow investigators to explore of the mutational and resistance landscape, plus markers of sensitivity to IO therapy, in patients with HR-positive breast cancer.

Erica L. Mayer, MD, MPH, discusses findings from the phase 2 PACE trial in patients with hormone receptor (HR)–positive/HER2-negative metastatic breast cancer.

Dr. Mayer on the PACE Trial in HR+/HER2– Breast Cancer

Erica L. Mayer, MD, MPH, assistant professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, describes studies involving tivozanib, a potent VEGF receptor tyrosine kinase inhibitor.

A phase I study investigated tivozanib as a monotherapy for patients with renal cell carcinoma. Tivozanib was active and well tolerated, demonstrating common toxicities of angiogenesis inhibitors such as hypertension and hoarse voice.

In a phase III trial, patients with renal cell carcinoma were randomized to tivozanib or sorafenib. Patients in the tivozanib arm had superior progression-free survival (PFS) (11.9 months vs 9.1 months) and needed fewer dose reductions.

Tivozanib has also been studied in breast cancer. In a phase I dose escalation trial, tivozanib was combined with weekly paclitaxel and demonstrated an overall response rate of 28 percent. The most common toxicities experienced in the trial were fatigue, gastrointestinal toxicity, mild neutropenia, and neuropathy. The maximum tolerated doses identified were tivozanib at 1.5 mg/day and paclitaxel at 90 mg/m

Erica L. Mayer, MD, MPH

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