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Key Clinical Summary: Differentiation of emerging endocrine therapies in ER⁺/HER2⁻ mBC based on MoA and clinical role

This is a micro-learning module summary of Prof Mark Pegrum’s session which you can find here. Before participating please read our CME and disclosure information which can be found here.

Acknowledgment: This activity is supported by an educational grant from Pfizer Inc. and Arvinas. This online education program has been designed for healthcare professionals globally.

Introduction

This summary reviews the latest advances in endocrine therapies for estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC). It focuses on novel agents, including oral selective estrogen receptor degraders (SERDs), proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degraders, and their mechanisms of action, clinical trial data, and implications for treatment selection, especially in the context of ESR1 mutations and endocrine resistance.

Mechanisms of Emerging Endocrine Therapies

Emerging therapies include oral SERDs, PROTACs, and complete estrogen receptor antagonists (CERANs), which target the ER through degradation pathways, and selective estrogen receptor covalent antagonists (SERCAs). These novel agents offer distinct mechanisms to overcome endocrine resistance in ER-positive breast cancer.

  • Oral SERDs, such as camizestrant and others, bind to the ER and induce a conformational change that leads to receptor degradation via the proteasome pathway, thereby reducing ER signaling and tumor growth.
  • PROTACs, exemplified by vepdegestrant, are bifunctional molecules that simultaneously bind the ER and an E3 ubiquitin ligase, promoting ubiquitination and proteasomal degradation of the ER protein, effectively lowering ER levels and inhibiting cancer cell proliferation.
  • CERANs, such as palazestrant, act as full antagonists by blocking both the ligand-binding and transcriptional activation functions of the ER, preventing the ER from binding estrogen and coactivators, thus fully inhibiting ER-mediated gene transcription.
  • SERCAs, such as H3B-6545, covalently bind to a specific cysteine residue in the ER ligand-binding domain, irreversibly inhibiting ER activity by preventing receptor dimerization and DNA binding, leading to suppression of ER-driven tumor growth.

ESR1 Mutations and Clinical Impact

ESR1 gene mutations, first identified in the 1990s, are associated with constitutive ER activation and resistance to conventional endocrine therapies like tamoxifen and aromatase inhibitors (AIs). While rare in early-stage breast cancer (<1%), ESR1 mutations are prevalent in metastatic settings, occurring in up to 40% of patients at the point of third-line therapy. These mutations drive tumor proliferation and metastatic progression, making them critical targets for emerging therapies in mBC.

Key Clinical Trials

EMERALD Trial: This phase 3 trial evaluated the oral SERD elacestrant versus standard endocrine therapy (fulvestrant or AI) in patients with ER+/HER2- mBC who had progressed or relapsed after prior endocrine therapy.

  • Elacestrant demonstrated superior progression-free survival (PFS) versus the standard of care in patients with ESR1 mutations (hazard ratio [HR] 0.5, p=0.0005).
  • Adverse events (AEs) included nausea, vomiting, and anorexia.
  • Ongoing studies such as the phase 1b/2 ELEVATE umbrella study is exploring elacestrant combination regimens.

EMBER-3 Trial: Imlunestrant, another oral SERD, was compared to fulvestrant or exemestane in a phase 3 trial involving patients with ER+/HER2- advanced breast cancer progressing after AI therapy ± CDK4/6 inhibitors.

  • Imlunestrant showed improved PFS in the ESR1-mutant population (HR 0.62, p<0.001).
  • Common AEs included cytopenias, musculoskeletal pain, hypocalcemia, fatigue, and gastrointestinal symptoms.

VERITAC-2 Trial: Vepdegestrant, the first PROTAC evaluated in a phase 3 trial, was compared to fulvestrant in patients with ER+/HER2- mBC after prior CDK4/6 inhibitor plus endocrine therapy.

  • The trial met its primary endpoint, with improved PFS with vepdegestrant versus fulvestrant in the ESR1-mutant population (HR 0.52, p<0.001) .
  • Toxicities included fatigue, liver enzyme elevations, gastrointestinal effects, cytopenias, arthralgia, and anorexia.

SERENA-6 Trial: This pivotal phase 3 study introduced a novel treatment paradigm by using ctDNA to detect emergent ESR1 mutations in patients without clinical progression on AI plus CDK4/6 inhibitors. Patients were randomized to the oral SERD camizestrant with continued CDK4/6 inhibitor plus a placebo for AI, or continued AI plus CDK4/6 inhibitor, with a placebo for camizestrant.

  • The trial showed significant PFS improvement (HR 0.44, p<0.0001) with camizestrant versus AI, supporting early intervention based on molecular resistance detection.
  • AEs included neutropenia, photopsia, and bradycardia, though none of the bradycardia events were grade 3/4.

Clinical Considerations and Future Directions

Differences in trial populations and designs limit direct comparisons between agents. However, the consistent efficacy of oral SERDs and PROTACs in ESR1-mutant mBC highlights their potential to overcome endocrine resistance. The use of ctDNA monitoring for early detection of resistance mutations represents a promising strategy to optimize treatment timing and outcomes.

Ongoing combination studies with CDK4/6 inhibitors, mTOR inhibitors, and other targeted agents may further enhance therapeutic options. Safety profiles vary among agents, necessitating careful management of side effects such as nausea, cytopenias, and cardiac effects.

Conclusion

Emerging endocrine therapies targeting the ER through novel degradation mechanisms, including oral SERDs and PROTACs, offer significant advances in managing ER+/HER2- mBC, particularly in patients harboring ESR1 mutations. Clinical trials demonstrate improved PFS with these agents and introduce new paradigms for early intervention guided by molecular monitoring. These developments hold promise for improving patient outcomes and expanding personalized treatment strategies in this challenging disease setting.