Estrogen Receptor Degrader Research Articles

Long-term estrogen-deprived estrogen receptor α-positive breast cancer cell migration assisted by fatty acid 2-hydroxylase.

The risk of breast cancer (BC) recurrence is high in postmenopausal women, though the underlying molecular mechanisms are not yet fully understood. We developed a long-term estrogen-deprived (LTED) cell line from MCF-7 cells, which we used as an in vitro model for aromatase inhibitor (AI)-resistant estrogen receptor α (ERα)-positive postmenopausal BC. We also describe the involvement of fatty acid 2-hydroxylase (FA2H) in the modulation of LTED cell migration. Small interfering RNA specific to FA2H (siFA2H) could reduce cell migration, whereas the introduction of plasmid expressing FA2H, but not its inactive mutant, resulted in enhanced migration. Moreover, proliferation of the LTED cells was not affected by modulation of FA2H expression. Fulvestrant (FUL), a selective estrogen receptor degrader used to treat AI-resistant ERα-positive postmenopausal BC, was found to induce degradation of ERα together with a decrease in ER-mediated transcription; however, FA2H protein expression and migration remained unchanged. Overall, the findings of this study suggest that FA2H is one of the drivers of LTED cell migration, and that LTED cells resistant to FUL therapy may be involved in malignancy and metastatic mechanisms.

Pharmacologic Induction of ERα SUMOylation Disrupts Its Chromatin Binding.

Estrogen receptor α (ERα)-positive breast cancer patients are typically treated with ERα inhibitors, including selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). However, the distinct pharmacological properties of various ERα inhibitors remain incompletely understood. In this study, we employed formaldehyde cross-linking followed by ERα immunoprecipitation and mass spectrometry to reveal that fulvestrant, the first FDA-approved SERD, induces the interaction between ERα and SUMO E3 ligases PIAS1 and PIAS2. Biochemical and genomic assays confirmed that fulvestrant induces SUMOylation of ERα, which inhibits ERα's binding to chromatin DNA. In addition, raloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD) were identified as compounds that similarly induce ERα SUMOylation and inhibit its chromatin interaction. Our findings reveal a mechanism by which select ERα inhibitors disrupt ERα function through SUMOylation, offering insights for the development of next-generation ERα-targeted therapies.

8018 Improving Anti-Breast Cancer Activities by Optimizing Torsion Angle Energies

Abstract Disclosure: D.R. Zak: None. E.C. Fink: None. G.R. Hancock: None. K.S. Young: None. S.W. Fanning: None. Overexpression of estrogen receptor alpha (ER-alpha) is found in 70% of breast cancer tumors. Normally, ER-alpha remains inactive and sequestered in the cytoplasm until estrogen binds to the ligand-binding domain (LBD) to enable nuclear translocation, coregulator recruitment, and subsequent activation of proliferative ER-alpha-dependent transcriptomic profiles. The majority of breast cancers are treated successfully with ER-targeted endocrine therapies, but hotspot ER-alpha LBD mutants are selected for, namely Y537S and D538G causing therapeutic resistance, relapse, and aggressive metastatic disease. The selective estrogen receptor modulator (SERM) lasofoxifene (laso) and selective estrogen receptor degrader (SERD) elacestrant (RAD1901) are chemically distinctive and show great promise in the ER-alpha mutant setting with potent anti-tumor effects and improved side effect profiles compared to the standard-of-care SERD fulvestrant (ICI). To elucidate the structural-transcriptional relationships of these ligands, we created a laso/RAD1901 chemical hybrid T6I-29 that demonstrated both canonical and unexpected therapeutic mechanisms of action. However, it possesses reduced anti-proliferative potency compared to ICI. We hypothesized that minor chemical changes to T6I-29 could improve potency while maintaining its favorable pharmaceutical profiles. To address this hypothesis, we performed quantum mechanical calculations of a series of T6I-derivatives. The addition of a methyl linker within the scaffold core significantly improved the torsion angle energies of the ligand binding pose. Multiple derivatives were synthesized based on these computations. The new compound T6I-B2 exerted profound anti-proliferative effects on breast cancer cells and adopted a unique ligand binding pose within the LBD. This approach shows that T6I-SERM potency can be improved by optimizing ligand torsion angle energies. Presentation: 6/3/2024

Induction of the TEAD Co-activator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer.

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer, and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation (H3K27ac) profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders (SERDs), such as fulvestrant, promote expression of VGLL1, a co-activator for TEAD transcription factors. VGLL1, acting via TEADs, promoted expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients.

Ionizable Drugs Enable Intracellular Delivery of Co-Formulated siRNA.

Targeting complementary pathways in diseases such as cancer can be achieved with co-delivery of small interfering ribonucleic acid (siRNA) and small molecule drugs; however, current formulation strategies are typically limited to one, but not both. Here, ionizable small molecule drugs and siRNA are co-formulatedin drug-rich nanoparticles. Ionizable analogs of the selective estrogen receptor degrader fulvestrant self-assemble into colloidal drug aggregates and cause endosomal disruption, allowing co-delivery of siRNA against a non-druggable target. siRNA is encapsulated in lipid-stabilized, drug-rich colloidal nanoparticles where the ionizable lipid used in conventional lipid nanoparticles is replaced with an ionizable fulvestrant analog. The selection of an appropriate phospholipid and formulation buffer enables endocytosis and potent reporter gene knockdown in cancer cells. Importantly, siRNA targeting cyclin E1 is effectively delivered to drug-resistant breast cancer cells, demonstrating the utility of this approach. This strategy opens the possibility of using ionizable drugs to co-deliver RNA and ultimately improve therapeutic outcomes.

Discovery of non-antiproliferative selective estrogen receptor degraders (SERDs) based on scaffold optimization of elacestrant

Elacestrant, the first oral selective estrogen receptor degrader (SERD), has been approved for ER positive breast cancer in 2023. Recent study showed that elacestrant has moderate pharmacokinetic property and the oral bioavailability is 11 %. In this study, we have performed docking analyses of elacestrant with different cytochrome P450 isoforms. The results indicated that tetrahydronaphthalene scaffold of elacestrant located closely to Heme iron center of P450s and might undergo rapid metabolism by CYP3A4. Therefore, we have changed the tertiary carbon atom to nitrogen atom of the scaffold to attenuate the metabolic effect. The most interesting finding is that compound B16 exhibited significant degradation of ERα at 5 μM but didn't show antiproliferative activity at high concentrations in MCF-7 and T47D cells. Compound B16 may serve as an ER probe to investigate ER status in ER positive breast cancer cells.

Molecular Modeling Studies of Similar Molecules to Selective Estrogen Receptor Degrader Elacestrant as Inhibitors of SARS-COV-2.

Coronavirus 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) strain. Many anticancer compounds have been repurposed as effective anti-coronavirus agents and are currently in a clinical trial to be evaluated for treatment. Elacestrant is a novel selective estrogen receptor degrader (SERD). A fingerprint Tanimoto-based 2-dimensional similarity search was performed in the PubChem database using elacestrant as a prototype. The chemical compounds were downloaded, and virtual screening, molecular docking, and molecular dynamics were further used to identify the most active molecules in the binding pocket SARS-COV-2 main protease. Eight compounds with superior docking score, gscore, and glide binding energy were identified. Molecular dynamic simulations (MD) were performed at 100 ns to remove the false interactions between the receptor and the active ligands. The results showed that all the compounds displayed good stability. Further, the ADMET results showed that compounds CID58023104 was observed to be deemed a hit compound; hence, CID58023104 and could be optimize, derivatize, and explore for further development as an anti-coronavirus agent targeting SARS-COV-2 main protease.

637P AC699, a novel chimeric estrogen receptor degrader, in a phase I study in breast cancer

637P AC699, a novel chimeric estrogen receptor degrader, in a phase I study in breast cancer

Use of differential scanning calorimetry as a rapid, effective in-process check method for impurity quantitation of an early clinical batch of Giredestrant (GDC-9545)

Giredestrant (GDC-9545) is a selective estrogen receptor degrader (SERD) that was developed for treatment of ER+/HER2− metastatic breast cancer. An anhydrous crystalline tartrate salt was identified as the solid form suitable for clinical development. An early clinical batch of the active pharmaceutical ingredient (API)/drug substance failed to pass the GMP purity specifications owing to the presence of a substantial amount of high molecular weight impurities (oligomers), as determined by size exclusion chromatography. Several trial rework batches were manufactured using various re-slurry and recrystallization conditions to purge impurities in the drug substance to adhere to purity specifications. Based on the melting point depression of the API in presence of oligomers in these rework batches, a differential scanning calorimetry method was developed to quantify impurity content as a function of melting point onset of the API. This thermal analysis method was used as a surrogate for chromatography as a rapid, effective in-process check method for impurity quantitation to enable the timely release of the final reworked clinical batch. Post release, the % w/w oligomer value determined by calorimetry was in excellent agreement to that obtained by size exclusion chromatography.

OBHSA, a novel selective estrogen receptor degrader, overcomes tamoxifen resistance through cell cycle arrest and unfolded protein response-mediated apoptosis in breast cancer

Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.

Endocrine therapy for early breast cancer in the era of oral selective estrogen receptor degraders: challenges and future perspectives.

Growth and survival of hormone receptor positive breast cancer cells are dependent on circulating hormones (e.g., estrogen and progesterone). Endocrine therapy improved outcomes in both early and advanced hormone receptor positive breast cancer. These treatments include drugs with different mechanisms of action, namely selective estrogen receptor modulators (SERM), aromatase inhibitors, and selective estrogen receptor degraders (SERDs). SERDs represent estrogen receptor antagonists, favoring its degradation and thus interfering with proliferation genes transcription and activation. Fulvestrant is the first approved SERD, administered intramuscularly for treating advanced breast cancer. Oral SERDs have been tested to overcome the limitation of the intramuscular administration, and to increase SERD bioavailability. Recently, an oral SERD, Elacestrant, has been approved by the Food and Drug Administration (FDA) for patients carrying an ESR1 mutation. In fact, oral SERDs seem to be effective in tumors harboring ESR1 mutations, a well known mechanism of resistance to endocrine therapy (especially aromatase inhibitors). More recently, oral SERDs have been tested in patients with early hormone receptor positive breast cancer, although their impact on survival and in this curative setting compared to standard endocrine therapy still needs to be elucidated. The best timing and duration of SERD administration and specific biomarkers in (neo)adjuvant setting remain largely unknown.

Estrogen Receptor Blockade Potentiates Immunotherapy for Liver Metastases by Altering the Liver Immunosuppressive Microenvironment.

The immune microenvironment of the liver plays a major role in controlling the expansion of hepatic metastases and is regulated by estrogen. We show that treatment of tumor-bearing mice with an estrogen receptor degrader potentiated an anti-metastatic effect of immunotherapy. Our results provide mechanistic insight into clinical findings and a rationale for evaluating the efficacy of combination anti-estrogen and immunotherapy for prevention and/or treatment of hepatic metastases in female patients.

Elacestrant in the treatment landscape of ER-positive, HER2-negative, ESR1-mutated advanced breast cancer: a contemporary narrative review.

Estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer with ESR1 mutations presents a significant therapeutic challenge due to its adaptive resistance mechanisms to chemotherapy, especially endocrine treatment. Elacestrant, a novel oral selective estrogen receptor degrader (SERD), has emerged as a promising agent in this treatment-resistant era. A comprehensive search was conducted on pivotal clinical trials, including the RAD1901-005 Trial, EMERALD TRIAL, ELIPSE, and ELEVATE, focusing on their methodologies, patient populations, treatment regimens, and outcomes. This narrative review describes the available preclinical and clinical evidence on elacestrant, focusing on its pharmacodynamics, pharmacokinetics, efficacy, and safety within the existing literature. Elacestrant has demonstrated excellent activity against ESR1 mutations associated with resistance to first-line endocrine therapies. Clinical trials have shown improved progression-free survival in patients with advanced ER+/HER2-, ESR1-mutated breast cancer. Safety profiles indicate a tolerable side effect spectrum consistent with other agents. Its oral bioavailability offers a convenient alternative to injectable SERDs, with potential implications for patient adherence and quality of life. The review also discusses the comparative efficacy of elacestrant relative to existing endocrine therapies and its possible use in combination regimens. Ongoing clinical trials assessing elacestrant and other SERDs will yield data that might aid clinicians in determining the optimal selection and order of endocrine treatment drugs for ER+ breast cancer. The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in Breast Cancer treatment, moving towards more personalized and effective regimens.

A review of endocrine therapy for hormone-dependent breast cancer

Purpose of the study: to provide current data on pharmacotherapy of hormone-dependent breast cancer (hdBC) and to consider the feasibility of introducing new hormone therapy drugs for breast cancer into clinical practice. Material and Methods. We analyzed 80 publications available Pubmed, Springer, Cochrane Library, etc. concerning the study of pharmacological characteristics of various groups of drugs for the treatment of hdBC, of which 49 were included in this review. Results. Currently, there are several approaches to the treatment of hdBC. Selective estrogen receptor modulators and aromatase inhibitors are the most studied and frequently used drugs. The cyclin-dependent kinase 4/6 inhibitors can be present in both the first- and second-line therapy. Currently, close attention is paid to the development of new drugs based on genomic profiling of the tumor, which is the standard of treatment for hdBC, and contributes to the personalization of therapy. Conclusion. Further development of drugs holds great promise for increasing overall survival and more accurate prognosis, response to conventional systemic therapy, and individualization of pharmacotherapy for hdBC. However, further research and development of new drugs is required. In this regard, the introduction of oral selective estrogen receptor degraders into practice and the development of new drugs that block estrogen-dependent and independent signaling to estrogen receptors are the most promising trends.

Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs-selective estrogen receptor modulators-or SERDs-selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2- BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects.

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [14C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [14C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Degradation of estrogen receptor α induced by ionizing radiation contributes to senescence of ER+ breast cancer cells.

e12544 Background: According to the clinical and pathological characteristics, breast cancer is usually classified into estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive and triple negative. Among them, ER+ breast cancer accounts for more than two-thirds of total breast cancer. Nowadays, both ionizing radiation and endocrine therapy are used for the treatment of ER+ breast cancer. In our previous studies, it was found that significant cellular senescence and reduction of endogenous estradiol (E2) were induced by carbon ion or X-ray exposure in ER+ breast cancer cells. However, the underlying mechanism remains unclear. Methods: Two human ER+ breast cancer cell lines, MCF7 and T47D, were chosen to investigate the senescence-associated indications after 1-10 Gy of X-ray exposure. Since the elevated estrogen receptor α (ERα) is the most significant characteristic of ER+ breast cancer, the levels of ERα were detected by qRT-PCR and West Blotting analysis. In addition, MCF7 tumors were established in BALB/C nude mice and discerned using immunohistochemistry after local exposure of tumors to 2 Gy of X-rays. Results: It was confirmed that the cell survival decreased in a dose-dependent manner after 1-10 Gy of X-ray exposure in both cell lines. Increased p21 protein expression which was considered as a senescence biomarker and enhanced senescence-associated β-galactosidase activity were also observed after X-ray exposure. Meanwhile, distinct cell cycle arrest was induced by 2 Gy of X-rays in T47D cells or by 8 Gy of X-rays in MCF7 cells, implying that T47D cells were prone to enter senescence. Furthermore, both the mRNA levels and protein levels of ERα were significantly decreased at 24 hours in the two cell lines when the exposure dose was up to 4 Gy of X-rays. Reduction of glucocorticoid-regulated kinase 3 (SGK3), a transcriptional target for ERα, was also observed in both cell lines, in according with the reported SGK3-dependent survival mediated by ERα/E2 dimer in ER+ breast cancer cells. In vitro experiments, the results verified the ERα degradation and the proliferating inhibition indicated by suppression of Ki67 protein in MCF7 tumor after 2 Gy exposure. Conclusions: These findings reveal that the degradation of estrogen receptor α induced by ionizing radiation contributes to the senescence of ER+ breast cancer cells and thereby inhibits the tumor growth. The results provide a potential therapeutic strategy to enhance the radiosensitivity of ER+ breast cancer cells through regulations of ERα or ERα-regulated kinase SGK3 in radiotherapy.

TACTIVE-K: Phase 1b/2 study of vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in combination with PF-07220060, a cyclin-dependent kinase (CDK)4 inhibitor, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer.

TPS1131 Background: Vepdegestrant (ARV-471) is an investigational, orally administered PROTAC ER degrader. Initial results from a phase 1b cohort of a first-in-human phase 1/2 study (NCT04072952) showed that vepdegestrant, in combination with the CDK4/6 inhibitor palbociclib, had robust clinical activity (clinical benefit rate [CBR]: 63.0%) in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. PF-07220060 is an investigational CDK4-selective inhibitor, which in contrast to CDK4/6 inhibitors, spares CDK6 blockade and demonstrates less neutropenia in in vivo models. A first-in-human phase 1/2a study (NCT04557449) demonstrated promising antitumor activity with PF-07220060 in pts with advanced solid tumors with a CBR of 52.4%. Preclinical tumor models have shown that vepdegestrant + PF-07220060 effectively suppresses tumor growth to a greater extent than either agent alone. This open-label, multicenter phase 1b/2 study (NCT06206837) will evaluate the combination of vepdegestrant + PF-07220060 in pts ≥18 y with confirmed ER+/HER2- advanced breast cancer. Methods: The phase 1b portion will use an escalation/de-escalation approach to determine the recommended phase 2 dose (RP2D) of the combination of vepdegestrant and PF-07220060. The phase 2 portion will further evaluate the preliminary antitumor activity, safety, and pharmacokinetics (PK) of the combination at the RP2D. Pts (N≈65) will receive vepdegestrant orally once daily continuously and PF-07220060 orally twice daily continuously. The primary endpoint of the phase 1b portion is the number of pts with dose-limiting toxicities; secondary endpoints are antitumor activity (objective response rate [ORR], duration of response [DOR], CBR), progression-free survival (PFS), safety, and PK. The primary endpoint of the phase 2 portion is ORR; secondary endpoints are antitumor activity (DOR, CBR), PFS, safety, plasma concentrations of study drugs, and changes in circulating tumor DNA. Previously presented at ESMO Breast Cancer 2024, FPN: 264TiP, M Telli, et al. Reused with permission. Clinical trial information: NCT06206837 .

Imlunestrant, an oral selective estrogen receptor degrader (SERD), in combination with human epidermal growth factor receptor 2 (HER2) directed therapy, with or without abemaciclib, in estrogen receptor (ER) positive, HER2 positive advanced breast cancer (aBC): EMBER phase 1a/1b study.

1027 Background: Imlunestrant is a next-generation, oral SERD designed to deliver continuous ER-target inhibition. In the first-in-human Phase 1a/b EMBER study (NCT04188548), imlunestrant demonstrated favourable safety, PK, and clinical benefit when administered as monotherapy or with targeted therapy in ER+, HER2- aBC. Here we present clinical data of imlunestrant with HER2 targeted therapy, in patients (pts) with ER+, HER2+ aBC enrolled in EMBER. Methods: Pts were randomized to imlunestrant (400mg po daily) + trastuzumab (H), with or without (±) abemaciclib (Part C) or received maintenance treatment with imlunestrant + H + pertuzumab (P) (Part E), at standard doses in 21-day cycles. Key eligibility (Part C): ≥ 2 prior HER2 directed regimens, no prior CDK4/6i or fulvestrant; (Part E): received 1st line induction taxane chemotherapy (any duration) + H + P, without disease progression and ≤1 prior therapy for aBC. Key endpoints included safety, PK, ORR, CBR and PFS. Results: Overall, 45 pts with ER+/HER2+ aBC received the following combinations: imlunestrant + H (n=18), imlunestrant + H + abemaciclib (n=21; 1 pt received 800 mg imlunestrant), and imlunestrant + H + P (n=6). Baseline characteristics, safety, and preliminary efficacy are presented below (Table). Most TEAEs were grade 1-2. Common TEAEs with imlunestrant + H were fatigue (33%) and nausea (28%); with imlunestrant + H + abemaciclib were diarrhea (100%), neutropenia (57%), fatigue (52%) and nausea (48%); and with imlunestrant + H + P were diarrhea (50%) and arthralgia (50%). Imlunestrant PK was consistent with those previously reported with no drug-drug interactions observed with the combinations. From Part C, sequencing of baseline plasma ctDNA samples (n=37) identified prevalent mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%). Clinical activity of imlunestrant in this ER+/HER2+ population, while based on small numbers, is promising. Conclusions: Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab was well tolerated, showed no drug-drug interactions, and demonstrated preliminary antitumor activity in pts with ER+/HER2+ aBC. Clinical trial information: NCT04188548 . [Table: see text]

Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer.

3074 Background: Endocrine therapy is a critical component of treatment for over 200,000 patients diagnosed yearly with estrogen receptor positive (ER+)/HER2- breast cancer. Although selective ER degraders (SERDs) have improved progression-free survival in this patient population, as monotherapy they have shown very limited overall response rates (ORR). AC699 is a novel chimeric degrader that binds, ubiquitinates and degrades ERα by bringing it into close proximity with an E3 ligase. This mechanism of action may result in greater specificity and more complete target blockade compared to SERDs. Initial results from the ongoing first-in-human dose escalation study of AC699 (NCT05654532) are presented here. Methods: The study employed a 3+3 design, with the option of adding backfill patients to each cohort cleared and deemed safe. Patients must have had locally advanced or metastatic ER+/HER2- breast cancer and received at least 2 prior lines of endocrine treatment, or at least 1 prior line if combined with a CDK4/6 inhibitor. AC699 was administered orally once daily in 28-day cycles. Tumor responses were assessed every 2 cycles using RECIST v1.1 criteria. The relationship between ESR1 mutational status and anti-tumor activity was investigated as an exploratory analysis. Results: A total of 22 patients had received AC699 in 3 dose cohorts (100, 200 and 300 mg) at the time of data cutoff. The median age was 61 years and the median lines of prior therapy was 5 (range 2-10). Prior treatments included CDK4/6 inhibitor (100%), aromatase inhibitor (91%), fulvestrant (82%), novel oral SERD or covalent antagonist (SERCA) (23%), and ER chimeric degrader (14%). Eighteen patients had measurable disease while 4 had bone lesions only. There were no dose-limiting toxicities, dose reductions or discontinuations for treatment-related AEs, and the maximum tolerated dose was not reached. The most common treatment-emergent AEs were fatigue (23%), dehydration (18%) and nausea (18%). All treatment-related AEs were Grade 1 or 2, including nausea (18%) and hot flushes (14%). Fifteen patients had at least 1 scan before the data cutoff date and of these, 3 were not evaluable for ORR due to having bone lesions only. Among the 12 evaluable patients, 4 (33%) achieved partial response: 3 confirmed and one unconfirmed. The clinical benefit rate (CBR) which also includes patients with stable disease ≥24 weeks was 42% (5/12). In the subgroup of evaluable patients harboring a confirmed ESR1 mutation, the ORR was 67% (4/6), the CBR was 83% (5/6) and the median time on treatment was 168 days (range 56-336), with 4 of 7 patients still receiving AC699. Conclusions: Preliminary data from the ongoing phase 1 trial evaluating AC699 indicate promising safety, tolerability, and anti-tumor activity, at doses up to 300 mg orally once daily. A phase 2 study will begin enrolling in early 2024. Clinical trial information: NCT05654532 .