P3, N=510, Active, not recruiting, Olema Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Baseline ESR1 mutations in EV-DNA were associated with shorter progression-free survival (PFS) across the cohort, with the Y537S mutation showing a particularly strong impact on the outcome of fulvestrant-treated patients. In contrast, PIK3CA mutations in EV-DNA did not significantly correlate with PFS, whereas in ctDNA, they were linked to poor outcomes. Altogether, this study positions EV-DNA as a valuable biomarker alongside ctDNA, enriching the understanding of different analytes in liquid biopsy and supporting strategies for HR+/HER2-mBC in precision oncology.

P3, N=812, Recruiting, Hoffmann-La Roche | Trial completion date: Sep 2032 --> Dec 2030 | Trial primary completion date: Aug 2026 --> Mar 2027

Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

P3, N=240, Recruiting, MedSIR | Not yet recruiting --> Recruiting | Initiation date: Sep 2024 --> Dec 2024

While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations...Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.

P1/2, N=136, Terminated, Sanofi | Trial completion date: Dec 2027 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2027 --> Nov 2024; Sponsor decision to prematurely stop the study, not linked to any safety concern.

P3, N=460, Recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd. | Initiation date: Feb 2025 --> Nov 2024

These results suggest that the suppression of FOXO3a and ERα led to the increased expression of TGF-α, EGFR, and HER2 and subsequent cell proliferation in Ful-R. This study highlights the potential development of therapeutic drugs targeting FOXO3a for the treatment of HER2-positive, estrogen, and progesterone receptor-negative her2-type proliferative breast cancers.

Further, IGFBP-3 expression was increased by treatment with the GPER1 agonist G-1 and attenuated upon treatment with P17, a YAP/TAZ inhibitor. These data suggest that IGFBP-3 modulates breast cancer cells and is a mediator of breast cancer cell response to fulvestrant and tamoxifen.

P1, N=16, Completed, Jiangsu Simcere Pharmaceutical Co., Ltd. | Recruiting --> Completed | N=32 --> 16

Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. 51 exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates 51 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.

P1, N=214, Active, not recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting

P3, N=460, Recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment...First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.

P1, N=6, Active, not recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting | N=10 --> 6

P1/2, N=350, Recruiting, Shandong Suncadia Medicine Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=18, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Not yet recruiting --> Recruiting

No abstract available

P1, N=16, Completed, Stemline Therapeutics, Inc. | Recruiting --> Completed

We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.

Dose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with significantly higher mortality and shorter treatment duration. These findings contrast with previous analyses showing no effect of dose reduction, likely due to considering immortal time bias in this study.

P1, N=18, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

P3, N=460, Not yet recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd.

Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer.

Plasma samples were collected after first-line aromatase inhibitor (AI) therapy and before initiating second-line treatment with Fulvestrant... The PredicineCARE Ultra ctDNA NGS assay showcased a superior ability to detect low tumor fractions and low-frequency mutations in HR-positive, HER2-negative breast cancer patients, significantly outperforming standard liquid biopsy assays. This enhanced sensitivity offers substantial benefits for early identification of treatment resistance and disease progression, potentially allowing for more timely and tailored therapeutic interventions.

Median PFS after detection of ESR1 mutation was 3.2 months (range 1.9 –30.7), with all patients receiving HER2-directed therapy and four patients receiving Fulvestrant... Patients who develop ESR1 mutations in the setting of HER2+ mBC most often had point mutations in L536, E380 and D538, and had high rates of co-mutation with PIK3CA, which may have prognostic implications. To date, clinical trials regarding ESR1 mutations in breast cancer have excluded patients with HER2+ disease. These patients should be included in future studies of ESR1-targeted therapies.

Among those treated with endocrine therapies, 36 were treated with AI combined with Fulvestrant... The sensitive ctDNA NGS assay effectively identified gene variations and tumor fraction levels as prognostic markers in advanced HR-positive breast cancer, demonstrating significant implications for personalized treatment.

None of the patients received ESR1-targeted therapy with Elacestrant. Our findings indicate that the level changes of ctDNA ESR1 mutations have implications with regards to treatment sensitivity and resistance to various therapies in patients with HR+/HER2- mBC. These results suggest a potentially effective method for monitoring treatment response and guiding future therapy by providing new insights into targeting ESR1 pathways to overcome resistance.

Samuraciclib (CT7001), a once-daily oral CDK7 inhibitor, combined with the SERD fulvestrant had a favorable safety profile and clinical activity in patients with HR+/HER2− advanced breast cancer (BC) previously treated with a CDK4/6i [Coombes, 2023]. The most frequent treatment-related AEs were similar to the known safety profiles from both previous samuraciclib and elacestrant studies. With no drug-drug interactions between the treatments, further study of combination treatment in expansion C4 is supported. Preliminary signs of antitumor activity were observed.

Elacestrant demonstrated a significant improvement in mPFS vs SOC in patients with both high and low ESR1 VAF. The clinical benefit and activity of elacestrant vs SOC was maintained regardless of type of ESR1 mutation variant and the abundance/quantity of ESR1 mutations in patients with ER+/HER2- mBC. In all patients with ER+/HER2, ESR1-mut mBC, elacestrant may replace fulvestrant-based combinations, and delay chemotherapy or ADC-based regimens.

Pharmacologic targeting of estrogen signaling (either by HSD17B7 inhibition or with fulvestrant) and chemokine inflammation both decrease local E2 and prevent macrophage polarization. Overall, these findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth and offer potential therapeutic insight to treat these patients. We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity.

Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer.

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.

P1, N=25, Not yet recruiting, University of Chicago

P3, N=4220, Recruiting, Stemline Therapeutics, Inc. | Not yet recruiting --> Recruiting

Imlunestrant, as monotherapy and combined with abemaciclib, has a manageable safety profile with preliminary evidence of antitumor activity in patients with ER+ EEC.

P2, N=30, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=10, Recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd.

Estrogen receptor one (ESR1) gene mutations, driving resistance to aromatase inhibitors (AIs), may guide the use of fulvestrant or emerging oral selective estrogen receptor degraders (SERDs) like elacestrant. Targeting mutations like breast cancer gene 1 and 2 (BRCA 1/2) with Poly (ADP-ribose) polymerase (PARP) inhibitors or the PI3K/AKT/mTOR pathway provides therapeutic options. The advent of antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) and novel agents targeting Trophoblast cell surface antigen-2 (Trop-2) introduces further complexity, underscoring the need for early intervention targeting specific genomic alterations in metastatic BC.

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. 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.

HIF-1α induced ERβ gene transcription and protein expression in hypoxic cells via binding to HRE in the ESR2 promoter. The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the NSCLC tumor growth.