Oral Selective Estrogen Receptor Research Articles

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]

Artificial intelligence (AI) –powered H&E whole-slide image (WSI) analysis to predict recurrence in hormone receptor positive (HR+) early breast cancer (EBC).

571 Background: The recurrence risk (RS) based on transcriptomic profiles or Ki-67 level of HR+ EBC has been used for adjuvant treatment decisions and may also aid selecting patients who could benefit from novel treatments including CDK4/6 inhibitor or oral selective estrogen receptor degraders (SERDs). Artificial intelligence-powered H&E whole slide image (WSI) models can be a practical approach for this biomarker without the need of additional tissue samples. We developed ML-based models of histopathologic features from an H&E WSI to approximate RS of 21-gene assay (OncotypeDx) using various algorithms of different complexities. Methods: The development dataset was composed of 1,009 cases from TCGA-BRCA with gene expression profiles and 483 EBC cases from Samsung Medical Center with RS results. The prediction model was developed in two-stages. First, Lunit SCOPE, an AI-powered H&E WSI analyzer, detects various cell types and segments tissue areas resulting in various cell densities in tissue regions of interest. Next, four traditional ML models were applied on top of the first stage results. In addition, a deep learning model based on multiple instance learning (DL-MIL) was developed using three features: a supervised convolutional neural network, a supervised cell detection model, and an AI-based pathology profiling analyzer, for extracting semantic contents. The model performance was validated using two independent EBC test sets: 248 cases for comparison with the RS results (set 1), and 708 cases with DFS (set 2). Results: The cross-validation performance of the four traditional ML algorithms had area under the curve of receiver operating characteristics curve (AUROC) ranging from 0.728 to 0.779, where mitotic cell density, tumor cell density, and fibroblast density in cancer area were the variables with the highest importance for all four models. The DL-MIL model had cross validation performance of AUROC 0.831. In test set 1, DL-MIL model showed the highest discrimination with AUROC of 0.828 compared to traditional ML models where logistic regression showed the highest discrimination with AUROC of 0.786 (Table). The DL-MIL model showed the highest performance among the models to predict DFS with hazard ratio (HR) of 2.48 (1.47-4.18). Conclusions: Histopathomic models can accurately predict the RS of high risk as well as poor DFS from only H&E WSIs. These AI models can be a practical tool for treatment selection including emerging drugs such as SERDs. [Table: see text]

Abstract PO4-27-07: A Phase 3, randomized, open-label study of upfront camizestrant vs standard endocrine therapy as adjuvant treatment for ER-positive/HER2-negative early breast cancer with intermediate-high or high risk of recurrence (CAMBRIA-2)

Abstract Background: Camizestrant is a next-generation oral selective estrogen receptor (ER) degrader and pure ER antagonist being investigated in early and advanced breast cancer (BC). In postmenopausal women with advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative BC and disease recurrence or progression on or after ≤1 endocrine therapy (ET) in the advanced setting, camizestrant significantly prolonged progression-free survival compared with fulvestrant in the Phase 2 SERENA-2 trial. Camizestrant may also provide benefit in the early BC setting. Following locoregional therapy (surgery ± radiotherapy), standard adjuvant treatment of ET with or without chemotherapy and/or a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has shown significant benefit in decreasing the risk of recurrence of stage I–III ER-positive/HER2-negative BC. However, BC recurrence as incurable metastatic disease is still common. Thus, adjuvant therapeutic options with improved clinical outcomes are needed. The CAMBRIA-2 study (NCT05952557) aims to assess whether upfront camizestrant can improve outcomes compared with standard ET as adjuvant treatment in patients with ER-positive/HER2-negative early BC with an intermediate-high or high risk of recurrence after definitive locoregional therapy. Trial design: This ongoing Phase 3, randomized, open-label study is enrolling women (pre-, peri-, or postmenopausal) and men with ER-positive/HER2-negative (HER2-negative status defined as immunohistochemistry 0, or 1+, or in situ hybridization-negative) early BC who are at intermediate-high or high risk of recurrence (as defined in the protocol) after having completed definitive locoregional therapy (surgery ± radiotherapy) ± (neo)adjuvant systemic chemotherapy, and who have no evidence of disease. Patients may have received up to 12 weeks of (neo)adjuvant ET prior to randomization. Patients are randomized (1:1) to receive camizestrant 75 mg ± abemaciclib ± luteinizing hormone-releasing hormone (LHRH) agonist or standard ET of the investigator’s choice (any aromatase inhibitor or tamoxifen) ± abemaciclib ± LHRH agonist for up to 7 years. The primary endpoint is invasive BC-free survival (IBCFS) (Standardized Definitions for Efficacy End Points [STEEP] 2.0 criteria). Secondary endpoints include invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Primary endpoint analysis will use a stratified log-rank test adjusting for stratification factors, assuming a two-sided significance level of 5%. Approximately 5500 patients will be randomized. Clinical trial identification: NCT05952557 Editorial acknowledgment: Writing assistance was provided by Clare Davis of BOLDSCIENCE Inc., funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca Funding: This study was supported by AstraZeneca. Citation Format: Sibylle Loibl, Yeon Park, Sara Tolaney, Ioanna Gioni, Simon Johnston, Teresa Klinowska, Ingrid A. Mayer, Raquel Nunes, Barbara Pistilli, Mary Stuart, Angela Quintana, Andrew Walding, Michael Gnant. A Phase 3, randomized, open-label study of upfront camizestrant vs standard endocrine therapy as adjuvant treatment for ER-positive/HER2-negative early breast cancer with intermediate-high or high risk of recurrence (CAMBRIA-2) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-07.

Abstract PS15-01: A first-in-human phase 1 study of SIM0270, a brain-penetrant oral selective estrogen receptor degrader (SERD), in patients with ER+/HER2- locally advanced or metastatic breast cancer

Abstract Background: ER+/HER2- breast cancer is the most prevalent subtype, and endocrine-based therapy is the standard treatment. SIM0270 is a brain-penetrant and highly potent oral SERD that has demonstrated ER degradation and robust antitumor activity across various preclinical models, including those with intracranial xenograft tumors. Methods: This Phase 1 study evaluates the safety, pharmacokinetics and preliminary anti-tumor activity of SIM0270 as monotherapy and/or in combination with palbociclib or everolimus in patients with HR+/HER2- advanced or metastatic breast cancer. The primary objective of the phase 1a study, which consisted of the dose escalation stage and the dose expansion stage, is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of SIM0270 as monotherapy. A Bayesian Optimal Interval design (BOIN) was adopted. SIM0270 was administered orally daily in 28-day cycles. Here we report preliminary monotherapy data. Results: As of May 22nd 2023, 45 female patients were enrolled, receiving SIM0270 at dose levels of 10 mg (n=4), 30 mg (n=4), 60 mg (n=9), 90 mg (n=6), 120 mg (n=11), 200 mg (n=5), or 300 mg (n=6). The median age was 56 years (range, 40-73) and ECOG performance status was 0 (18%) or 1 (82%). Most patients were heavily pretreated, with a median of 2 prior endocrine-based therapies (range, 0-5) and a median of 2 prior chemotherapies (range, 0-8). Thirty-one patients (69%) received prior fulvestrant, 42 (93%) received prior aromatase inhibitors, and 28 (62%) received prior CDK4/6 inhibitors. Visceral metastases were present in 33 patients (72%), and brain metastases in 7 patients (16%). The most common TEAEs were sinus bradycardia (51%), anemia (38%), hypalbuminaemia (31%), hypercholesterolaemia (24%), urinary tract infection (24%), asthenia (24%), electrocardiogram (ECG) QT prolonged (24%), and dizziness (22%). Most of the TEAEs were Grade 1-2. Grade 3 TRAEs were ECG QT prolonged, gamma-glutamyltransferase(γ-GT) increased and dizziness in 2 patients each. All AEs were manageable with dose interruption or reduction, except only 1 patient discontinued treatment of SIM0270 due to TRAE (Grade 3 γ-GT increased). Four patients experienced dose-limiting toxicities (DLTs): 1 with Grade 3 ECG QT prolonged at 200mg dose level, 1 with Grade 3 ECG QT prolonged and 2 with Grade 3 dizziness at 300mg dose level. All DLTs were resolved with dose interruption then reduction. The MTD of single-agent SIM0270 was established as 200mg QD. Pharmacokinetic analysis revealed a T1/2 of approximately 70 hours, and the AUC and Cmax increased in an approximately linear manner with dose escalation. Concentration in cerebrospinal fluid was measured in 1 patient after 41 days treatment of SIM0270, which is consistent with preclinical data and suggested high concentration of SIM0270 in the brain of patients. Among 31 response evaluable patients (per RECIST 1.1 criteria), 4 PRs (3 unconfirmed) were observed, yielding an ORR of 12.9%. Brain lesions were all stable in 4 evaluable patients per RANO-BM criteria. In patients with ESR1 mutations at baseline and samples available for analysis, 4/6(67%) exhibited a reduction or loss of mutant ESR1 upon SIM0270 treatment. Conclusions: Single-agent SIM0270 was well tolerated and showed favorable antitumor activity in heavily pretreated advanced or metastatic ER+/HER2- breast cancer patients, including those previously treated with CDK4/6 inhibitors and fulvestrant. Phase 1a dose expansion with single-agent SIM0270 is ongoing, and the RP2D will be determined based on further accumulative data of tolerability and efficacy. (NCT05293964) Citation Format: Jiong Wu, Jian Zhang, Qingyuan Zhang, Yuping Sun, Hongtao Li, Yongmei Yin, Yehui Shi, Wenfeng Li, Yunjiang Liu, Min Yan, Chen Yang, Lili Zhu, Yang Yang, Liting Xue. A first-in-human phase 1 study of SIM0270, a brain-penetrant oral selective estrogen receptor degrader (SERD), in patients with ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-01.

Abstract PS17-01: Key drivers of therapeutic response and resistance to giredestrant from GO39932: a Phase Ia/b study in patients with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer

Abstract BACKGROUND Several investigational oral selective estrogen receptor antagonists and degraders (SERDs) are under investigation. These were partly developed to benefit patients (pts) with breast cancer (BC) who acquired resistance to standard-of-care (SoC) endocrine therapies (ET); e.g., through gain of ESR1 mutations that enable estrogen-independent ER activity. One such SERD, giredestrant (G), demonstrates activity in pts with ESR1-wild type (WT) or -mutant (m) tumors, and in pts who progressed on other ETs. Results from Phase I/III trials in ER-positive, HER2-negative, locally advanced/metastatic BC (ER+, HER2– LA/mBC) showed that next-generation SERDs had increased activity in ESR1m tumors vs SoC ETs. However, enthusiasm was hindered by heterogeneous responses, driven in part by study design differences. Across acelERA BC (NCT04576455), EMERALD (NCT03778931), SERENA-2 (NCT04214288), and AMEERA-3 (NCT04059484), 30–50% of pts progressed rapidly (< 2 months) when treated with SoC ETs or next-generation SERDs, while others benefited for ≥ 1 year. We present an exploratory biomarker analysis aimed at understanding the mechanistic basis for heterogeneous responses to SERDs in ER+, HER2– LA/mBC, by assessing a Phase Ia/b G cohort (NCT03332797) with paired baseline and on-treatment (tx) biopsies. METHODS Pts had ≤ 2 prior therapies for LA/mBC; disease recurrence/progression while on adjuvant ET for ≥ 24 months and/or ET for ER+, HER2– LA/mBC; and tumor response/stable disease for ≥ 6 months. Single-agent dose-escalation stage: 10, 30, 90, or 250 mg G once daily (QD) on Days (D) 1–28 of 28-D cycles (C). Dose-expansion stage: 30, 100, or 250 mg G QD. 100 mg G + 125 mg palbociclib on a 21-D on/7-D off schedule was also explored. Pre-/perimenopausal pts received LHRH agonists. Paired pre- and on-tx (C2D8) tumor biopsies (n = 29) were immunolabeled for ER, progesterone receptor, and Ki67, and assessed via bulk RNA-sequencing. Pre-tx liquid biopsies (n = 85) were evaluated by FoundationOne Liquid CDx assay. To validate our clinical observations, we generated a SERD-resistant MCF7 cell line and tested its sensitivity to other therapies. RESULTS We compared fast-progressing pts (FP; progression-free survival [PFS] < 2 months) with those experiencing long-term benefit (LTB; PFS > 12 months). LTB was significantly associated with high tumor baseline ER pathway activity. Although the benefit of G was of larger magnitude among pts with ESR1m tumors compared with SoC ET in acelERA BC, here pts with predominantly ESR1WT tumors received LTB on G tx. At the molecular level, G acted on LTB tumors by suppressing cell cycle- and ER-associated genes. In contrast, G had no effect on the transcriptome of FP tumors, which had lower baseline ER activity than LTB tumors. FP tumors were instead enriched for multiple cancer-associated pathways, e.g., RAS/MAPK and PI3K, which may drive resistance to G and thus enable fast progression. By liquid biopsy, most FP pts (> 90%) did not harbor a mutation in the associated pathway (e.g., NF1, KRAS), and thus could not be identified by genomic profiling alone. FP tumors were instead enriched for multiple cancer-associated pathways by gene expression. We explored these mechanisms further in the SERD-resistant cell line, which was similarly enriched for EGFR and MAPK activation vs standard MCF7 cells. Although cells became resistant to ER-targeted drugs, they acquired sensitivity to EGFR/MAPK inhibitors e.g., gefitinib, cobimetinib. CONCLUSIONS We identified molecular features associated with LTB to G and revealed a set of oncogenic pathways associated with FP pts on tx; demonstrating that these pathways represent acquired dependencies and potential therapeutic targets for SERD-resistant tumors and FP pts. Citation Format: Jackson Liang, Christy Ong, Jennifer Giltnane, Junko Aimi, Ching-Wei Chang, Mary Gates, Jennifer Eng-Wong, Pablo Perez-Moreno, Komal Jhaveri, Elgene Lim, Nicholas Turner, Heather Moore. Key drivers of therapeutic response and resistance to giredestrant from GO39932: a Phase Ia/b study in patients with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-01.

Abstract RF01-01: SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer

Abstract Background Camizestrant, a next-generation oral selective estrogen receptor (ER) degrader (SERD) and pure ER antagonist, has demonstrated statistically significant and clinically meaningful progression-free survival (PFS) benefit over fulvestrant at both 75 and 150 mg once-daily doses in the Phase 2 SERENA-2 (NCT04214288) study in post-menopausal women with ER+ HER2- advanced breast cancer. SERENA-3 (NCT04588298) was established to explore the biological effects of three camizestrant dose levels in post-menopausal women with ER+ HER2- primary breast cancer. Methods Post-menopausal women with ER+ HER2- primary breast cancer scheduled to undergo curative intent surgery were randomly assigned in Stages 1 and 2 to pre-surgical treatment with camizestrant at 75, 150 or 300 mg once daily for 5 to 7 days or, in a sequential Stage 3, randomly assigned to camizestrant at 75 or 150 mg once daily for 12 to 15 days. Image-guided tumor biopsies were accessed as pre-treatment samples, while on-treatment ultrasound-guided tumor biopsies were obtained on the last day of camizestrant treatment. The primary objective was to explore the effect of camizestrant on ER expression by comparison of pre-treatment and on-treatment biopsies as assessed by immunohistochemistry (IHC) H-score. Secondary objectives included assessment of Ki67 and progesterone receptor (PgR) expression, and also of safety and tolerability, with exploratory pharmacodynamic (PD) assessment using other transcriptomic and proteomic technologies. The study was undertaken in 17 centers across 3 countries (Georgia, Mexico and the United Kingdom). Results 135 patients were randomized and received treatment. 76 patients received camizestrant for 5 to 7 days at doses of 75 mg (n=30), 150 mg (n=33), and 300 mg (n=13); 59 received camizestrant for 12 to 15 days at doses of 75 mg (n=30) and 150 mg (n=29). Baseline disease characteristics, and ER, Ki67 and PgR levels were well balanced across arms and stages. Pharmacokinetic (PK) observations in all stages were commensurate with steady-state predictions derived from previous studies. PD data for ER and Ki67 are shown in Table 1. Camizestrant reduced ER H-score by approximately 65% irrespective of dose or duration. While the 75 mg dose reduced Ki67 score to a lesser degree than 150 mg and 300mg after 5–7 days exposure, after 12–15 days exposure 75 and 150 mg reduced Ki76 score to a similar substantial degree (82% reduction). PD results assessed by additional transcriptomics and proteomics assays were concordant with the IHC analyses. No serious adverse events were reported. All treatment-emergent adverse events were grade 1, apart from one patient with a grade 2 visual impairment, and one patient with grade 3 diarrhea. Conclusions SERENA-3 is the first study investigating the effect of multiple dose levels of camizestrant with different treatment durations on ER, Ki67 and PgR expression in post-menopausal women with primary ER+ HER2˗ breast cancer. SERENA-3 demonstrated that the 75 mg dose of camizestrant achieves maximal levels of ER degradation and Ki67 suppression. Together with SERENA-2, this provides strong evidence supporting 75 mg as the optimal dose of camizestrant, including for the early disease setting, and highlights the additive value of a specifically designed multi-dose pre-surgical PD study for optimal dose selection. Table 1 Citation Format: John Robertson, Teimuraz Gogitidze, Zaza Katashvili, Juan Enrique Bargallo Rocha, Ekaterine Arkania, Iain Moppett, Kwok-Leung Cheung, Gia Nemsadze, Maxine Ajimi, Itziar Irurzun-Arana, Justin Lindemann, Teresa Klinowska, Alastair Mathewson, Christopher Morrow, Myria Nikolaou, Giorgi Dzagnidze. SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-01.

Abstract PO3-19-09: SERENA-1: Results from a Phase 1 study (Parts I/J) testing the next-generation oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833) in combination with capivasertib in women with ER+, HER2 advanced breast cancer

Abstract Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+/HER2− advanced breast cancer. Data for camizestrant as monotherapy and in combination with palbociclib or abemaciclib have been presented previously.1–3 Here we present data from parts I and J (dose ranging and expansion, respectively), which examined camizestrant in combination with the pan-AKT inhibitor capivasertib. Methods: The primary objective was to determine the safety and tolerability of camizestrant 75 mg once daily (QD) in combination with capivasertib 400 mg twice daily (BID; intermittent: 4 days on, 3 days off). Secondary objectives included investigation of anti-tumor response and pharmacokinetics (PK). Participants were women of any menopausal status (pre-menopausal women received concomitant ovarian function suppression). Prior treatment with an endocrine therapy (ET) in the advanced setting was required with no limit on the number of lines of prior ET. Prior treatment with ≤2 lines of chemotherapy in the advanced setting was permitted. Prior treatment with CDK4/6 inhibitors (CDK4/6i) and/or fulvestrant was also permitted. Results: As of 21 March 2023, 29 patients had received camizestrant in combination with capivasertib. Patients were heavily pretreated in the advanced setting (48% prior chemotherapy, 90% prior CDK4/6i, 55% prior fulvestrant) and 72% had visceral metastases. The safety and tolerability profile of the combination of camizestrant and capivasertib was broadly consistent with that of each drug individually.4,5 In the 29 patients, adverse events considered related to camizestrant and/or capivasertib in >15% of patients (%; n grade 1/n Grade 2/n Grade >3) included diarrhea (66%; 14/2/3), visual effects (62%; all Grade 1), bradycardia (34%; all Grade 1), nausea (34%; 6/4/0), fatigue (21%; 4/2/0) maculopapular rash (17%; 0/3/2) and aspartate aminotransferase increased (17%; 3/0/2). The PK and safety data indicated no clinically relevant drug–drug interactions between camizestrant and capivasertib. The objective response rate was 29.6% (8/27), the clinical benefit rate at 24 weeks was 51.7% (15/29), and median progression–free survival was 8.3 months. Overall, 12 patients had a detectable ESR1 mutation (ESR1m) at baseline (Cycle 1, Day 1) and an evaluable Cycle 2, Day 1 (C2D1) result; of these, ESR1m was reduced by >50% at C2D1 in 91.7% of patients (11/12), including 66.7% (8/12) of patients where ESR1m was cleared. Conclusions: Camizestrant 75 mg QD in combination with capivasertib 400 mg BID was well tolerated and associated with encouraging clinical and pharmacodynamic activity. These data support further evaluation of this combination in women with ER+/HER2− advanced breast cancer.

The value of oral selective estrogen receptor degraders in patients with HR-positive, HER2-negative advanced breast cancer after progression on ≥ 1 line of endocrine therapy: systematic review and meta-analysis

BackgroundCurrently, the value of oral selective estrogen receptor degraders (SERDs) for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on ≥ 1 line of endocrine therapy (ET) remains controversial. We conducted a meta-analysis to evaluate progression-free survival (PFS) and safety benefits in several clinical trials.Materials and methodsCochrane Library, Embase, PubMed, and conference proceedings (SABCS, ASCO, ESMO, and ESMO Breast) were searched systematically and comprehensively. Random effects models or fixed effects models were used to assess pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for treatment with oral SERDs versus standard of care.ResultsA total of four studies involving 1,290 patients were included in our analysis. The hazard ratio (HR) of PFS showed that the oral SERD regimen was better than standard of care in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET (HR: 0.75, 95% CI: 0.62-0.91, p = 0.004). In patients with ESR1 mutations, the oral SERD regimen provided better PFS than standard of care (HR: 0.58, 95% CI: 0.47-0.71, p < 0.00001). Regarding patients with disease progression following previous use of CDK4/6 inhibitors, PFS benefit was observed in oral SERD-treatment arms compared to standard of care (HR: 0.75, 95% CI: 0.64-0.87, p = 0.0002).ConclusionsThe oral SERD regimen provides a significant PFS benefit compared to standard-of-care ET in patients with HR+/HER2- aBC after progression on ≥ 1 line of ET. In particular, we recommend oral SERDs as a preferred choice for those patients with ESR1m, and it could be a potential replacement for fulvestrant. The oral SERD regimen is also beneficial after progression on CDK4/6 inhibitors combined with endocrine therapy.

Elacestrant for ER-Positive HER2-Negative Advanced Breast Cancer.

This article aims to discuss elacestrant, an oral selective estrogen receptor downregulator approved by the Food and Drug Administration (FDA) in January 2023 for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. PubMed, Embase, Medline, Clinicaltrials.gov, and the National Comprehensive Cancer Network (NCCN) were searched from inception to August 31, 2023. Clinical trials published in English were included and relevant information regarding methodology and results were extracted. Phase 1 and 3 trials showed elacestrant was safe and improved progression-free survival in patients with endocrine receptor 1 (ESR1) mutations who failed cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus 1 prior endocrine therapy compared with standard of care (SOC) (fulvestrant, anastrozole, letrozole, or exemestane monotherapy). Elacestrant maintains a comparable adverse event profile with other endocrine therapies and offers an alternative to typical sequential therapy which can delay the use of or be used after traditional chemotherapy. Elacestrant is currently being studied in CDK 4/6 inhibitor naïve patients and as a component of combination therapy for first-line use which could lead to future indications. Elacestrant gained FDA approval in January 2023 and can be considered in patients with HR+ HER2- advanced breast cancer and ESR1 mutations who have progressed despite therapy with either CDK 4/6i plus aromatase inhibitors (AI) or fulvestrant or chemotherapy.

399P Results from a first-in-human phase Ia/b study of LX-039, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal patients with ER+, HER2- advanced breast cancer (ABC)

399P Results from a first-in-human phase Ia/b study of LX-039, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal patients with ER+, HER2- advanced breast cancer (ABC)

481P Second generation oral selective estrogen receptor degraders (SERDs) in breast cancer: A systematic review and meta-analysis of clinical trials

481P Second generation oral selective estrogen receptor degraders (SERDs) in breast cancer: A systematic review and meta-analysis of clinical trials

The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance.

Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

An imidazopyridine that selectively degrades ERαand is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis.

Modeling the novel SERD elacestrant in cultured fulvestrant-refractory HR-positive breast circulating tumor cells

PurposeMetastatic hormone receptor-positive (HR+) breast cancer initially responds to serial courses of endocrine therapy, but ultimately becomes refractory. Elacestrant, a new generation FDA-approved oral selective estrogen receptor degrader (SERD) and antagonist, has demonstrated efficacy in a subset of women with advanced HR+breast cancer, but there are few patient-derived models to characterize its effect in advanced cancers with diverse treatment histories and acquired mutations.MethodsWe analyzed clinical outcomes with elacestrant, compared with endocrine therapy, among women who had previously been treated with a fulvestrant-containing regimen from the recent phase 3 EMERALD Study. We further modeled sensitivity to elacestrant, compared with the currently approved SERD, fulvestrant in patient-derived xenograft (PDX) models and cultured circulating tumor cells (CTCs).ResultsAnalysis of the subset of breast cancer patients enrolled in the EMERALD study who had previously received a fulvestrant-containing regimen indicates that they had better progression-free survival with elacestrant than with standard-of-care endocrine therapy, a finding that was independent estrogen receptor (ESR1) gene mutations. We modeled elacestrant responsiveness using patient-derived xenograft (PDX) models and in ex vivo cultured CTCs derived from patients with HR+breast cancer extensively treated with multiple endocrine therapies, including fulvestrant. Both CTCs and PDX models are refractory to fulvestrant but sensitive to elacestrant, independent of mutations in ESR1 and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) genes.ConclusionElacestrant retains efficacy in breast cancer cells that have acquired resistance to currently available ER targeting therapies. Elacestrant may be an option for patients with HR+/HER2- breast cancer whose disease progressed on fulvestrant in the metastatic setting.Translational Relevance.Serial endocrine therapy is the mainstay of management for metastatic HR+breast cancer, but acquisition of drug resistance highlights the need for better therapies. Elacestrant is a recently FDA-approved novel oral selective estrogen receptor degrader (SERD), with demonstrated efficacy in the EMERALD phase 3 clinical trial of refractory HR+breast cancer. Subgroup analysis of the EMERALD clinical trial identifies clinical benefit with elacestrant in patients who had received prior fulvestrant independent of the mutational status of the ESR1 gene, supporting its potential utility in treating refractory HR+breast cancer. Here, we use pre-clinical models, including ex vivo cultures of circulating tumor cells and patient-derived xenografts, to demonstrate the efficacy of elacestrant in breast cancer cells with acquired resistance to fulvestrant.

A phase 1b/2 dose escalation and expansion study of OP-1250 in combination with ribociclib or alpelisib in patients with advanced and/or metastatic estrogen receptor–positive (ER+)/HER2-negative (HER2-) breast cancer.

TPS1127 Background: Therapies targeting the estrogen receptor (ER) are standard of care in the management of ER+/HER2- metastatic breast cancer (MBC) and when administered concurrently with cyclin-dependent kinase (CDK) inhibitors are the most effective first-line therapy. CDK 4/6 inhibitors plus endocrine therapy improve progression-free survival and, for some agents, overall survival for patients with MBC. However, most patients will acquire resistance, highlighting an unmet need for more effective endocrine options in ER+ disease. OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity. OP-1250 potently inactivates both wild-type and mutant forms of ER, the latter of which confers ligand independent activity as a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with CDK4/6 inhibitors demonstrated synergistic activity in models of both wild-type ER and those with ESR1 (the gene that encodes ER) activating mutations, and in brain metastasis. OP-1250 is orally bioavailable with a favorable pharmacokinetic (PK) profile supportive of once-daily dosing, and a low probability of drug:drug interactions, making it an attractive agent for patients with ER+/HER2- MBC. Methods: The study (NCT05508906) is an open-label, multicenter, 2-part study of OP-1250 in combination with either the CDK4/6 inhibitor ribociclib or the PI3K inhibitor alpelisib for patients with MBC. Eligibility includes adults with evaluable (measurable or non-measurable) ER+/HER2- recurrent, locally advanced or MBC confirmed by histology/cytology, ≤2 prior hormonal regimens (prior CDK4/6 inhibitors allowed) and ≤ 1 prior line of chemotherapy. Patients in the alpelisib arm must have a PIK3CA mutation. A total of 30 patients will be enrolled in each arm. The dose escalation cohorts will evaluate the safety and PK of varied OP-1250 doses (30mg, 60mg, or 120mg) administered orally (PO) every day (QD) in combination with approved dosages of either ribociclib 600 mg PO QD or alpelisib 300 mg PO QD to identify the recommended phase 2 doses (RP2D). The dose expansion cohorts will assess additional safety and PK parameters and further explore the anti-tumor activity of OP-1250 in combination with ribociclib or alpelisib. Tolerability, safety and PK of OP-1250 in combination with ribociclib or alpelisib constitute the primary endpoints. Overall response rate, clinical benefit rate and duration of response are key secondary endpoints. Enrollment at approximately 20 sites in the United States and Australia is ongoing. Clinical trial information: NCT05508906 .

Update Breast Cancer 2023 Part 2 – Advanced-Stage Breast Cancer

AbstractIn recent years, a number of new therapies have led to advances in the treatment of patients with advanced breast carcinoma. These substances are mainly CDK4/6 inhibitors and other substances that can overcome endocrine resistance, oral selective estrogen receptor degraders, antibody drug conjugates (ADCs), and PARP inhibitors. This review summarizes and evaluates the latest study results that have been published in recent months. This includes the overall survival data of the Destiny-Breast03 study, the first analysis of the CAPItello-291 study, the comparison of CDK4/6 inhibitor treatment with chemotherapy in the first line of therapy (RIGHT Choice study), the first analysis of the Destiny-Breast02 study in the treatment setting after T-DM1 treatment, and the first analysis of the Serena-2 study.Most of these studies have the potential to significantly change the therapeutic landscape for patients with advanced breast carcinoma and show that the continued rapid development of new therapies is always producing new results.

Efficacy of oral selective estrogen receptor degraders (SERD)s in the treatment of estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC): A stratified analysis of the ESR1 wild type (wt) and mutant (mt) subgroups.

1096 Background: Oral SERDs are a novel drug class developed to counteract endocrine resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, and the FDA has most recently limited approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. Questions remain on whether patients with ESR1wt tumours stand to benefit from SERDs. We conducted an IPD meta-analysis of the trials EMERALD, SERENA2, ACELERA and AMEERA3 to compare survival outcomes of SERDs in the 2nd or 3rd line setting against endocrine therapy (ET), using KMSubtraction to unveil HRs of unreported ESR1wt subgroups from AMEERA3 and EMERALD. Meta-analysis results were stratified by ESR1 status. Methods: RCTs investigating the efficacy of novel SERDs versus ET for ER+, HER2- MBC, and which reported the Kaplan Meier (KM) plots of progression free survival (PFS) were selected after a systematic search of Embase and PubMed from inception until January 21,2023. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM plots in all overall and reported subgroup cohorts, deriving IPD. A bipartite matching algorithm, KMSubtraction was used to subtract patients in the reported subgroup from the overall cohort, to derive survival data for unreported ESR1wt subgroups. An IPD meta-analysis was then performed, pooling data by ESR1 mutation. Results: A total of 1216 patients were included in this analysis. In the pooled analysis of the overall cohort, PFS benefit was observed with SERDs compared to treatment of physician's choice (TPC) (HR 0.787, 95%CI 0.683-0.908, p&lt;0.001). In the ESR1mt subgroup SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p&lt;0.001) compared with TPC. In the ESR1wt subgroup, SERDs demonstrated no significant PFS benefit (HR 0.948, 95%CI 0.790-1.137, p=0.565) when compared to TPC. KMSubtraction was implemented on AMEERA3 to reveal survival data in ESR1wt subgroup. Amcenestrant revealed no significant PFS difference in the ESR1wt population (HR 1.197, 95% CI 0.857-1.670, p=0.291) when compared to ET. Additionally, a separate analysis of EMERALD was performed using KMSubtraction to derive survival data of the ESR1wt subgroup comparing Elacestrant vs Fulvestrant. No significant PFS difference was observed between the 2 agents in the ESR1wt population (HR 0.832, 95% CI 0.587-1.178, p=0.299). Conclusions: Our results suggest that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup. These findings are in line with the recent FDA approval of Elacestrant for patients with ESR1mt tumours. [Table: see text]

Clinical activity of camizestrant, a next-generation SERD, versus fulvestrant in patients with a detectable ESR1 mutation: Exploratory analysis of the SERENA-2 phase 2 trial.

1066 Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer with disease recurrence or progression after ≤1 endocrine therapy in the advanced setting in the Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant and clinically meaningful benefit vs F in progression-free survival (PFS) in the overall study population (Oliveira M et al. SABCS 2022 Annual Meeting. Abstract GS3-02.). Methods: Baseline circulating tumour DNA was collected at screening and/or Cycle 1 Day 1 and analysed by next-generation sequencing. A post hoc exploratory analysis compared investigator assessed PFS with camizestrant (data from 75 and 150 mg combined) vs F in patients with detectable baseline ESR1 (the gene that encodes ERα) hotspot mutations ( ESR1m). Patients were divided into subgroups based on whether 1 or &gt;1 ESR1m variants were detected, the specific ESR1m, and whether mutations were detected in BRCA1/2 or the MAPK pathway. The most prevalent mutations are presented. A Cox proportional hazards model was used to compare PFS. Results: 48/147 (32.7%) patients treated with camizestrant and 35/73 (47.9%) treated with F had a detectable ESR1m in at least 1 baseline sample. ESR1m were detected in 6/9 (67%) patients with a BRCA1/2 mutation and 5/26 (19%) with a MAPK pathway alteration; however, the numbers were too small to analyse efficacy in these subgroups. Conclusions: Camizestrant showed improved outcome vs F in patients with a detectable ESR1m at baseline and in the subgroups tested. The greatest median PFS improvement was seen in patients where a single ESR1m variant was detected, suggesting that early intervention upon detection of an ESR1m may provide the maximum patient benefit for camizestrant, a hypothesis that is being tested in the SERENA-6 clinical trial (NCT04964934). Clinical trial information: NCT04214288 . [Table: see text]

Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans.

GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases

In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs' inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs.