Second-Line Strategies to Overcome Resistance to Oestrogen Therapy in Patients with ER+/HER2- Metastatic Breast Cancer: A Year in Review

Background: Adjuvant endocrine therapy (ET) is the standard of care (SOC) for the treatment of estrogen receptor-positive (ER+) human epidermal growth factor receptor-2 negative (HER2-) early-stage breast cancer. Despite optimized adjuvant treatments for patients with high risk of recurrence, patients continue to experience local and distant relapses, and new therapies are warranted. In the phase 3 EMERALD trial, single-agent elacestrant was evaluated vs SOC ET in ER+/HER2− metastatic breast cancer. Elacestrant significantly prolonged progression-free survival (PFS) vs SOC ET in the overall population (HR = 0.70; 95% CI, 0.55-0.88; P = 0.0018) and in patients with ESR1-mut tumors (HR = 0.55; 95% CI, 0.39-0.77; P = 0.0005) (Bidard, JCO 2022). In those pts with ≥12 months of prior ET+ CDK4/6 inhibitor (CDK4/6i) and ESR1-mut tumors, median PFS with elacestrant was 8.6 vs 1.9 months with SOC ET (Bardia, SABCS 2022). In patients with tumors without detectable ESR1-mut, a numerical difference was observed (HR = 0.86; 95% CI: 0.63-1.19). As elacestrant significantly prolonged PFS in the metastatic setting relative to endocrine monotherapy, with more pronounced activity in patients with endocrine-sensitive tumors, it is hypothesized that elacestrant should prolong invasive breast cancer-free survival (IBCFS) in the earlier adjuvant setting among patients who received prior adjuvant ET with or without a CDK4/6i. In addition, elacestrant can antagonize the estrogen receptor in tumor cells with a non-degradative antagonist function. Unlike other oral SERDs in development, elacestrant exhibits both degradative and partial agonist properties (Wardell, ERC 2015). Elacestrant could offer a new class of medication in the adjuvant setting and merits further therapeutic evaluation for patients with ER+/HER2- breast cancer with a high risk of recurrence. Methods: ELEGANT (NCT06492616) is a global, multicenter, randomized, open-label phase 3 study designed to evaluate elacestrant compared with SOC ET (aromatase inhibitor or tamoxifen) in patients with early breast cancer and a high risk of recurrence. A total of 4,220 patients will be randomized 1:1 to continue SOC ET or switch to elacestrant therapy for a duration of 5 years. Eligible patients are women or men with ER+/HER2− node-positive breast cancer who have completed 24 months (but not more than 60 months) of adjuvant ET and have ECOG PS ≤1. Patients who received a prior CDK4/6i or a poly ADP-ribose polymerase (PARP) inhibitor must have already completed or discontinued these treatments. Exclusion criteria include inflammatory breast cancer, any history of prior invasive breast cancer, and >6 months continuous interruption of prior SOC adjuvant ET or discontinuation of adjuvant ET >6 months prior to randomization. The primary endpoint is IBCFS. Key secondary endpoints include distant relapse-free survival (DRFS) and overall survival (OS). Additional secondary endpoints include invasive disease-free survival (IDFS), safety, and patient-reported outcomes. Exploratory endpoints include PK and biomarker analyses. Time-to-event endpoints will be reported using Kaplan-Meier estimates. Baseline demographics and other characteristics will be descriptively summarized. Citation Format: Aditya Bardia, Virginia Kaklamani, Joyce O’Shaughnessy, Peter Schmid, J. Thaddeus Beck, Michelino De Laurentiis, Giuseppe Curigliano, Hope S. Rugo, Debu Tripathy, William J. Gradishar, Michail Ignatiadis, David A. Cameron, Giulia Tonini, Simona Scartoni, Jennifer Crozier, Leo Viana Nicacio, Tomer Wasserman, Sara M. Tolaney. ELEGANT: Elacestrant versus standard endocrine therapy in women & men with node-positive, estrogen receptor-positive, HER2-negative, early breast cancer with high risk of recurrence in a global, multicenter, randomized, open-label phase 3 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-21.

Activating ESR1 mutations have recently been reported as a key mechanism leading to Aromatase Inhibitor (AI) resistance. ESR1 mutations occur rarely in primary breast cancers. However, in large retrospective studies, ESR1 mutations occurred in up to 39% of Estrogen-Receptor(ER)-positive metastatic breast cancer resistant to AI. Numerous hotspot mutations have been identified, most of them affecting the ligand-binding domain (LBD) and leading to ligand-independent activation of the ER and to resistance to AI. Phosphatidylinositol 3-kinase (PI3K)/AKT pathway is involved in key Cellular Mechanisms and mutations in PIK3CA and AKT1 are frequently reported in breast cancer. In this study, we propose to use a capture-based Next Generation Sequencing (NGS) assay and to use the barcoding and polishing features in our analysis pipeline. This assay will be able to detect all mutations on AKT1, PIK3CA, ESR1 and other genes on circulating tumor DNA (ctDNA) extracted from blood samples of patients with breast cancer. We consider that this exon-screening strategy is relevant according to the recent knowledge. We plan to prospectively include women with advanced breast cancer about to begin standard-of-care first line endocrine therapy (ET). Patients will be required to have histologically confirmed ER-positive, HER2-negative breast cancer and documented loco-regionally advanced or metastatic disease, not amenable to surgery or radiation with curative intent. Patients with endocrine sensitive disease (no prior ET or relapse more than 12 months after completing adjuvant ET) as well as patients with endocrine resistant disease (relapse while on adjuvant ET or within 12 months of completing adjuvant ET) will be enrolled. ET can be prescribed alone or in combination with a targeted therapy. Nevertheless, we will recruit at least 25% of patients with exclusive ET in the endocrine sensitive group. Peripheral-blood samples, for analysis of ctDNA, will be obtained from participating patients at pre-specified time points: at start of ET to determine the baseline mutational status of ESR1, PIK3CA, AKT1 and other genes included in a panel of genes of interest in solid tumors, and then, at evaluation of response to therapy until disease progression or end of study. Patients will be followed for 36 months or until disease progression. Determination of progression will be done per local investigator. The primary objective is to describe the prevalence of activating ESR1 mutations affecting the LBD, using NGS, from the start of ET to progression or end of study. Secondary objectives include to describe the prevalence of ESR1 mutations affecting other domains, the prevalence of ESR1 mutations in patients with and without endocrine resistance at enrolment and the prevalence of PIK3CA and AKT1 mutations, to demonstrate that ESR1, PIK3CA and AKT1 mutations whatever their times of onset are predictors of progression free survival. As of June 2018, 8 sites were opened to recruitment and 18 pts were included; the target enrollment is 146. The trial is supported by AstraZeneca. Citation Format: Massard V, Uwer L, Salleron J, Deblock M, Kieffer A, Rios M, Gilson P, Lesur A, Harle A, Merlin JL. CICLADES: Monitoring of ESR1, PIK3CA and AKT1 ctDNA mutations during real-life follow-up of patients with advanced breast cancer treated with endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-03-02.

Background: With more hormonal therapies (HT) based treatment (tx) available, predictive markers that could lead to a selection of the optimal tx is necessary. The predictive role of ctDNA mutations in ER+/HER2- MBC after prior HT is less well characterized in Asian patients (pts). Methods: ER+/HER2- MBC pts starting HT based salvage tx after refractory to at least one-line of HT were eligible. ctDNA was extracted from pre- and post-tx plasma and prepared for next-generation sequencing (NGS) analysis. The targeted NGS mutations included regions of ESR1 ligand-binding domain, PIK3CA mutation hotspots, and TP53 mutation hotspots. 96% of the samples were sequenced at an average depths >10000x using the Ion Torrent platform. Progression-free survival (PFS) was defined from the start of the salvage tx to the date of progression. Results: From 2015/08 to 2019/04, a total of 129 and 70 pts treated with HT based tx had pre- and post-tx ctDNA tested, respectively. The median age is 60 (32-92). 14%, 7%, 55%, and 19% of pts received HT only, HT + CDK4/6 inhibitor, HT + everolimus, and HT + metronomic chemotherapy, respectively. With mutation ctDNA > 0.5% as a threshold for positive calling, 79 (61.2%), 33 (25.6%), and 23 (17.8%) pts have at least one ESR1, PIK3CA, and TP53 mutation, respectively and 48 (37.3%) pts have >1 ESR1 mutation genotypes. When compared to other clinical trial data, Asian ER+ MBC pts had significantly higher ESR1 mutation rate as compared to the Western population (p < 0.001) (Table 1). Detectable PIK3CA and TP53 mutation pre-tx was significantly (median PFS 9.8 vs 4.8 months (mos), p= 0.002) and marginally (median PFS 7.9 vs 5.2 mos, p = 0.08) associated with shorter PFS, respectively; but neither the presence of at least one single or multiple clones of ESR1 mutation(s) was associated with PFS (p = 0.52). Conversely, pts without any detectable ctDNA mutation had marginally better PFS (median 12.0 vs 6.5 mos, p = 0.051). With respect to the impact of each ESR1 mutation genotype, the presence of E380Q is associated with significantly shorter PFS (median PFS 7.9 vs 3.4 mos, p = 0.033) while Y537S, D538G, and Y537C were not. When the threshold for the positive calling of ctDNA was raised to 2.5%, ESR1 Y537S mutation became a significant factor for shorter PFS (median PFS 9.1 vs 4.4 mos, p = 0.041); PIK3CA remained as a significant factor for shorter PFS (median 9.3 vs 4.4 mos, p <0.001). In the HT + everolimus cohort (n = 71), PIK3CA mutation ctDNA remained as a poor PFS factor (median PFS 5.9 vs 2.6 mos, p = 0.01) but neither TP53 or ESR1 mutations were significantly associated with PFS. When pre- and post-treatment ctDNA were included in the analysis, the emergence of ESR1 mutations was associated with a better PFS (p = 0.05) while the loss of ESR1 mutations or gain/loss of PIK3CA mutations are not associated with PFS in the HT-treated cohort. Conclusion: PIK3CA and ESR1 Y537S and E380Q mutations detected by ctDNA had predictive impact for late-line HT based tx but PIK3CA mutation is a better predictor marker than ESR1 mutation in pts treated with HT + everolimus. Table 1 A comparison of the proportion and distribution of ESR1 mutation genotypes among the Taiwan cohort and other clinical trial studiesStudiesESR1 mutation (%)% of ESR1-positive patients withY537SD538GY537CPALOMA3 (n = 360) Fribbens et al. 201691(25.3)25565SoFEA (n = 161) Fribbens et al. 201663(39.1)25465FERGI (n = 156) Spoerke et al. 201657(37.3)33545Taiwan cohort (n = 129)79(61.2)538153 Citation Format: Tom Wei-Wu Chen, Ming-Shen Dai, Dwang-Ying Chang, Ching-Hung Lin, I-Chun Chen, Ming-Yang Wang, Ling-Yi Huang, An Hsu, De-Wei Zhuo, Kien Thiam Tan, Yen-Jung Lu, Shu-Han Chang, Ann-Lii Cheng, Yen-Shen Lu. PIK3CA and ESR1 mutations detected in circulating tumor DNA (ctDNA) are predictive factors for late-line hormone-based therapies in ER+/HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-21.

Background: The EMERALD trial (NCT03778931) reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with single-agent elacestrant vs standard of care (SOC) endocrine therapy (ET) in patients with ER+/HER2− mBC and tumors harboring ESR1 mutation following progression on prior ET+CDK4/6i; mPFS 3.8 months with elacestrant vs 1.9 months with SOC (HR=0.55; 95% CI, 0.39-0.77; P = 0.0005) (Bidard 2022). In those patients with prior ET + CDK4/6i ≥12 months and ESR1-mutated tumors, median PFS with elacestrant was 8.6 vs 1.9 months with SOC ET (HR = 0.41; 95% CI, 0.26-0.63) (Bardia 2022). The PFS benefit associated with elacestrant was maintained across ESR1 mutation variants D538G, Y537S, and Y537N, which represent nearly 90% of ESR1-mutated tumors. Variant allele frequency in circulating tumor DNA correlates with tumor disease burden and predicts outcomes in patients with advanced breast cancer. This new analysis evaluates the clinical benefit of single-agent elacestrant in patients with high vs low ESR1 variant allele frequency (VAF). Methods: Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy were randomized 1:1 to receive oral elacestrant or SOC (investigator’s choice of AI or fulvestrant). A post-hoc subgroup analysis was performed in patients with ESR1-mutated endocrine-sensitive tumors (prior exposure to ET+CDK4/6i ≥12 months) detected in plasma ctDNA using Guardant Health360 gene panel to evaluate the benefit of elacestrant vs SOC by ESR1 VAF. Median VAF was 1.2% (95% CI 0.04-56.1). High and low VAF were defined as ≥1.2% and <1.2%, respectively. Results: In patients with low ESR1 VAF (n=79) who received prior ET+CDK4/6i ≥12 months, a clinically meaningful improvement in mPFS favoring elacestrant compared with SOC was observed, 8.6 with elacestrant vs 1.9 with SOC (HR = 0.51, 95% CI 0.26-0.99, P = 0.049). In patients with high ESR1 VAF (n=79), mPFS with elacestrant was 9.1 vs 1.9 for SOC (HR=0.36, 95% CI 0.19-0.69, P = 0.001). Baseline characteristics and additional data will be presented at the meeting. Conclusions: 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. Citation Format: Aditya Bardia, Javier Cortés, Francois Clement-Bidard, Guillermo Streich, José García-Sáenz, Janice Lu, Giulia Tonini, Simona Scartoni, Alessandro Paoli, Alessio Fiascarelli, Alessandro Bressan, Monica Binaschi, Tomer Wasserman, Virginia Kaklamani. Elacestrant vs SOC in ER+, HER2- advanced or metastatic breast cancer (mBC) with ESR1-mutated tumors: ESR1 allelic frequencies and clinical activity from the phase 3 EMERALD trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-01-25.

TPS1131 Background: Endocrine therapy(ET) resistance is a major challenge in treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC); estrogen receptor (ESR1) mutations are an important mechanism of resistance. The standard of care (SOC) first-line treatment for ER+, HER2– MBC is ET plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Despite the benefit of ET and CDK4/6i, disease progression and acquired resistance to the combination remain a challenge. Novel, more effective ETs that can overcome resistance are needed to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a novel oral, complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD) that acts by blocking both transcriptional activation function domains, AF1 and AF2, regardless of ESR1 mutation status. As monotherapy, palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in heavily-pretreated patients during phase 1/2 studies, regardless of ESR1 mutation status (NCT04505826; Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patients with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Adult patients are eligible with a diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1 or 2 prior lines of ET with the last ET duration of ≥6 months; must have received and have disease progression on CDK4/6i with ET for MBC. Prior chemotherapy for MBC is not allowed. The study included a dose selection phase, where participants were randomized to 90 mg qd or 120 mg qd palazestrant or SOC; enrollment in this phase is complete. After the dose selection of palazestrant, the study will continue with the selected dose compared to SOC ET at a 1:1 randomization. Overall, 510 patients will be randomized to palazestrant or SOC ET during the study. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations (dual primary endpoint). Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, exposure and patient-reported outcomes in patients with and without ESR1 mutations. Study recruitment began in November 2023. Clinical trial information: NCT06016738 .

TPS22 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patietns with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for 16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1 mutations. The study started recruitment in November 2023. Clinical trial information: NCT06016738 .

Background: For patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC) and progression on combination endocrine therapy plus palbociclib/ribociclib, abemaciclib can be effective and well-tolerated, conferring durable clinical benefit in a subset of patients (Wander SA et al. JNCCN 2021). We previously reported that, even in patients with ESR1-mutant (ESR1-MUT) HR+ MBC, some - but not all - still achieve long-term disease control with abemaciclib (Wander SA et al. SABCS 2020). How to identify which patients are likely to benefit from abemaciclib after progression on combination endocrine therapy and CDK4/6 inhibition is not known and, more generally, predicting tumor response to CDK4/6 inhibition has been an area of ongoing research. Because resistance to CDK4/6 inhibition can occur through multiple mechanisms, we hypothesized that a comprehensive resistance panel, rather than single genetic markers or immunohistochemical readouts, would provide an effective predictive tool. Methods: To determine which patients with ESR1-MUT MBC and progression on endocrine therapy plus palbociclib/ribociclib benefit from abemaciclib, we examined a multicenter cohort of such patients who had genomic profiling by standard commercially available assays, the majority of which were via plasma-based cell-free DNA (cfDNA) genotyping assays. We generated a curated list based upon prior literature of CDK4/6i resistance drivers that had been validated in tumor biopsy specimens and in laboratory models: these genes were involved in cell cycle regulation (CCNE1/2, RB1, AURKA) and growth factor signaling pathways (ERBB2, FGFR1/2, AKT1, PTEN, KRAS, FAT1). Progression-free survival (PFS) was defined as time from abemaciclib initiation to time of discontinuation due to disease progression or death; patients who discontinued due to toxicity were right-censored. To examine the cellular effects of different mutations, we also studied the impact of ESR1-MUT, RB1 loss, and KRAS activation on the growth and survival (using an ATP abundance-based assay) of patient-derived circulating tumor cell (CTC) lines treated with palbociclib and abemaciclib in vitro. Results: Among patients with ESR1-MUT MBC with disease progression on endocrine therapy plus palbociclib/ribociclib (n=28), absence of co-existing genomic alterations in our curated panel was associated with greater clinical benefit with subsequent abemaciclib. Patients lacking a mutation in this resistance panel (n=17) had a median PFS of 7.0 months (95% CI: 4.1-13.2); patients with at least one mutation in this panel (n=11) had a median PFS of 3.5 months (95% CI: 2.1-5.4). The difference in PFS was statistically significant (p=0.02, log-rank test). On univariable Cox regression the hazard ratio for patients with a mutation in the resistance panel was 2.8 (95% CI: 1.1-7.1, p=0.03). In vitro, two out of three patient-derived cell lines with ESR1-MUT remained sensitive to abemaciclib, while those with mutation in RB1 or KRAS were less sensitive to abemaciclib. Conclusions: In our study, absence of co-existing genomic alterations in a curated panel was associated with greater clinical benefit with subsequent abemaciclib among patients with ESR1-MUT MBC with prior disease progression on endocrine therapy plus palbociclib/ribociclib. While a small dataset, this is the first demonstration of a genomic panel associated with continued CDK4/6 inhibitor sensitivity. Future directions include testing this panel outside of ESR1-MUT MBC and refining the panel in additional datasets with increased sample size, to guide therapy selection for patients with HR+ MBC. Citation Format: Jamie O Brett, Taronish D Dubash, Andrzej Niemierko, Veronica Mariotti, Leslie SL Kim, Jing Xi, Apurva Pandey, Siobhan Dunne, Azadeh Nasrazadani, Maxwell R Lloyd, Laura M Spring, Douglas Micalizzi, Maristela Onozato, Dante Che, Adam Brufsky, Kevin M Kalinsky, Cynthia X Ma, Joyce O’Shaughnessy, Hyo S Han, A. John Iafrate, Shyamala Maheswaran, Daniel A Haber, Aditya Bardia, Seth A Wander. Association between co-existing genomic alterations and abemaciclib benefit in patients with metastatic hormone receptor-positive breast cancer with ESR1 mutations following disease progression on prior endocrine therapy plus palbociclib or ribociclib [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD2-03.

Current Value Frameworks—What's New?

Background: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), adding a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy (ET) has improved outcomes and is the current standard-of-care treatment in the first-line setting. However, resistance to first-line treatment develops in most patients (pts), which is often attributed to acquired mutations in ESR1. Limited data exist for ET-based treatment options after progression on prior ET and CDK4/6 inhibitors, and most pts will transition to chemotherapy for further treatment. Therefore, there is a significant unmet need for more effective ET in pts with ER-positive, HER2-negative MBC to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant demonstrated better tumor shrinkage in ESR1-wt and ESR1-mut models when compared to fulvestrant; it also showed efficacy in brain metastasis models. In a phase 1/2 monotherapy study in pts with heavily pretreated ER-positive, HER2-negative advanced breast cancer (BC) or MBC (NCT04505826), palazestrant showed a tolerable safety profile, promising antitumor efficacy, and favorable pharmacokinetics (PK) supporting once a day (qd) dosing. The recommended Phase 2 dose of palazestrant is 120 mg qd. Methods: The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Eligible pts are women (pre- or post-menopausal) or men who have a confirmed diagnosis of ER-positive, HER2-negative locally advanced evaluable BC or MBC not amenable to curative therapy. ER and HER2 status are determined according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Patients must have Eastern Cooperative Oncology Group performance status 0 or 1. Prior treatments must include 1 or 2 prior lines of ET as monotherapy or in combination with a CDK4/6 inhibitor for MBC; must have received CDK4/6 inhibitor in combination with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC; most recent ET given for ≥6 months. Prior chemotherapy in the metastatic setting is not permitted. Patients (N∼500) are randomized to palazestrant or standard-of-care ET monotherapy, and are stratified by ESR1 mutation status, prior lines of ET for advanced disease (1 vs 2 lines), and presence or absence of visceral disease. The primary endpoint of progression-free survival will be assessed by blinded independent central review in pts with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in pts with and without ESR1 mutations. The study is planned to be conducted globally. Citation Format: Arlene Chan, Jane Meisel, Komal Jhaveri, Joo Hyuk Sohn, Meritxell Bellet- Ezquerra, Jason Schroeder, Mark Shilkrut, Barbara Pistilli. OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy [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 PO3-18-09.

Background: The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is widely utilized as the first-line treatment for hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients. However, there has been long debates on the choice between CDK4/6i plus ET and chemotherapy (CT), especially those with visceral metastasis or visceral crisis. Several prospective trials suggested a suspected superiority of CDK4/6i over CT, however, conclusions vary among different studies due to the complexity of treatment lines and different inclusion criteria. Here we report CDK4/6i plus ET versus CT in first line treatment of HR+/HER2- MBC in a real-world setting. Methods: The medical records of patients diagnosed with HR+/HER2- MBC from 2020 to 2023 in 6 institutions were retrospectively evaluated. And patients received first-line CDK4/6i plus ET or first-line CT were included in this study. Results: A total of 339 patients were available for analysis. 244 (72%) patients received CDK4/6i plus ET and 95 (28%) patients received CT. The median PFS of CDK4/6i plus ET cohort was significantly superior to CT group (17.2 months versus 9.1 months, hazard ratio = 0.49; 95% CI, 0.36 to 0.66; P < 0.0001). Subgroup analysis showed similar results, except subgroup of patients with visceral crisis (hazard ratio =0.73; 95% CI, 0.37 to 1.43; P = 0.36) or primary endocrine resistance (hazard ratio =0.59; 95% CI, 0.33 to 1.06; P = 0.08). The median overall survival was not reached. No significant difference of grade 3 or worse adverse events was observed in two groups (25.8% vs 26.3%, P = 0.93). Conclusions: In a real-world setting, first line CDK4/6i plus ET showed better efficacy than chemotherapy in patients with HR+/HER2- MBC, while CT and ET showed similar results in patients with visceral crisis or primary endocrine resistance. Safety profile was similar between two groups. This study provides real-world data for future clinical decision. Citation Format: Biyun Wang, Yifan Chen, Yizhao Xie, Yuan Peng, Ning Xie, Die Sang, Xinhua Han, Yanxia Zhao, Juanjuan Li. First line CDK4/6 inhibitors plus endocrine therapy versus chemotherapy for HR+/HER2- metastatic breast cancer patients in real world: a multicenter YOUNGBC-30 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-07-16.

Background: Abemaciclib is a potent oral cyclin-dependent kinase (CDK) 4 and 6 inhibitor that demonstrated statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR) in combination with endocrine therapy (ET) in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced and metastatic breast cancer patients in Phase 3 studies. In contrast to NCCN guidelines, cytotoxic chemotherapy is still often initiated early in the course of HR+, HER2- advanced breast cancer despite absence of visceral crises, potentially denying patients effective and tolerable standard-of-care regimens containing ET. The current study aims to compare the efficacy and safety of abemaciclib in combination with ET to chemotherapy in patients with HR+, HER2- advanced breast cancer with ≥1 site of visceral metastases. Trial design: I3Y-MC-JPCU is a multicenter, open-label, randomized, controlled study of abemaciclib in combination with fulvestrant compared to physician’s choice of chemotherapy in women with HR+, HER2- locally advanced or metastatic breast cancer who have poor prognosis due to visceral metastases. Approximately 300 patients will be randomized 1:1 to Arm A (abemaciclib, 150 mg BID, in combination with fulvestrant, n=150) or Arm B (physician’s choice of chemotherapy [capecitabine, docetaxel, nab-paclitaxel, or paclitaxel], n=150). Stratification factors will include liver metastasis, sensitivity to endocrine therapy (sensitive vs primary resistance vs secondary resistance, and postmenopausal status (natural/surgical/therapeutic radiation vs GnRH use). It will be conducted in the USA. Accrual is planned to start in 2019. Eligibility: Key inclusion criteria are postmenopausal HR+, HER2- patients with locally advanced recurrent and unresectable or metastatic HR+, HER2- breast cancer and ≥1 site of visceral metastasis as well as disease progression after ≥1 line of ET in (neo)adjuvant or metastatic setting. Individuals will be excluded if they have visceral crisis, have received prior systemic therapy other than ET for metastatic disease, have received >1 prior ET for metastatic disease, and/or have been treated with fulvestrant or any CDK 4 and F6 inhibitor for any duration. Objectives: The primary objective is ORR. Secondary objectives include PFS, time to response, duration of response, time to second disease progression (PFS2), and safety. Exploratory objectives include healthcare resource utilization, patient reported outcomes, and relationship of pharmacogenomics/biomarkers to clinical outcomes. Statistical Methods: Comparability of abemaciclib in combination with fulvestrant to chemotherapy will be evaluated with respect to ORR and PFS. The study is designed to demonstrate comparability using a 10% ORR margin and a 20% PFS margin. Comparability will declared if the posterior probability the true difference is less than the comparability margin is at least 80%. PFS comparability will be assessed only if ORR comparability is declared after a gatekeeping testing strategy. The tested hypotheses will be 1) ORR comparability: ≥80% posterior probability that true ORRArm B - true ORRArm A <10% with 10% the defined margin for ORR comparability; and 2) PFS comparability (gated secondary endpoint): ≥80% posterior probability that true PFS hazard ratioArm A/Arm B - 1 <0.2, with 0.2 being the defined margin for PFS comparability. Citation Format: Peter Kaufman, John Glaspy, Wei Zhang, Andrew Koustenis, Yanyun Chen, Adam Brufsky. A randomized trial of abemaciclib in combination with fulvestrant compared to chemotherapy in women with HR+, HER2- advanced breast cancer with visceral metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-05.

e13068 Background: ESR1 and PIK3CA mutations inform the use of targeted agents such as alpelisib and elacestrant in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) following progression. Each of these mutations predict a worse prognosis and shorter response to endocrine therapy (ET). The prevalence of PIK3CA and ESR1 mutations detected via cell-free tumor DNA (ctDNA) in mBC is about 35% and 33%, respectively, and the co-occurrence rate ranges from 10-15%. Here, we evaluate the incidence and outcomes of pts with mBC HR+/HER2- harboring co-occurring ESR1 and PIK3CA mutations as detected by ctDNA in a real-world tertiary care center with a predominantly Hispanic patient population. Methods: We analyzed pts with HR+/HER2- mBC with ctDNA testing (Guardant360) between Jan 1, 2020 and Jan 31, 2023 at Miami Cancer Institute. We determined the rate of co-occurrence of activating PIK3CA and ESR1 mutations (co-mutation group). In these pts, demographics, disease characteristics, response to alpelisib + ET, and overall survival (OS) after diagnosis of mBC were collected. For comparison, we analyzed pts with PIK3CA mutations but no ESR1 mutation detected who had received alpelisib + ET ( PIK3CA only group). Results: 372 patients with a diagnosis of mBC who underwent ctDNA testing during the study period, 80 (21.5%) had at least one activating PIK3CA mutation, and 37 (9.95%) had a co-occurring ESR1 mutation. Median age was 70 vs 69 years in the PIK3CA only group compared to the co-mutation group, with 82% vs 92% being post-menopausal, respectively. In the PIK3CA only group, 36.4% were of Hispanic ethnicity, while 70.3% of those in the co-mutation group were Hispanic. Most pts received prior CDK4/6 inhibitor (91% in PIK3CA only group vs 97% with co-mutation). 16 (43.2%) of the 37 patients in the co-mutation group were treated with alpelisib + ET after detection of the co-occurring mutation via ctDNA, and outcomes were compared to the PIK3CA only group. Pts in the PIK3CA only group were treated with alpelisib + ET for a median of 7.23 months vs 4.24 months in the co-mutation group (p=0.6023). Reason for discontinuation, most commonly progressive disease (63.6% in PIK3CA only vs 62.5% in co-mutation) was similar between groups. A partial response or better was seen in 30% of the PIK3CA only group vs 20% of the co-mutation group. OS was 138 months for PIK3CA only vs 98 months for the co-mutation group (p=0.96). Conclusions: The incidence of co- PIK3CA and ESR1 mutations in this predominantly Hispanic patient population was consistent with previously reported literature. We identified a trend towards worse OS and shorter duration on treatment with alpelisib + ET in the co-mutation group as compared to the PIK3CA alone group. Further studies are needed to understand the optimal sequencing of therapy in pts with co-mutation in ESR1 and PIK3CA.

Background: Selective estrogen receptor (ER) degraders (SERDs) result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor, palbociclib, in ER-positive (+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). We previously presented preliminary results (ASCO 2019). Here we describe safety, pharmacokinetics (PK), ER gene (ESR1)profiling and updated antitumor activity for SAR439859 monotherapy dose escalation. Methods: Part A of this open-label, Phase 1/2 first-in-human study (NCT03284957; TED14856) assessed SAR439859 dose escalation (3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Dose levels ranged from 20-600 mg once daily (QD). Primary objectives: dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended dose. Secondary objectives: safety, PK, tumor response (RECIST v1.1), pharmacodynamic (PD) inhibition of ER occupancy (18F-fluoroestradiol positron emission tomography[18F-FES PET] scan). Exploratory objective: mutation profiling of ESR1 (circulating tumor DNA was assessed for 12 ESR1 mutations at baseline and end of Cycle 2 using multiplex droplet digital polymerase chain reaction). Results: As of May 29, 2019, 16 patients were treated. Median age: 59.5 years (range 40-79); ECOG performance status: 0 (62.5%) or 1 (37.5%); median prior anticancer therapies in the advanced setting: 3 (range 1-8). All patients had ≥ 1 treatment-emergent adverse event (TEAE), mostly grade 1-2; most frequent were hot flushes, diarrhea, constipation, nausea (all 37.5%) and decreased appetite (31.3%). Most frequent TEAEs related to treatment were hot flushes (31.3%), diarrhea, nausea (both 25%), decreased appetite, constipation, night sweats, asthenia (all 18.8%), arthralgia and fatigue (both 12.5%); no event was grade ≥ 3. There were no DLTs at any of the five dose levels (maximum administered dose 600 mg QD); MTD was not reached. In 18F-FES PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. PK profile showed rapid SAR439859 absorption (median tmax ~ 3 hours) and an apparent terminal half-life of ~ 8 hours after first administration. After repeated QD administration, there was no or low accumulation and exposure (Cmax/AUC0-24h) increased with doses up to 600 mg. Food intake did not have a major effect on exposure. Best overall response (BOR) was confirmed partial response (PR) in one patient at 150 mg QD (6.3%) and stable disease (SD) in eight patients (50.0%) including seven (43.8%) with long-term SD (≥ 24 weeks). Seven had progressive disease (43.8%). Tumor shrinkage > 10% was seen in eight patients (50.0%), without any dose dependency. ESR1 mutations were detected at baseline in 11 patients (68.8%), with five patients harboring > 1 mutation. Similar BOR was seen regardless of ESR1 mutation status with SD seen in 54.5% (6/11) of patients with ESR1 mutations and SD/PR seen in 60.0% (SD: 2/5; PR: 1/5) of patients with wild-type ESR1. Conclusions: SAR439859 demonstrated a favorable safety profile and high ER occupancy in pretreated patients with ER+/HER2- mBC. Most patients had ESR1 mutations. Preliminary antitumor activity was encouraging in both ESR1 mutated and wild-type patients. With no DLTs and no MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK. Additional data on PK, PD, antitumor activity and the ESR1 mutational profile, and any correlations, will be presented. Funding: Sanofi. Citation Format: Mario Campone, Aditya Bardia, Gary A Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Jeffrey Ming, Marina Celanovic, Hannah M Linden. Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-02.

Background: Endocrine therapy (ET) when administered with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has improved outcomes in patients (pts) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment. Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. Most pts will acquire resistance to ET, with mutations in ESR1 constituting the most common mechanism of resistance. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant in combination with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut xenograft models and showed efficacy in brain metastasis xenograft models. In a Phase 1/2 monotherapy study in pts with ER-positive, HER2-negative MBC, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose (RP2D) of 120 mg. The aim of this study is to evaluate the safety, PK, and antitumor activity of palazestrant + ribociclib or alpelisib in pts with ER-positive, HER2-negative advanced BC or MBC. Methods: Eligible pts have evaluable ER-positive, HER2-negative advanced BC or MBC; ≤2 prior ETs (prior CDK4/6 inhibitors allowed); and ≤1 prior line of chemotherapy. In the alpelisib arm, pts must have a PIK3CA mutation in the tumor or ctDNA. Patients are administered oral palazestrant at escalating doses of 30, 60, and 120 mg qd in combination with the approved dose of oral ribociclib (600 mg qd; days 1–21 of 28-day cycle) or approved dose of oral alpelisib (300 mg qd) in a 3+3 design to identify the RP2D. The dose-expansion part will assess additional safety and PK parameters and the antitumor activity of palazestrant in combination with ribociclib or alpelisib (NCT05508906). Results: As of June 15, 2023, 10 pts have received 30 mg and 60 mg doses of palazestrant in combination with ribociclib (n=6) or alpelisib (n=4). No dose-limiting toxicities have been observed. After administration in the first two combination dose levels of 30 and 60 mg, palazestrant exposure was consistent with monotherapy administration; exposure data show no drug–drug interactions (DDI) when compared to published exposure parameters. Most reported treatment-emergent adverse events (TEAEs) were grade 1 or 2 and consistent with the known safety profiles of all 3 drugs. In the ribociclib arm, the TEAEs occurring in ≥2 pts included grade 1 nausea (n=4), grade 1 constipation (n=2), and neutropenia (grade 2, n=1; grade 3, n=3). For the 3 pts in the 30 mg palazestrant + alpelisib cohort, the only TEAE occurring in ≥2 pts was grade 1 diarrhea. One pt had grade 1 hyperglycemia. Conclusions: In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels. Updated data will be presented. Citation Format: Virginia Borges, Carlos Alemany, Nancy Lin, Sara Nunnery, Cynthia Ma, Margaret Tonda, Morena Shaw, Arlene Chan. A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/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 PO4-04-12.

Background: Imlunestrant is a next-generation, brain-penetrant, oral SERD and pure estrogen receptor (ER) antagonist that delivers continuous ER inhibition, including in ESR1-mutant cancers. Methods: This phase-3, randomized, open-label trial (NCT04975308) enrolled patients (pts) with ER+, HER2- ABC that recurred or progressed on/after an aromatase inhibitor, alone or with a CDK4/6 inhibitor (CDK/6i). No other prior therapy for ABC was allowed. Pts were randomized 1:1:1 to imlunestrant (400 mg once daily [QD]), physician’s choice standard-of-care (SOC) ET (fulvestrant or exemestane per label), or imlunestrant (400 mg QD) + abemaciclib (150 mg twice daily). Primary endpoints were investigator-assessed PFS of imlunestrant vs SOC in pts with ESR1 mutations (ESR1m) and all pts and of imlunestrant + abemaciclib vs imlunestrant in all concurrently randomized pts. Secondary endpoints included OS (tested if the corresponding PFS was statistically significant), PFS by BICR, ORR, and safety. Results: Overall, 874 pts were randomized (imlunestrant, n=331; SOC, n=330; imlunestrant + abemaciclib, n=213), 60% received prior CDK4/6i (imlunestrant, 59%; SOC, 57%; imlunestrant + abemaciclib, 65%). A total of 256 pts had ESR1m (imlunestrant, n=138; SOC, n=118). Imlunestrant significantly improved PFS vs SOC in pts with ESR1m (HR, 0.62; 95% CI, 0.46-0.82; P<0.001; median PFS [mPFS] 5.5 vs 3.8 months). Imlunestrant did not significantly improve PFS in the overall population (n=661; HR, 0.87; 95% CI, 0.72-1.04; P=0.12). Imlunestrant + abemaciclib significantly improved PFS vs imlunestrant in all pts (n=426; HR, 0.57; 95% CI, 0.44-0.73; P<0.001; mPFS 9.4 vs 5.5 months), with benefit observed regardless of ESR1m or PI3K pathway mutation status and in CDK4/6i pretreated pts. Investigator and BICR assessments were consistent across all endpoints. In all pts with measurable disease, ORR was 12% for imlunestrant; 8% for SOC; and 27% for imlunestrant + abemaciclib. All OS analyses were immature and ongoing; favorable trends were observed for imlunestrant vs SOC in pts with ESR1m (31% events; HR, 0.55; 95% CI, 0.35-0.86; P<0.01 [not statistically significant]) and in all pts (23% events; HR, 0.69; 95% CI, 0.50-0.96; [not inferentially tested]). OS analyses were less mature for imlunestrant + abemaciclib vs imlunestrant (15% events; HR, 1.34; 95% CI, 0.81-2.21; P=0.25). In post-hoc analyses, imlunestrant had lower 12-month cumulative incidence of central nervous system progression vs SOC in pts with ESR1m (2% vs 7%; HR, 0.18; 95% CI, 0.04-0.90) and all pts (2% vs 3%; HR, 0.47; 95% CI, 0.16-1.38), though absolute numbers were small. Common all-grade TEAEs with imlunestrant were fatigue (23% vs 13% SOC), diarrhea (21% vs 12%), and nausea (17% vs 13%), mostly grade 1. Notably, all-grade bradycardia (2% vs 0% SOC), photopsia (0% each), and dyslipidemia (7% vs 9%) were infrequent or not observed with imlunestrant. Common grade ≥3 TEAEs with imlunestrant were anemia (2% vs 3% SOC), and neutropenia (2% each). Common all-grade/grade ≥3 TEAEs with imlunestrant + abemaciclib were diarrhea (86%/8%), nausea (49%/2%), and neutropenia (48%/20%). Grade ≥3 TEAEs rates were 17% for imlunestrant, 21% for SOC and 49% for imlunestrant + abemaciclib. Discontinuation of imlunestrant and imlunestrant + abemaciclib due to AEs was low (4% and 6%, respectively). Conclusion: Imlunestrant significantly improved PFS vs SOC in pts with ESR1m, and imlunestrant + abemaciclib significantly improved PFS vs imlunestrant in all pts regardless of ESR1m status. Imlunestrant had a favorable safety profile alone and combined with abemaciclib, thus providing an all-oral targeted therapy option for ET-pretreated pts with ER+, HER2- ABC. Citation Format: Komal Jhaveri, Patrick Neven, Monica Lis Casalnuovo, Sung-Bae Kim, Eriko Tokunaga, Philippe Aftimos, Cristina Saura, Joyce O’Shaughnessy, Nadia Harbeck, Lisa A. Carey, Giuseppe Curigliano, Antonio Llombart-Cussac, Elgene Lim, María de la Luz García Tinoco, Joohyuk Sohn, André Mattar, Qingyuan Zhang, Chiun-Sheng Huang, Chih-Chiang Hung, Jorge Luis Martinez Rodriguez, Manuel Ruiz Borrego, Rikiya Nakamura, Kamnesh R. Pradhan, Christoph Cramer von Laue, Emily Barrett, Shanshan Cao, Xuejing Aimee Wang, Lillian M. Smyth, François-Clément Bidard. Imlunestrant, an Oral Selective Estrogen Receptor Degrader (SERD), as Monotherapy & Combined with Abemaciclib, for Patients with ER+, HER2- Advanced Breast Cancer (ABC), Pretreated with Endocrine Therapy (ET): Results of the Phase 3 EMBER-3 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS1-01.