Selective Estrogen Receptor Degrader Research Articles

Adverse event signal mining and serious adverse event influencing factor analysis of fulvestrant based on FAERS database

Fulvestrant, as the first selective estrogen receptor degrader, is widely used in the endocrine treatment of breast cancer. However, in the real world, there is a lack of relevant reports on adverse reaction data mining for fulvestrant. To perform data mining on adverse events (AEs) associated with fulvestrant and explore the risk factors contributing to severe AEs, providing a reference for the rational use of fulvestrant in clinical practice. Retrieved adverse event report information associated with fulvestrant from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, covering the period from market introduction to September 30, 2023. Suspicious AEs were screened using the reporting odds ratio (ROR) and proportional reporting ratio methods based on disproportionality analysis. Univariate and multivariate logistic regression analyses were conducted on severe AEs to explore the risk factors associated with fulvestrant-induced severe AEs. A total of 6947 reports related to AEs associated with fulvestrant were obtained, including 5924 reports of severe AEs and 1023 reports of non-severe AEs. Using the disproportionality analysis method, a total of 210 valid AEs were identified for fulvestrant, with 45 AEs (21.43%) not listed in the product labeling, involving 11 systems and organs. The AEs associated with fulvestrant were sorted by frequency of occurrence, with neutropenia (325 cases) having the highest number of reports. By signal strength, injection site pruritus showed the strongest signal (ROR = 658.43). The results of the logistic regression analysis showed that concurrent use of medications with extremely high protein binding (≥ 98%) is an independent risk factor for severe AEs associated with fulvestrant. Age served as a protective factor for fulvestrant-related AEs. The co-administration of fulvestrant with CYP3A4 enzyme inhibitors did not show statistically significant correlation with the occurrence of severe AEs. Co-administration of drugs with extremely high protein binding (≥ 98%) may increase the risk of severe adverse reactions of fulvestrant. Meanwhile, age (60–74 years) may reduce the risk of severe AEs of fulvestrant. However, further clinical research is still needed to explore and verify whether there is interaction between fulvestrant and drugs with high protein binding through more clinical studies.

Next generation selective estrogen receptor degraders in postmenopausal women with advanced-stage hormone receptors-positive, HER2-negative breast cancer.

Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular biomarkers that also serve as predictive indicators. More than two thirds of breast tumors are classified as luminal with positive hormone receptors (HR), indicating that cancer cells proliferation is promoted by hormones. Endocrine therapies play a vital role in the effective treatment of breast cancer by manipulating the signaling of estrogen receptors (ER), leading to a reduction in cell proliferation and growth rate. Selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene, function by blocking estrogen's effects. Aromatase inhibitors (AI), including anastrozole, letrozole and exemestane, suppress estrogen production. On the other hand, selective estrogen receptor degraders (SERDs), like fulvestrant, act by blocking and damaging estrogen receptors. Tamoxifen and AI are widely used both in early- and advanced-stage disease, while fulvestrant is used as a single agent or in combination with other agents like the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, ribociclib) or alpelisib for advanced-stage disease. Currently, SERDs are recognized as an effective therapeutic approach for the treatment of ER-positive breast cancer, showing proficiency in reducing and blocking ER signaling. This review aims to outline the ongoing development of novel oral SERDs from a practical therapeutic perspective, enhancing our understanding of the mechanisms of action underlying these compounds.

Abstract PS15-04: A Phase 1b/2 study of palazestrant (OP-1250), an oral complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD), with palbociclib in ER-positive, HER2-negative, advanced or metastatic breast cancer patients

Abstract Background: Palazestrant (OP-1250) is a small molecule oral complete estrogen receptor (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 improved tumor growth inhibition and shrinkage when combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. In a Phase 1/2 monotherapy clinical study in patients with ER-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose of 120 mg. In this study, pts received palazestrant at escalating doses of 30, 60, 90, and 120 mg qd in combination with palbociclib (125 mg qd) and no dose-limiting toxicities were observed. Palazestrant did not affect palbociclib PK and no drug–drug interactions (DDIs) occurred. Here we report updates on safety, efficacy, and PK from the ongoing study of palazestrant in combination with palbociclib. Methods: Patients with advanced or metastatic breast cancer with progression on or after ≤1 line of endocrine therapy (prior CDK4/6 inhibitor therapy and ≤1 chemotherapy allowed) were enrolled to receive oral palazestrant 120 mg qd with oral palbociclib 125 mg qd for 21 of 28 days (NCT0526610). Results: As of May 12, 2023, 33 patients have been treated with palazestrant in combination with palbociclib; 12 pts were dosed in the dose-escalation phase and 21 patients were dosed in the dose-expansion phase of the study. Twenty-two patients (67%) received prior CDK4/6 inhibitor therapy; 15 patients received prior palbociclib. Thirteen of 25 patients (52%) with available baseline ctDNA had an ESR1 mutation. The most common (≥20%) treatment-emergent adverse events (TEAEs) were neutropenia, nausea, vomiting, constipation, and diarrhea. Most of these events were grade 1 or 2. The most common grade 3 or 4 related AE was neutropenia (18/33 [55%] were grade 3; 3/33 [9%] were grade 4). The steady-state exposure of palazestrant when dosed with 125 mg palbociclib was consistent with the monotherapy study. Palbociclib exposure at steady-state was comparable to published monotherapy data when combined with palazestrant at all dose levels tested. As of the data cut-off, there were 4 partial responses (2 confirmed) out of 19 response-evaluable patients, with a clinical benefit rate (CBR) of 42% (8/19) across all patients and 67% (6/9) in patients with ESR1 mutations. Conclusions: Palazestrant and palbociclib dosed in combination were well tolerated with a safety profile consistent with the individual profiles of each drug as monotherapy, and there were no DDIs. Tumor responses and clinical benefit were observed in this population of patients, including those who received prior CDK4/6 inhibitors. Expanding on our previous report, these data provide the rationale to continue advancing the clinical development of palazestrant with the approved dose of palbociclib. Updated data will be presented. Citation Format: Arlene Chan, Daphne Day, Phuong Dinh, Michael Slancar, Janine Lombard, Vinod Ganju, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Gurpreet Mathauda-Sahota, Caitlin Murphy. A Phase 1b/2 study of palazestrant (OP-1250), an oral complete estrogen receptor antagonist (CERAN) and selective ER degrader (SERD), with palbociclib in ER-positive, HER2-negative, advanced or metastatic breast cancer patients [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 PS15-04.

Abstract PO3-04-13: SUMIT-ELA: Phase 1b/2 combination of cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib and selective estrogen receptor degrader (SERD) elacestrant in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. Samuraciclib (CT7001), a once daily oral CDK7 inhibitor has demonstrated a favorable safety profile and clinical activity in combination with fulvestrant (SERD) in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor [1]. Extended benefit was observed in patients with no TP53-mutation per circulating tumor DNA (ctDNA) analysis detectable at baseline. Limitations in the pharmacokinetic (PK) properties and route of administration (intramuscular only) of fulvestrant mean that oral alternatives are desirable. Recently, the EMERALD phase 3 study of the oral SERD elacestrant demonstrated a significant PFS benefit over standard of care endocrine treatment in the ER+/HER2- advanced or metastatic breast cancer population previously treated with a CDK4/6 inhibitor. [2]. Non-clinical data indicate that the underlying biology driving samuraciclib combination with endocrine therapy translates from fulvestrant to elacestrant, clinical evaluation is warranted [3]. This open-label Phase 1b dose escalation and Phase 2 dose expansion study will evaluate the safety, efficacy and pharmacokinetics of samuraciclib in combination with elacestrant. ctDNA analysis is informative for both elacestrant and samuraciclib, via ESR1-mutation status and TP53-mutation status respectively, and is an integral part of the study design. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. The study will enrol ~48 patients. All patients will undergo baseline Guardant360 ctDNA analysis to establish their ESR-1 and TP53-mutation status. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. Initially both samuraciclib and elacestrant will be administered once daily in a dose escalation/de-escalation approach under supervision of the study Safety Review Committee. The primary endpoint in Phase 1b is the identification of tolerable combination dose levels for both samuraciclib and elacestrant and in Phase 2 expansion to quantify the progression free survival benefit of the combination. Secondary endpoints are tolerability, clinical benefit response at 24 weeks, overall response rate, duration of response, best percent change in tumor size, pharmacokinetics and correlations between ctDNA detectable ESR1 and TP53 mutations and efficacy/safety finding in this patient population. The study opened for recruitment in June 2023.

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 PO1-23-10: Multi-omics analysis identifies the mechanism in cross-resistance to endocrine therapy and CDK4/6 inhibitor in breast cancer

Abstract Background In advanced/metastatic breast cancer (MBC) or recurrent breast cancer on prior endocrine therapy (ET), selective estrogen receptor downregulator (SERD) of fulvestrant and CDK4/6i are the mainstream therapy regimen. In the clinical, fulvestrant combined with CDK4/6i is the second-line therapy for breast cancer (BC) that had progressed during previous endocrine therapy. The alternation of backbone from aromatase inhibitor or tamoxifen (endocrine sensitive) to fulvestrant (endocrine resistance) partially comes from the mechanism of ET resistance. Moreover, in the PALOMA-2 trial, approximately 30% of patients developed into recurrence after two years of CDK4/6i treatment, indicating that the ET backbone may affect CDK4/6i efficacy, bringing an emerging clinical issue of cross-resistance. However, whether the cross-resistance of ET would be more sensitive to CDK4/6i or impair the efficacy of CDK4/6i is still an ambiguous and heterogeneous issue. Also, in CDK4/6i resistance, whether the mechanism of ET resistance is associated with the dysregulation of the cell cycle or activation of other “bypass” signaling pathways is not fully understood. Methods We use a 3D and 2D culture of ET-sensitive cell S0.5, tamoxifen-resistant cell TAM, and fulvestrant-resistant cell 182R6 as our model. The 3D culture was performed by using the Tools 3d culture plus kit. Drug responses to fulvestrant and ribociclib were conducted by using CCK-8 assay. The potential target and pathway involved in the mechanisms of cross-resistance were analyzed by using multi-omics analysis of sequential window acquisition of all theoretical mass spectra (SWATH-MS), RNA-seq, micro-western array (MWA), traditional western blots, and open access database. Results In comparison with S0.5, the sensitivity to fulvestrant was indeed reduced in 182R6 cell; however, we found the sensitivity to ribociclib was also reduced in 182R6 cell, which was in contrast to the ribociclib-sensitive TAM cell. The different response to ribociclib between 182R6 and TAM, indicating that cross-resistance between fulvestrant and ribociclib existed in the model of 182R6 and TAM would be another control for 182R6 to find the target with or without cross-resistance. With multi-omics analysis of SWATH-MS, RNA-seq, MWA, western blots, and open access database, we found some unique or high expression of targets and pathways including EGFR, HER2, CDK6, CDK2, MAPK, and TNF-α pathways in cross-resistance R6 cell than in parental and TAM cell. We reconfirmed the above targets by 3D culture and found MAPK signaling pathway of p-ERK was not affected under ribociclib treatment, indicating the important role of the MAPK signaling pathway in ribociclib resistance. Conclusion To our knowledge, these results provide the first preliminary mechanism of cross-resistance between fulvestrant and ribociclib. We found fulvestrant resistant cell R6 exhibited the phenomenon of cross-resistance to ribociclib, which was in contrast to ribociclib-sensitive TAM cell. We also found some unique or high expression of target and pathway in cross-resistance R6 cells than in parental and TAM cells. In the future, with compound library screening and in vivo animal models, we expect to discover an FDA-approved drug or potential compound to overcome the cross-resistance between fulvestrant and ribociclib. Citation Format: Ming-Feng Hou, Chung-Liang Li, Chih-Po Chiang. Multi-omics analysis identifies the mechanism in cross-resistance to endocrine therapy and CDK4/6 inhibitor in 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 PO1-23-10.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [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 PO4-19-09.

Abstract PO3-19-08: A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial

Abstract Background. Premenopausal women diagnosed with HR+/HER2- breast cancer (BC) often have a different biology and worse prognosis. The SOFT and TEXT studies demonstrated an increase diseasefree survival (DFS) with ovarian function suppression (OFS) plus tamoxifen or exemestane compared to tamoxifen alone. Of note, high-risk clinicopathologic features, adjuvant chemotherapy, or aged ≤35 years correlated with greater OFS benefit. However, adding OFS in this context has intrinsic issues as higher toxicity, which led to treatment discontinuation (20% in SOFT trial), and suboptimal OFS was found in around 25% of patients (pts) with exemestane plus monthly triptorelin (SOFT-EST sub-study). Thus, new effective ET options without OFS are needed for premenopausal patients (pts). Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy to SOC treatments and specifically compared to fulvestrant in postmenopausal pts with HR+/HER2- metastatic BC at the phase III EMERALD trial. In menopausal patients with HR+/HER2- early BC, the window of opportunity SOLTI-1905 ELIPSE trial (NCT04797728), showed that elacestrant was associated with a 27.3% rate of Complete Cell Cycle Arrest (CCCA) and a statistically significant suppression of Ki-67. Among Luminal A tumors, the CCCA rate was 45% and the average decrease in Ki-67 was 64.6%, while no CCCA was reported and the suppression of Ki-67 was less pronounced (31.7%) in the Luminal B population. There is still a need for investigating elacestrant without OFS in the premenopausal scenario. We hypothesize that elacestrant as a single agent or in combination with triptorelin is an effective and safe treatment regimen in premenopausal pts with HR+/HER2-negative early BC capable of achieving an equivalent CCCA rate as a subrogate of effectiveness regardless the use of OFS Study design. PREMIERE is a parallel, non-comparative, two-arm, randomized 1:1, open-label, multicenter, exploratory study in premenopausal women with primary operable HR+/HER2-negative BC. The study aims to evaluate the biological effects of elacestrant with or without triptorelin. Participants must have histologically confirmed HR+ (≥ 10%) and HER2- operable early BC stage I to stage IIB >1 cm with a Ki-67 between 10-35%. The primary objective is to assess the ability of each treatment arm to induce CCCA determined by central assessment of Ki-67 (% Ki-67 ≤ 2.7%). No formal comparison between treatment arms is intended. Secondary objectives include evaluating the biological activity of elacestrant with or without OFS, antiproliferative activity, changes in gene expression including PAM50 subtype changes, and the effect of optimal vs suboptimal suppression on CCCA . Serum E2 and FSH levels will also be evaluated. Safety and tolerability will be assessed based on adverse events and clinical laboratory test results. Pts will undergo screening and randomization, with stratification by PAM50 subtype (Luminal A vs Non-luminal A). Treatment will be elacestrant 400 mg once daily or elacestrant 400 mg once daily plus triptorelin 3.75 mg days +1 and +29 for 30 (+7) days. Surgery or biopsy will be performed after treatment completion, and a post-surgery visit will mark the end of the active follow-up period. Patients will receive SOC treatment after surgery. 48 patients will be recruited in 9 sites within SOLTI Spanish network in 9 months period. This study is financially supported by Menarini-Stemline. Citation Format: Meritxell Bellet- Ezquerra, Cristina Hernando, Pablo Tolosa, Maria Vidal, Yolanda Fernández, Santiago González-Santiago, Pilar Sanchez, Susana De La Cruz, Vanesa Ortega, Xavier Gonzalez-Farré, Milana Bergamino, Alejandra Espinosa, Tomás Pascual. A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial [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 PO3-19-08.

Abstract PO3-04-12: SUMIT-BC: Phase 2 randomized study of fulvestrant with or without the cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. In an initial single-arm evaluation samuraciclib (CT7001), a once daily (QD) oral CDK7 inhibitor has demonstrated a favourable safety profile and clinical activity in combination with fulvestrant, a selective estrogen receptor degrader (SERD), in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor. There was evidence of enhanced benefit in patients with no detectable TP53 mutation from baseline circulating tumor DNA (ctDNA) analysis and in patients without baseline liver metastases [1]. Samuraciclib is associated with low grade gastrointestinal (GI) adverse events such as nausea, vomiting and diarrhea managed with simple prophylaxis and patient counselling. An instant release capsule formulation was used in the initial clinical evaluation of samuraciclib requiring patients to take multiple capsules designed to rapidly release a large amount of material high in the GI tract. In this study a novel single tablet formulation will be administered which may enhance GI tolerability (2). This Phase 2 open-label randomised study will evaluate the efficacy, safety, pharmacokinetics and Quality of Life (QoL) impact of samuraciclib in combination with fulvestrant in comparison to a fulvestrant monotherapy control arm. Consistent with the principles of the current Project OPTIMUS initiative, 2 dose levels of samuraciclib will be evaluated [3]. All patients will undergo baseline ctDNA evaluation of TP53 mutation status to permit a prospective evaluation of its patient selection biomarker potential. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. All patients will undergo baseline Guardant360 ctDNA analysis to establish their TP53 mutation status among others. 60 patients will be enrolled and will all receive fulvestrant 500mg IM administered on days 1, 15 and 29 and then monthly thereafter. Patients will be randomized 1:1:1 to fulvestrant alone, fulvestrant and samuraciclib 240mg QD or fulvestrant and samuraciclib 360mg QD. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. The pharmacokinetics of samuraciclib and fulvestrant will be studied though the first 6 months of the study, with highest intensity during month 1. To evaluate Quality of Life (QoL) The Functional Assessment of Cancer Therapy -Breast questionnaire (FACT-B) will be completed. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and the pharmacokinetics of fulvestrant and samuraciclib. QoL and correlations between ctDNA detectable TP53 mutations and efficacy/safety finding in this patient population will be reported. The study opened for recruitment in June 2023.

Abstract ED09-01: Emerging approaches to targeting pathways using precision medicine in breast cancer

Abstract The past few decades have yielded significant strides forward in the pursuit to extend survival for patients with breast cancer. Much of this success is directly attributed to breakthroughs in the development of targeted therapies intersecting advances in genomic medicine. Despite these achievements, challenges remain, and targeted therapeutic development is still evolving rapidly to offset them. The focus of this educational session is centered around reviewing the latest in targeted therapeutic advancements and precision medicine. Recent advances have centered on novel selective estrogen receptor degraders (SERDs) for advanced ESR1-mutated or endocrine-resistant disease. Antibody-drug conjugates (ADCs) continued to make gains, targeting HER2-positive/low advanced cancers as well as an expanded indications for TROP2-targeted ADCs. New ADCs are also on the horizon leveraging new cell surface targets. Emerging are forward-looking cell-surface methodologies that harness bispecific antibodies and T-cell engagers. Various strategies combining established targeted immunotherapies such as PD-1 and PD-L1 with additional therapies continue. Attempts to target the frequently mutated PI3K pathway have yielded some success, but clinical exploration continues using new approaches that utilize mutation specific inhibitors. Second generation PARP inhibitors have emerged recently and are being explored in a variety of indications with promising early results. Finally, understanding treatment resistance in particular with the use of longitudinal liquid biopsies is fueling further target discovery. Altogether, development in precision medicine is advancing rapidly with advanced genomics, novel targets, and cutting-edge drug modalities. Citation Format: M. Radovich. Emerging approaches to targeting pathways using precision medicine in 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 ED09-01.

Abstract PO1-05-08: Enhanced ER+ tumor growth inhibition of fulvestrant from effective oral delivery yielding elevated plasma concentrations

Abstract Fulvestrant has been a backbone of endocrine therapy (ET) for ER+/HER2- metastatic breast cancer (mBC) for over 20 years due to its nanomolar potency, purely antagonistic behavior, and well-tolerated adverse event (AE) profile. It remains the only selective estrogen receptor degrader (SERD) approved in ER+/HER2- mBC regardless of ESR1 mutation status. While ESR1 mutations reduce fulvestrant binding affinity, they do not implicitly lead to acquired resistance as with aromatase inhibitors (AIs) and can be overcome by increasing exposure.1 Further, preclinical evidence suggests that higher exposure to fulvestrant correlates with higher efficacy in rodents.2 Unfortunately, fulvestrant is currently delivered at its maximum feasible dose due to its poor solubility and a lack of effective drug delivery technologies. In response, several novel oral SERDs have been brought into clinical development to improve upon the efficacy of fulvestrant. However, multiple have failed to prove superior to fulvestrant in its intramuscular (IM) injection formulation and improvements from elacestrant (EMERALD) and camizestrant (SERENA-2) are largely attributed to patients with ESR1 mutations after prior ETs. Therefore, enabling higher exposure of fulvestrant could prolong progression-free survival and improve quality of life for ET-naïve mBC patients and those that have progressed on ETs. VeraMorph has leveraged a proprietary oral drug delivery technology to overcome the limitations of fulvestrant’s poor solubility and potentially help mitigate acquired resistance by improving exposure via daily oral dosing. The oral dosages, which consist of a novel polymer-based soft gummy, stabilize fulvestrant in simulated intestinal media up to 5 mg/mL without influencing fulvestrant permeability or causing cytotoxic effects. Pharmacokinetic (PK) studies of oral fulvestrant in rodents have demonstrated maximum plasma concentrations up to 450 ng/mL, a level roughly 20 times that of the average exposure from the monthly IM formulation in clinical settings. PK studies also demonstrated that oral exposure increased with a roughly dose-proportional relationship, with a reduction in AUC from day 1 to day 8 upon repeat dosing. In a cell-derived xenograft (CDX) study utilizing ER+ MCF-7 tumors implanted in athymic nude mice, once daily dosing via oral gavage of oral fulvestrant at 125 mg/kg was able to achieve a statistically significant 55% reduction in tumor growth by day 42 relative to a 50 mg/kg dose of the IM formulation delivered subcutaneously once per week, which was determined to create an equivalent exposure to the monthly IM human dose in separate studies. Oral fulvestrant yielded no observed adverse effects up to 125 mg/kg in both the 42-day CDX study in mice or an 8-day safety study in rats. Further, onset of action and acquired resistance are being tested by monitoring cell viability (via the MTT assay) with MCF-7 cells exposed to time profiles of fulvestrant exposure resembling oral and monthly intramuscular delivery. The study demonstrated that oral dosing reaches minimal cell viability 1-2 weeks faster than IM dosing. Also, preliminary data suggests that the onset of acquired resistance (as demonstrated by a resumption of cell growth) may occur faster from the steady exposure of IM dosing relative to the modulation of daily oral dosing. These results suggest that oral fulvestrant has the potential to finally realize the full potential of fulvestrant as an effective ET for metastatic breast cancer with a well-tolerated AE profile, enhanced efficacy, and reduced susceptibility to acquired resistance with applicability across all mBC patients. 1 Brett JO, Spring LM, Bardia A, Wander SA (2021) Breast Cancer Research, 23(1):1–15. 2 Wardell SE, et. al. (2020) Breast Cancer Research and Treatment, 179(1):67–77. Citation Format: Doug Godfrin, Matthew Butchbach. Enhanced ER+ tumor growth inhibition of fulvestrant from effective oral delivery yielding elevated plasma concentrations [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 PO1-05-08.

Abstract PO3-25-09: OKI-219, a PI3KαH1047R-mutant-selective inhibitor demonstrates efficacy as a single agent and drives combination responses with standard of care therapies in pre-clinical PI3KαH1047R mutant breast cancer models

Abstract Mutations in PI3Kα lead to constitutive activation of the PI3K/AKT/mTOR pathway and are highly prevalent in cancer. PI3KαH1047R is the most common amino acid substitution mutation and represents approximately one-third of all PI3Ka mutations, with 15% of breast cancers having a PI3KαH1047R mutation. In breast cancer, PI3KαH1047R mutations are associated with resistance to targeted therapies, including HER2- and estrogen receptor (ER)- targeted agents. Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme. This often leads to dose modification or discontinuation. Therefore, there is a significant need to develop new PI3Kα-targeted therapies that can avoid or minimize on-target toxicity and improve the safety and clinical benefit for patients. OKI-219 is an orally bioavailable, PI3KαH1047R mutant-selective inhibitor, with ~100-fold cellular selectivity for the H1047R mutation over wild-type. OKI-219 demonstrates selectivity across a panel of 412 kinases, with no other kinases showing >30% inhibition at 1 µM. In vitro, OKI-219 drives decreased phosphorylated AKT (pAKT) and decreased proliferation specifically in PI3KαH1047R mutant cell lines across several tumor types, including breast cancer. In vivo, as a monotherapy, OKI-219 demonstrates dose dependent antitumor activity in multiple human tumor xenograft models, including the H1047R mutant breast cancer CDX models T47D and HCC1954 and several PDX models, with regression rates up to 100% at doses that show no sign of the metabolic dysfunction (increased glucose or insulin) associated with wild-type protein inhibition. The in vivo antitumor activity correlates with pathway inhibition, measured by decreased pAKT in tumors. Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate that OKI-219 offers improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. OKI-219 is advancing into clinical trials. Citation Format: Molly A. Taylor, Qian Zhao, David Mareska, Maria Hoh, Yevgeniy Izrayelit, Kevin Litwiler, Mark L Boys, Rich Woessner, Duncan Walker, James D Winkler, Jennifer Diamond. OKI-219, a PI3KαH1047R-mutant-selective inhibitor demonstrates efficacy as a single agent and drives combination responses with standard of care therapies in pre-clinical PI3KαH1047R mutant breast cancer models [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 PO3-25-09.

Abstract PO4-27-05: A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations

Abstract Background: Estrogen receptor (ER) signaling sits at center of the tumor biology in ER+/HER2- breast cancers. Current standard of care involves hormone therapy with agents including selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Unfortunately, most patients eventually develop resistance to these therapies. Mutations in estrogen receptor 1 (ESR1) are partially responsible for the acquired resistance. Mutated estrogen receptors are still sensitive to fulvestrant but with a much less sensitivity. In January 2023, elacestrant received its first approval for the treatment of postmenopausal women or adult men with breast cancer harboring ESR1 mutations in US. However, there is still great unmet medical need for this population. FWD1802 is a third-generation oral SERD for ER-positive breast cancer patients. It binds competitively to ER, with a much higher affinity than that of fulvestrant. Preclinically, FWD1802 alone and in combination with palbociclib exhibits significant anti-tumor activity in the ER+/HER2- models and in ESR1-mutated models in vitro and in vivo. This ongoing phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and clinical activity of FWD1802 as monotherapy and in combination with palbociclib in ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations. Methods: This clinical study (CTR20232130) consists of three parts: monotherapy dose escalation (Part A), dose escalation in combination with palbociclib (Part B) and monotherapy dose expansion in ESR1-mutated patients (Part C). A conventional “3+3” design is used for this study. Approximately a total of 129 patients will be enrolled. FWD1802 is administered orally daily. In monotherapy dose escalation study (Part A), at each dose level, a single ascending dose (SAD) is followed by a 28-day continuous multiple ascending dose (MAD) period (defined as 1 cycle). In Part B dose, palbociclib (125 mg daily) is administered on a 28-day treatment cycle with 21-day on treatment and 7-day off treatment, along with the 28-day treatment cycle of FWD1802. The primary objectives include dose limiting toxicity (DLT), maximum tolerated dose (MTD), safety, tolerability, and the recommended phase 2 dose (RP2D) of FWD1802. Secondary objectives include pharmacokinetics characteristics of FWD1802 and its major metabolite as monotherapy and in combination with palbociclib. Preliminary anti-tumor activity including objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS) will also be evaluated. DLT evaluation will be conducted after the first cycle of multi-dose period, and tumor assessment will be conducted every 8 weeks by investigators according to RECIST version 1.1. Patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutation are eligible for the enrollment. Enrolled patients should have progressed disease, or failed from previous therapy, or intolerable or inaccessible to standard therapy. In addition, patients with ECOG score ≤1 and with adequate renal, cardiac, hepatic, and hematologic function are eligible for enrollment. The monotherapy dose escalation (Part A) is currently ongoing. The dose selection for Part B and Part C will be based on the data from the ongoing Part A. Clinical trial information: CTR20232130. Research Sponsor: Shenzhen Forward Pharmaceuticals Co., Ltd. (FORWARD PHARMA). Citation Format: Ling Zeng, Jin Liu, Dan Wu, Huiwen Ge, Zirui Bian, Chenggang Zhu. A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations [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 PO4-27-05.

Abstract PS12-09: Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292

Abstract Background AKT pathway activation is implicated in endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance in patients (pts) with HR+/HER2– advanced breast cancer (ABC). In CAPItello-291, capivasertib (C, a potent inhibitor of all 3 AKT isoforms) + fulvestrant (F) significantly improved PFS versus placebo F in pts with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of AKT and CDK4/6 pathways may delay CDK4/6i resistance or re-sensitize tumors to ET plus CDK4/6i, leading to improved clinical outcomes. CAPItello-292 (NCT04862663) is an ongoing Phase 1b/3 study examining the efficacy and safety of C + CDK4/6i (palbociclib [P], ribociclib [R]) + F in HR+/HER2– ABC. The recommended Phase 3 dose (RP3D) of C+P+F has been determined (C 400 mg BID, 4 days on/3 days off, P 125 mg, F 500 mg). Here we report ongoing Phase 1b data on C+P+F and C+R+F. Methods: Phase 1b of CAPItello-292 uses a keyboard design (mTPI-2) with the following planned doses: C 200 mg, 320 mg, 400 mg; P 75 mg, 100 mg, 125 mg; R 200 mg, 400 mg, 600 mg; F is fixed at 500 mg every 28 days + loading dose on cycle 1 day 15. Starting doses for C+P+F were C 320 mg BID, 4 days on/3 days off, P 125 mg QD) for 21 days of each 28-day cycle. Starting doses for C+R+F (ongoing) are C 400 mg BID, 4 days on/3 days off, R 400 mg QD for 21 days of each 28-day cycle. Eligible pts have HR+/HER2− ABC and ≥1 prior ET in the advanced setting or disease recurrence within 12 months of completing (neo)adjuvant ET (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Prior use of CDK4/6i, selective estrogen receptor degraders, and chemotherapy is permitted in Phase 1b. Phase 1b primary objectives: assess safety/tolerability; confirm RP3D. Objective response and clinical benefit rates (24 weeks; RECIST v1.1) were also assessed. Results: At data cut-off (Apr 21, 2023), 40 pts (median age: 58.5 years [range 38–82]) who were heavily pre-treated (as follows: 82.5% [33/40] prior CDK4/6i; 47.5% [19/40] prior F; 70.0% [28/40] prior chemotherapy [median 1.5 lines]) were treated with C+P+F. No new dose-limiting toxicities (DLTs) were observed since determination of RP3D. The most frequent adverse events (AEs) occurring in >40% of pts were diarrhea (70.0% [28/40]; 1/28 grade [G] ≥3), neutropenia (55.0% [22/40]; 20/22 G≥3), fatigue, and nausea (both 42.5% [17/40]; all G1/2). Hyperglycemia occurred in 17.5% (7/40) pts (1/7 G3). No treatment-related deaths or new safety risks were identified. At the RP3D, the median (range) duration of exposure to C was 8.6 months (1.7–14.1); 5/8 pts with measurable disease at baseline had confirmed partial response (objective response rate: 62.5%, 95% confidence interval [CI] 24.5–91.5). Two additional pts had stable disease ≥7 weeks as a best objective response. At 24 weeks, the clinical benefit rate was 53.8% (7/13; 95% CI 25.1–80.8).Enrollment into C+R+F is ongoing: as of May 05, 2023, 8 pts had been dosed (6/8 pts had completed cycle 1). Based on clinical and safety review, the safety review committee has endorsed dose escalation to the highest dose level of R; no DLTs have been reported so far, although data are preliminary.Preliminary ctDNA analyses of pts treated with C+P/R+F will be presented. Conclusions: C+P+F was tolerable in heavily pre-treated pts with HR+/HER2– ABC at all dose levels; AEs were as expected, given the known safety profile of the individual treatments. Evidence of clinical activity has been observed in pts treated with the RP3D; data collection is ongoing. Preliminary safety analysis of C+R+F suggests no critical tolerability concerns; more pts and longer follow-up is required to characterize the safety of the combination. Updated data will be presented. Funding: AstraZeneca Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited) Citation Format: Erika Hamilton, Patrick Neven, Barbara Pistilli, Muralidhar Beeram, Virginia Borges, Mario Campone, José Luiz Miranda Guimarães, Theodoros Foukakis, Annette Raskov Kodahl, Peter Lau, Elgene Lim, Iwona Ługowska, Greg Rychlik, Christopher Gresty, Claire Miller, Roberto Sommavilla, Dhivya Sudhan, Hope Rugo. Capivasertib plus cyclin-dependent kinase 4/6 inhibitor and fulvestrant in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated Phase 1b analysis from CAPItello-292 [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 PS12-09.

Abstract PO3-18-09: 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 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.

Abstract PO2-20-03: VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. In the phase 2 portion (VERITAC) of a first-in-human phase 1/2 study (NCT04072952), vepdegestrant 200 mg once daily (QD) was well tolerated and had clinical activity in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer and was selected as the recommended phase 3 dose (RP3D) for vepdegestrant monotherapy. A phase 1b cohort of the phase 1/2 study is evaluating the safety and clinical activity of vepdegestrant plus palbociclib in patients with ER+/HER2- breast cancer after prior endocrine-based therapy; prior cyclin-dependent kinase (CDK)4/6 inhibitor therapy was permitted. Preliminary results showed encouraging activity for the combination based on clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks); an increase in palbociclib exposure was observed relative to historical palbociclib pharmacokinetic data and was accompanied by a higher incidence of grade 3/4 neutropenia compared with prior palbociclib and endocrine therapy combination studies, which was managed by monitoring and standard palbociclib dose modifications. The global, randomized phase 3 VERITAC-3 study (NCT05909397) will compare the efficacy and safety of vepdegestrant plus palbociclib vs letrozole plus palbociclib as first-line treatment for patients with ER+/HER2- advanced breast cancer. An open-label study lead-in (SLI) will evaluate the safety and tolerability of vepdegestrant 200 mg QD plus 2 doses of palbociclib (100 mg QD and 75 mg QD) in patients with ER+/HER2- advanced breast cancer to select the RP3D of palbociclib for this combination. Trial Design: Approximately 50 and 1130 patients will be enrolled in the SLI and the phase 3 parts of the study, respectively. Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). Patients with measurable disease per RECIST v1.1 or nonmeasurable bone-only disease are eligible. Patients with disease recurrence during or ≤12 months after completion of adjuvant endocrine therapy are excluded. For the SLI, patients are randomized 1:1 to receive vepdegestrant 200 mg QD in combination with palbociclib 100 mg QD or 75 mg QD and are treated in 28-day cycles with vepdegestrant given continuously and palbociclib given for 21 days followed by 7 days off treatment. The objective of the SLI is to identify the RP3D of palbociclib in combination with vepdegestrant, which will be determined through the primary outcome measures of incidence of grade 4 neutropenia, study drug dose reduction, and study drug discontinuation within the first 4 cycles of treatment. Secondary outcome measures include safety, antitumor activity (objective response rate, CBR, and duration of response), and plasma concentrations of study drugs. In the planned phase 3 portion of the trial, patients will be randomized to vepdegestrant plus palbociclib or letrozole plus palbociclib. The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing. Citation Format: Seth Wander, Erika Hamilton, Mario Campone, Michael Danso, Sara Hurvitz, Hiroji Iwata, Colombe Chappey, Derek Yang, Julia Perkins Smith, Yuan Liu, Yuanyuan Zhang, Sibyl Anderson, Michelino de Laurentiis. VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced 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 PO2-20-03.

Abstract PO4-04-12: 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 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.

Abstract PO2-27-01: TFX06, a next-generation oral CERAN/SERD, shows favorable safety and PK profile, extracranial and intracranial efficacy in patients with ER+/HER2- breast cancer: Preliminary results from a phase 1/2 first-in-human trial

Abstract Aims: TFX06 is an investigational oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) (Wu J, et al., 2023 AACR annual meeting). A Phase 1/2, multicenter, open-label dose-escalation and dose-expansion study (CTR20230789) was initiated in China to evaluate TFX06 in previously heavily treated patients with ER+/HER2- locally advanced and/or metastatic breast cancer. The primary objectives were to assess safety and tolerability, recommended Phase 2 dose (RP2D), and pharmacokinetics (PK). Methods: A 3+3 dose-escalation design was implemented. TFX06 tablets were orally administered at 60 mg/100 mg daily for 28 days of treatment cycle until disease progression or intolerant to TFX06. As of the cut-off date (Sept. 15, 2023), the Phase 1 study enrolled five patients with Stage IV diseases with distant metastases. Three were treated with TFX06 at 60 mg, the starting dose and two at the next dose level of 100 mg. Median age of patients were 50 years (39-65) with a ECOG score of 0-1. Two out of five patients carried estrogen receptor 1 (ESR1) mutations (ctDNA). Prior anticancer treatments included one or two lines of endocrine therapies, including fulvestrant, and/or one or two lines of chemotherapies. Clinical responses by investigator according to RECIST v1.1 were performed every two cycles to explore preliminary efficacy. Results: Three patients in 60 mg and one in 100 mg dose cohorts completed dose-limiting toxicity (DLT) observation period. No DLT observed. All treatment related adverse events (TRAEs) were grade 1-2 in severity, including nausea, drowsiness, decreases in WBC and neutrophils, and anemia. Analyses of plasma concentrations of TFX06 in all three patients receiving 60 mg revealed a similar PK profile with small variations in Cmax. The average steady-state Cmax and Cmin of TFX06 were 101 ng/mL and 65 ng/mL, respectively, and the Cmax of TFX06 was approximately 4-fold higher than that of fulvestrant administered intramuscularly at 500 mg in clinic (28 ng/mL). Two patients in the 60 mg cohort were evaluable for response assessment. One patient discontinued due to progressive disease (PD) after two cycles of treatment. This patient experienced a 17.1% decrease in target lesions in the lung; however, new metastases to bone observed. The other patient who carried ESR1 D538G mutation showed a decrease of 91% in ESR1 mutation burden 8 days after treatment, and a decrease of 34.2% in target lesions (partial response, PR), including a substantial shrinkage of 78.6% in the brain lesion (target lesion), as well as complete responses (CR) of non-target lesions in lung after 4 cycles of treatment. This patient remains on the study as of the cut-off date. Conclusions: Based on the preliminary results, oral administration of TFX06 at 60 or 100 mg once daily had favorable safety and PK profiles. TRAEs, such as gastrointestinal toxicities, bradycardia, and visual disturbances were not observed. Pleasingly, TFX06 demonstrated early extracranial and intracranial antitumor activity (PR) in a patient with a brain metastasis. Citation Format: Zhaojian Fu, Zhiye Zhang, Jia Song, Yang Chen, Douglas Fang, Wei Sha, Jian Zhang, Charles Ding. TFX06, a next-generation oral CERAN/SERD, shows favorable safety and PK profile, extracranial and intracranial efficacy in patients with ER+/HER2- breast cancer: Preliminary results from a phase 1/2 first-in-human trial [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 PO2-27-01.

Abstract PO1-19-12: VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. Vepdegestrant directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study (NCT04072952), vepdegestrant monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The global, randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of vepdegestrant vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Trial design: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N≈560) are randomized 1:1 to receive vepdegestrant 200 mg orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation subpopulation. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Citation Format: Mario Campone, Cynthia Ma, Michelino de Laurentiis, Hiroji Iwata, Sara Hurvitz, Seth Wander, Michael Danso, Dongrui Lu, Julia Perkins Smith, Yuan Liu, Lana Tran, Sibyl Anderson, Erika Hamilton. VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced 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 PO1-19-12.

Abstract PS15-02: A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor (ER)-positive advanced breast cancer (BC). D-0502, an orally bioavailable selective estrogen receptor degrader (SERD), has previously demonstrated antitumor activity in various ER-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer cell lines and xenograft models. The phase Ⅰ open-label study (NCT03471663) evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of D-0502 as monotherapy and in combination with palbociclib in female patients with ER+ and HER2- breast cancer. The dose escalation part of D-0502 monotherapy (phase Ⅰa) has been presented before (SABCS 2021, PS11-26 Abstract #1348). Here, we present the results of D-0502 monotherapy from the dose-expansion stage in phase Ⅰb study. Methods: In the single-agent dose-expansion stage of phase Ⅰb study, patients (n=60) received D-0502 (400 mg QD) in 28-day cycles. Eligible patients included females with confirmed ER+, HER2- locally advanced, or metastatic BC; ECOG 0-1; measurable disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. The primary objectives are to characterize the safety of D-0502. The secondary objectives are to evaluate the preliminary anti-tumor activity and the PK characteristic. Results: As of April 07, 2023, 60 female patients were enrolled and treated with 400mg single-agent D-0502. Median age was 57 (range: 32-82) years, 55.0% had an ECOG PS of 1. Disease progression resulting in treatment discontinuation occurred in 66.7% (40/60) of patients, and 6.7% (4/60) of patients discontinued treatment because of AEs. Treatment-related adverse events (TRAEs) were reported in 57 pts (95.0%), most of which were grade 1-2. No grade 4/5 TRAE has been reported. The incidence of serious adverse events was 6.7% (4/60). The most common (≥ 15%) TRAEs included vomiting, dizziness, nausea, increased aspartate aminotransferase and alanine aminotransferase, anaemia, decreased appetite, diarrhoea, and malaise. In the 51 efficacy evaluable patients, 8 patients had partial response (PR) and 27 had stable disease (SD); objective response rate (ORR) and disease control rate (DCR) were 15.7% (8/51) and 68.6% (35/51), respectively. The clinical benefit rate (CBR: CR + PR + SD ≥24 weeks) was 47.1% (24/51). The median PFS was 5.6 months (95% Cl: 2.0, 10.0). Conclusion: D-0502 monotherapy showed promising antitumor activity and tolerable toxicity in female patients with ER+ and HER2- locally advanced or metastatic BC. Currently this treatment is being evaluated in a phase Ⅲ study for patients with ER+ and HER2- locally advanced or metastatic BC in China. Citation Format: Jiayu Wang, Tao Sun, Qingyuan Zhang, Yanxia Shi, Xu Wang, Yiding Chen, Quchang Ouyang, Kunyan Li, Manojkumar Bupathi, w. Jeffery Edenfield, Andrea L.M. Silber, Hong Zong, Erika Hamilton, Dejan Juric, Kate Lathrop, Yihong Zhang, Kathryn Stazzone, Zhe Shi, Yaolin Wang, Ling Zhang, Binghe Xu. A Phase Ⅰb Study of D-0502 as Monotherapy for Advanced or Metastatic ER-Positive and HER2-Negative Breast Cancer: Results from the Dose-Expansion Stage [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 PS15-02.