Orserdu (elacestrant)

P3, N=240, Not yet recruiting, MedSIR

Until 2023, fulvestrant was the only approved SERD; fulvestrant is administered intramuscularly, and in some cases may also have limited efficacy in the setting of certain ESR1 mutations. Elacestrant's recent approval sheds light on the use of biomarkers such as ESR1 to gauge a tumor's endocrine sensitivity. Ongoing therapeutic and correlative biomarker studies will offer new insight and expanding treatment options for patients with advanced breast cancer.

P2, N=80, Recruiting, Stemline Therapeutics, Inc. | Trial primary completion date: Feb 2024 --> Feb 2025

However, following the breast cancer-specific FDA approvals of alpelisib+fulvestrant for PIK3CA-mutant disease in 2019 and elacestrant for ESR1-mutant disease in 2023, a significant shift in Level 1 actionability was observed between EUR (45%) and AFR (34%) attributed in part to the paucity of PIK3CA (26.3% vs. 36.2% in EUR) and ESR1 (4.1% vs. 7.5% in EUR) oncogenic alterations in AFR.We further observed AFR with CRC to have lower prevalence of MSI-H (5.8% vs.10.7% in EUR), TMB (12.5% vs. 18.8% in EUR) and BRAF V600E (5.1% vs. 9% in EUR). Correspondingly, in 2023, 16.4% of AFR with CRC have Level 1 alterations compared to 25.4% of EUR. Moreover, while AFR have higher rates of KRAS mutations (57.2% vs. 42.6% in EUR), they have a lower prevalence of the standard care biomarker KRAS G12C (3.4% vs. 7% of KRAS-mutant CRC in EUR) further exacerbating the disparities in CRC clinical actionability.Taken together, here we demonstrate that a significant disparity exists in the clinical actionability landscape of AFR with cancer compared to EUR, largely due to differences in relative mutational frequencies of Level 1 genomic alterations.

Fulvestrant is the first approved SERD with proven efficacy and good tolerability in clinical practice...Elacestrant is an orally bioavailable SERD that has been recently approved by the FDA for postmenopausal women with ER+, human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Other molecules of the same class currently tested in clinical trials are amcenestrant, giredestrant, camizestrant, and imlunestrant. The current review article offers a detailed pharmacological perspective of this emerging drug class, which may help with their possible future clinical applications.

The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.

P2, N=48, Recruiting, SOLTI Breast Cancer Research Group | Not yet recruiting --> Recruiting

P3; Not yet recruiting --> Recruiting

Novel endocrine options including oral selective estrogen receptor down-regulators (SERDs) are in late phases of development, with elacestrant being the first oral SERD to be approved for ESR1-mutant mBC...Trastuzumab deruxtecan offers a novel therapeutic option for patients with HR+/HER2-low mBC and sacituzumab govitecan is a novel therapeutic option for patients with HR+/HER2- mBC, including those with unmet treatment need in the later-line endocrine-refractory setting. Data gaps still exist regarding optimal sequencing of these novel agents; additional studies into mechanisms of resistance in the metastatic setting would provide further insights. Herein, we describe the current treatment options for HR+/HER2- mBC, including the latest practice-impacting data, and provide commentary on future directions.

P2, N=176, Not yet recruiting, German Breast Group

ELA led to an incremental cost-effectiveness ratio (ICER) of $8,672,360/quality-adjusted life year (QALY) gained compared with SOC in the overall population and $2,900,560/QALY gained compared with fulvestrant (FUL) in the ESR1(estrogen receptor 1) mutation subgroup. The two ICERs of ELA were significantly higher than the willingness-to-pay (WTP) threshold values of $150,000/QALY. ELA was not cost-effective for the second-/third-line treatment of patients with ER+/HER2-A/MBC compared with SOC in the US.

P1/2, N=106, Recruiting, Stemline Therapeutics, Inc.

OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

P1/2, N=48, Recruiting, Carrick Therapeutics Limited | Phase classification: P1b/2 --> P1/2

P1/2, N=48, Recruiting, Carrick Therapeutics Limited

P1/2, N=322, Recruiting, Stemline Therapeutics, Inc. | Phase classification: P1b/2 --> P1/2

For more than 20 years, fulvestrant (given as an intramuscular injection) was the only SERD approved by the US Food and Drug Administration for the treatment of ER+/HER2- metastatic breast cancer, and a standard second-line therapy following progression on an AI. This review discusses (1) the importance of routine testing for ESR1 mutations after disease recurrence or progression and the role of liquid biopsy in this regard; (2) elacestrant, a novel oral SERD approved in 2023 for the treatment of postmenopausal women and adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following 1 or more lines of endocrine therapy (unlike other SERDs, elacestrant is not associated with cardiac or ocular toxicity); and (3) new agents in development, including SERDs and innovative molecules targeting the ER-PROTACs, SERCAs, and CERANs-currently being tested in early-phase trials in combination with targeted agents, including CDK4/6 inhibitors.

P2, N=400, Recruiting, QuantumLeap Healthcare Collaborative | Not yet recruiting --> Recruiting

The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes' biology, lack of standards and difficulties in proving clinical utility.

P1/2, N=106, Recruiting, Stemline Therapeutics, Inc. | Phase classification: P1b --> P1/2

P1, N=16, Not yet recruiting, Stemline Therapeutics, Inc.

"Natera, Inc...announced its personalized and tumor-informed molecular residual disease (MRD) test, Signatera, will be used in a new breast cancer study called TREAT ctDNA (EORTC 2129-BCG). This international, multi-center, randomized, phase III clinical trial is being conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group in collaboration with Natera and Menarini Group (Menarini), a leading international pharmaceutical and diagnostics company....The study will screen approximately 1,900 patients across more than 120 sites in 12 countries throughout Europe and is expected to launch before the end of the year."

CONCLUSION More than 20% of the ER-positive, HER2-negative breast cancer patients with metastatic disease are eligible for targeted treatment with elacestrant. In addition, the high prevalence of mutations detected in our cohort indicates that liquid biopsy NGS panel testing can be used to monitor treatment response, track the development of resistance, and identify emerging genetic alterations that may guide treatment adjustments or the selection of alternative targeted therapies in breast cancer patients.

The SOFT and TEXT studies demonstrated an increase diseasefree survival (DFS) with ovarian function suppression (OFS) plus tamoxifen or exemestane compared to tamoxifen alone...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...48 patients will be recruited in 9 sites within SOLTI Spanish network in 9 months period. This study is financially supported by Menarini-Stemline.

Detection of specific mutations influenced treatment decisions, such as eligibility for alpelisib or PARP inhibitors and might further facilitate treatment with elacestrant in future treatment lines after its approval in Germany. These findings demonstrate the clinical impact of cftDNA testing in guiding personalized treatment selection. Additionally, the identification of such somatic alterations within a registry study like PRAEGNANT presents a unique opportunity to consider enrolling these patients into biomarker-guided clinical trials.

Unlike Y537S, cells harboring mutations at the dimer interface maintain their sensitivity to Selective Estrogen Receptor Degraders (SERDs), including Fulvestrant, recently FDA-approved Elacestrant, and Camizestrant, as well as Selective Estrogen Receptor Modulators (SERMs) including Tamoxifen and Raloxifene. Collectively, our finding unveiled a new class of ER mutations that enforce receptor dimerization and activation of the ER signaling pathway. The discovery opens up a new therapeutic interventional possibility, suggesting that targeting dimerization could emerge as a new strategy to combat these malignancies.

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...If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study...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.

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...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.

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...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.

In the phase 1b portion of ELECTRA, dose level 1 and dose level 2 have been completed. No patients experienced DLTs in either dose level 1 or dose level 2, and the combination was considered feasible in the respective dose levels. Dose level 3 (elacestrant 400 mg QD + abemaciclib 150 mg BID) is proceeding.

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). 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.

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]. 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.

Also, for second-line treatment, pts who did not receive prior treatment with a CDK4/6i, the combination of fulvestrant with a CDK4/6i (palbociclib, abemaciclib, and ribociclib) are among the recommended treatment options for this pt population (NCCN, 2022)... ELEVATE (NCT05563220) is a phase 1b/2 clinical trial that will evaluate the safety and efficacy of elacestrant combined with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib... In the Phase 1b portion of ELEVATE, elacestrant is being combined with various targeted agents enabling oral-oral combinations to determine a RP2D. Recruitment is actively ongoing; safety and PK results will be presented at the meeting from the completed phase 1b cohorts.

Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of endocrine therapy, and prior CDK4/6i, were randomized 1:1 to receive elacestrant or SOC (aromatase inhibitor or fulvestrant). Elacestrant showed significantly greater PFS when prior treatment duration with CDK4/6i was at least 12 months, suggesting prior exposure to CDK4/6i is a surrogate marker for endocrine sensitivity. In this population, elacestrant demonstrated superior efficacy, compared to SOC, even in patients with concomitant PIK3CA or TP53 mutations, expression of HER2 low, or presence of liver and/or lung metastases. These results suggest an active ER-driven pathway for this group despite the presence of other resistance mechanisms, where single-agent oral elacestrant could be an attractive option compared to combination therapies or intravenous HER2 low-targeted ADCs.

The 2023 FDA approval of elacestrant for individuals with HR+/HER2-, ESR1-mutated breast cancer highlights the immediate need for timely and sensitive ESR1 mutation detection... Our prototype nucleic acid-based assay streamlines sample-to-answer within 24 hours using liquid biopsy samples and multiplex RT-qPCR ESR1 mutation detection. Expanding liquid biopsy mutational analysis to exosomal RNA and DNA facilitates the future path for practical applications for breast cancer treatment options.

Phase 1 and 3 trials showed elacestrant was safe and improved progression-free survival in patients with endocrine receptor 1 (ESR1) mutations who failed cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) plus 1 prior endocrine therapy compared with standard of care (SOC) (fulvestrant, anastrozole, letrozole, or exemestane monotherapy). Elacestrant is currently being studied in CDK 4/6 inhibitor naïve patients and as a component of combination therapy for first-line use which could lead to future indications. Elacestrant gained FDA approval in January 2023 and can be considered in patients with HR+ HER2- advanced breast cancer and ESR1 mutations who have progressed despite therapy with either CDK 4/6i plus aromatase inhibitors (AI) or fulvestrant or chemotherapy.

The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.

"The study was submitted under the new Clinical Trial Regulation, and it is expected to start the activation process in the fourth quarter of 2023....Twelve countries have been selected to participate in the trial (Italy, France, Belgium, Spain, Ireland, Cyprus, Germany, Greece, the Netherlands, Portugal, Sweden and Switzerland) with more than 120 sites expected to screen approximately 1960 patients. The randomised, open label, superiority phase III trial will evaluate whether elacestrant can delay the occurrence of metastasis or death compared to standard adjuvant endocrine therapy in patients with early-stage ER+/HER2- breast cancer and molecular relapse."

VERITAC-3 will compare vepdegestrant + palbociclib vs letrozole + palbociclib as 1st-line treatment in pts with ER+/HER2- locoregional recurrent/metastatic breast cancer; 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. In the phase 3 portion, pts (N≈1130) will be randomized to vepdegestrant + palbociclib or letrozole + palbociclib. The primary endpoint is PFS by BICR.

Outcomes included the number of deaths avoided, adverse events avoided, patients requiring subsequent treatment, fulvestrant administrations avoided, reduction in emergency room-, inpatient-, and outpatient visits, and the number of hours of missed work and impaired activity avoided. The model showed that among the explored patient population, treating patients with elacestrant resulted in a meaningful reduction of clinical events and HRU while showing improvements in work productivity and activities of daily living.

P2, N=174, Not yet recruiting, Northwestern University

SCR-6852 is a novel SERD with high potency in inducing ERα protein degradation and pure antagonistic activity on ERɑ signaling in vitro and in vivo. Due to the high brain penetrability, SCR-6852 could be used to treat breast patients with brain metastasis.