amcenestrant (SAR439859) / Sanofi - LARVOL DELTA

Serum estradiol (sE2) levels in premenopausal (PreM) women receiving neoadjuvant ovarian function suppression (OFS) with the oral SERD amcenestrant, alone, or in combination with letrozole or abemaciclib in the I-SPY2 Endocrine Optimization Pilot (EOP). (ASCO 2025) - P2 | "Clinical Trial Registration Number: NCT01042379 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Combination therapy • Breast Cancer • Oncology • Solid Tumor

Synthesis of Amcenestrant (SAR439859): A Copper-Catalyzed Cross-Coupling Reaction as a Sustainable Alternative to Palladium-Catalyzed Suzuki Reaction. (PubMed, Org Lett) - "A cross-coupling reaction between an enol triflate and an aryl Grignard reagent using a copper catalyst, followed by a deprotection step, a Mitsunobu reaction, and a saponification, allowed for the synthesis of Amcenestrant (SAR439859). This approach, avoiding an expensive and toxic transition metal, is as efficient as the classical route but less expensive for accessing this selective estrogen-receptor degrader (SERD)."

Journal • ER

Pre-Clinical Rationale for Amcenestrant Combinations in HER2+/ER+ Breast Cancer. (PubMed, Int J Mol Sci) - "In this study, the pre-clinical rationale is explored for combining amcenestrant (Amc), a selective oestrogen receptor degrader (SERD), with HER2-targeted therapies including trastuzumab, trastuzumab-emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs)...Additivity and synergy were observed between Amc and the TKIs neratinib, lapatinib and tucatinib in all cell lines...Higher ER expression in MDA-MB-361 and BT-474-T was associated with greater potential for synergy. In conclusion, the combination of Amc- and HER2-targeted treatments has potential as a therapeutic strategy for the treatment of HER2+/ER+ breast cancer and warrants further clinical investigation to validate safety and efficacy in patients."

Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • ER • HER-2

Transcriptomic Analysis in Liver Spheroids Identifies a Dog-Specific Mechanism of Hepatotoxicity for Amcenestrant. (PubMed, Toxicol Sci) - "Analysis of liver samples from a three-month dog toxicity study conducted with amcenestrant showed downregulation of several genes associated with PXR and FXR, corroborating the in vitro results. These results support the hypothesis that dogs are uniquely susceptible to cholestatic hepatotoxicity following administration of amcenestrant due to species-specific antagonism of FXR and highlight the value of in vitro liver spheroids to investigating mechanisms of toxicity and possible species differences."

Journal • Cholestasis • Hepatology • Liver Failure • ER

AMEERA-3: Phase 2 Study of Amcenestrant (SAR439859) Versus Physician's Choice in Locally Advanced or Metastatic ER-positive Breast Cancer (clinicaltrials.gov) - P2 | N=367 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Sponsor decision to prematurely stop the study, not linked to any safety concern.

Monotherapy • Trial termination • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

New Oral Selective Estrogen Receptor Degraders Redefine Management of Estrogen Receptor-Positive Breast Cancer. (PubMed, Annu Rev Med) - "There are currently five oral SERDs in published and ongoing clinical trials-elacestrant, camizestrant, giredestrant, imlunestrant, and amcenestrant-with more in development. They offer a reasonably well-tolerated oral therapy option with low discontinuation rates in studies. This review summarizes the currently available literature on this new class of drugs."

Journal • Review • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Evaluation of Orally Administered Amcenestrant (SAR439859) in Japanese Postmenopausal Patients With Advanced Breast Cancer (AMEERA-2) (clinicaltrials.gov) - P1 | N=10 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Sponsor decision to prematurely stop the study, not linked to any safety concern.

Monotherapy • Trial termination • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-1: Phase 1/2 Study of Amcenestrant (SAR439859) Single Agent and in Combination With Other Anti-cancer Therapies in Postmenopausal Women With Estrogen Receptor Positive Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=136 | Terminated | Sponsor: Sanofi | Trial completion date: Dec 2027 ➔ Nov 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2027 ➔ Nov 2024; Sponsor decision to prematurely stop the study, not linked to any safety concern.

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Oral SERDs changing the scenery in hormone receptor positive breast cancer, a comprehensive review. (PubMed, Cancer Treat Rev) - "Oral SERDs constitute an exciting new drug class. Ongoing and future research will further refine the role of these drugs next to standard endocrine treatments and targeted therapies."

Journal • Review • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER

DN-ODE: Data-driven neural-ODE modeling for breast cancer tumor dynamics and progression-free survivals. (PubMed, Comput Biol Med) - "To validate this approach, experiments are conducted with early-phase clinical trial data from the Amcenestrant (an oral treatment for breast cancer) dataset (AMEERA 1-2), aiming to predict pharmacodynamics in the later phase (AMEERA 3)...We also introduce Principal Component Analysis visualizations for encoder results, demonstrating the DN-ODE's capability to discern individual distributions and diverse tumor growth patterns. Therefore, DN-ODE facilitates comprehensive drug efficacy assessments, pinpoints potential responders, and aids in trial design."

Journal • Breast Cancer • Infectious Disease • Oncology • Solid Tumor

Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Primary Results From AMEERA-5. (PubMed, J Clin Oncol) - P3 | "The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified."

Journal • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Primary Results From AMEERA-5 (J Clin Oncol) - P3 | N=1,068 | AMEERA-5 (NCT04478266) | Sponsor: Sanofi | "Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively."

P3 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

I-SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant amcenestrant +/- abemaciclib +/- letrozole in molecularly selected patients (pts) with HR+ HER2- stage 2/3 breast cancer (BC). (ASCO 2024) - P2 | "Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy."

Clinical • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • ER • HER-2

AMEERA-3: Phase 2 Study of Amcenestrant (SAR439859) Versus Physician's Choice in Locally Advanced or Metastatic ER-positive Breast Cancer (clinicaltrials.gov) - P2 | N=367 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Mar 2024 ➔ Sep 2024

Metastases • Monotherapy • Trial completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Joint modeling of tumor dynamics and progression-free survival in advanced breast cancer: Leveraging data from amcenestrant early phase I-II trials. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "We demonstrated that the instantaneous rate of change in TS (TS slope) was an important predictor of PFS and the developed joint model was able to predict well the PFS of amcenestrant phase II monotherapy trial using only early phase I-II data. This provides a good modeling and simulation tool to inform early development decisions."

Journal • Metastases • P1/2 data • Breast Cancer • Oncology • Solid Tumor

Pharmacological insights on novel oral selective estrogen receptor degraders in breast cancer. (PubMed, Eur J Pharmacol) - "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."

Journal • Review • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-3: Phase 2 Study of Amcenestrant (SAR439859) Versus Physician's Choice in Locally Advanced or Metastatic ER-positive Breast Cancer (clinicaltrials.gov) - P2 | N=367 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Dec 2023 ➔ Mar 2024

Metastases • Monotherapy • Trial completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Evaluation of Orally Administered Amcenestrant (SAR439859) in Japanese Postmenopausal Patients With Advanced Breast Cancer (AMEERA-2) (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Nov 2023 ➔ Nov 2024

Metastases • Monotherapy • Trial completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-4: a randomized, preoperative window-of-opportunity study of amcenestrant versus letrozole in early breast cancer. (PubMed, Breast Cancer Res) - P2 | "Both amcenestrant and letrozole demonstrated antiproliferative activity in postmenopausal women with previously untreated, operable ER+/HER2- breast cancer and had good overall tolerability."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Solid Tumor • ER • HER-2

Second generation oral selective estrogen receptor degraders (SERDs) in breast cancer: A systematic review and meta-analysis of clinical trials (ESMO 2023) - "SERD plus Palbociclib resulted in higher rates of AEs (p<0.01). Table: 481P Characterization of ESR1mut and response to SERD (Amcenestrant, Elacestrant, and Camizestrant) Conclusions Our study supports the favorable safety profile of the new generation oral SERD and presents its efficacy according to ESR1mut. Further studies shall assess the potential biomarker role of individual ESR1mut."

Retrospective data • Review • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-3: Phase 2 Study of Amcenestrant (SAR439859) Versus Physician's Choice in Locally Advanced or Metastatic ER-positive Breast Cancer (clinicaltrials.gov) - P2 | N=290 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Sep 2023 ➔ Dec 2023

Metastases • Monotherapy • Trial completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer. (PubMed, J Clin Oncol) - P2 | "AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC."

Journal • Metastases • Monotherapy • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer (J Clin Oncol) - P2 | N=290 | AMEERA-3 (NCT04059484) | Sponsor: Sanofi | "Between October 22, 2019, and February 15, 2021, 290 patients were randomly assigned to amcenestrant (n = 143) or TPC (n = 147). PFS was numerically similar between amcenestrant and TPC (median PFS [mPFS], 3.6 v 3.7 months; stratified hazard ratio [HR], 1.051 [95% CI, 0.789 to 1.4]; one-sided P = .643). Among patients with baseline mutated ESR1; (n = 120 of 280), amcenestrant numerically prolonged PFS versus TPC (mPFS, 3.7 v 2.0 months; stratified HR, 0.9 [95% CI, 0.565 to 1.435]). Overall survival data were immature but numerically similar between groups (HR, 0.913; 95% CI, 0.595 to 1.403)."

P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Efficacy of oral selective estrogen receptor degraders (SERD)s in the treatment of estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC): A stratified analysis of the ESR1 wild type (wt) and mutant (mt) subgroups. (ASCO 2023) - "Amcenestrant revealed no significant PFS difference in the ESR1wt population (HR 1.197, 95% CI 0.857-1.670, p=0.291) when compared to ET. Additionally, a separate analysis of EMERALD was performed using KMSubtraction to derive survival data of the ESR1wt subgroup comparing Elacestrant vs Fulvestrant... Our results suggest that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup. These findings are in line with the recent FDA approval of Elacestrant for patients with ESR1mt tumours. >"

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

AMEERA-2: Evaluation of Orally Administered Amcenestrant (SAR439859) in Japanese Postmenopausal Patients With Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: May 2023 ➔ Nov 2023

Metastases • Monotherapy • Trial completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2