amcenestrant (SAR439859) / Sanofi - LARVOL DELTA

Oral selective estrogen receptor degraders in ER+/HER2- breast cancer: a systematic review with pooled analysis of metastatic randomized trials and narrative synthesis of adjuvant evidence. (PubMed, Front Oncol) - "We searched PubMed, Cochrane CENTRAL, and conference abstract archives (SABCS, ESMO, ASCO; 2020-2026) for Phase II/III randomized controlled trials comparing oral SERDs (giredestrant, imlunestrant, elacestrant, camizestrant, vepdegestrant, amcenestrant) with standard endocrine therapy in ER-positive, HER2-negative breast cancer. This evidence synthesis across the full breast cancer continuum offers a framework for clinical decision-making as oral SERDs expand from advanced to early-stage disease. https://www.crd.york.ac.uk/prospero/display_record.php, identifier CRD420261358420."

Journal • Retrospective data • Review • 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 • Targeted Protein Degradation • 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. (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

Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6). (ASCO 2022) - P3 | "Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022."

Clinical • 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

AMEERA-3, a phase II study of amcenestrant (AMC) versus endocrine treatment of physician's choice (TPC) in patients (pts) with endocrine-resistant ER+/HER2− advanced breast cancer (aBC) (ESMO 2022) - P2 | "Pts were randomized 1:1 to AMC 400 mg QD (4 x 100 mg capsules) or single agent TPC (fulvestrant, aromatase inhibitor, or tamoxifen) and stratified for the presence of visceral metastasis, prior CDK4/6 inhibitor (i), and ECOG performance status 0 or 1. The safety profile of AMC was consistent with earlier studies. Clinical development of AMC continues, with a focus on earlier-line breast cancer indications for pts with endocrine-sensitive disease in AMEERA-5 and -6."

Clinical • P2 data • Breast Cancer • HER2 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-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=251 | Recruiting | Sponsor: Sanofi | Trial completion date: Jan 2024 ➔ May 2024 | Trial primary completion date: Jan 2024 ➔ May 2024

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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=224 | Recruiting | Sponsor: Sanofi | Trial completion date: Jan 2021 ➔ Jun 2021 | Trial primary completion date: Jan 2021 ➔ Jun 2021

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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 | Active, not recruiting | Sponsor: Sanofi | Recruiting ➔ Active, not recruiting | N=251 ➔ 136

Enrollment change • Enrollment closed • Monotherapy • Breast Cancer • Estrogen Receptor Positive 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=224 | Recruiting | Sponsor: Sanofi | N=156 ➔ 224

Enrollment change • Monotherapy • Breast Cancer • Estrogen Receptor Positive 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=156 | Not yet recruiting | Sponsor: Sanofi

Monotherapy • New P1/2 trial • Breast Cancer • Estrogen Receptor Positive 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=156 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Breast Cancer • Estrogen Receptor Positive 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=305 | Recruiting | Sponsor: Sanofi | Trial completion date: Mar 2022 ➔ Oct 2022 | Trial primary completion date: Mar 2022 ➔ Oct 2022

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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=305 | Recruiting | Sponsor: Sanofi | Trial completion date: Oct 2022 ➔ Mar 2023 | Trial primary completion date: Oct 2022 ➔ Mar 2023

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Dec 2023 ➔ Dec 2027 | Trial primary completion date: Dec 2023 ➔ Dec 2027

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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=259 | Recruiting | Sponsor: Sanofi | Trial completion date: Jul 2021 ➔ Dec 2021 | Trial primary completion date: Jul 2021 ➔ Dec 2021

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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=251 | Recruiting | Sponsor: Sanofi | Trial completion date: May 2023 ➔ Jan 2024 | Trial primary completion date: May 2023 ➔ Jan 2024

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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.

Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Estrogen Receptor Positive 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 | Active, not recruiting | Sponsor: Sanofi | Trial completion date: Aug 2024 ➔ Dec 2023 | Trial primary completion date: Aug 2024 ➔ Dec 2023

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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=259 | Recruiting | Sponsor: Sanofi | Trial completion date: Jan 2022 ➔ Jun 2022 | Trial primary completion date: Jan 2022 ➔ Jun 2022

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive 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=251 | Recruiting | Sponsor: Sanofi | Trial completion date: May 2024 ➔ Aug 2024 | Trial primary completion date: May 2024 ➔ Aug 2024

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

Selective Estrogen Receptor Degraders Induce Bradycardia by Modulating Nuclear Estrogen Signaling. (PubMed, JACC Basic Transl Sci) - "Giredestrant and camizestrant induced significant bradycardia in wild-type zebrafish embryos, whereas fulvestrant and amcenestrant (SERDs that do not induce bradycardia in patients) did not alter heart rate. Mutations in gper, esr2a, and esr2b did not confer resistance to SERD-induced bradycardia, whereas esr1 mutant embryos were protected. These findings demonstrate that SERD-associated bradycardia is mediated through Esr1 signaling, supporting an on-target adverse effect."

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

Efficacy and safety of treatments in HR+HER2- advanced breast cancer after cyclin-dependent kinase 4/6 inhibitors progression: A network meta-analysis and scoping review (ESMO 2025) - "The camizestrant (HR=0.49, 95% CI: 0.32–0.76), ribociclib plus ET (HR=0.57, 95% CI: 0.39–0.84), capivasertib plus ET (HR=0.59, 95% CI: 0.48–0.72), elacestrant (HR=0.70, 95% CI: 0.55–0.89), and abemaciclib plus ET (HR=0.73, 95% CI: 0.57–0.94) showed superior PFS compared to ET monotherapy. Camizestrant, ribociclib plus ET, and capivasertib plus ET demonstrated a significantly better PFS compared with amcenestrant or palbociclib plus ET. ADCs including trastuzumab deruxtecan (T-DXd) (PFS HR=0.59, ORR OR=3.53), sacituzumab govitecan (SG) (PFS HR=0.63, ORR OR=1.63), and datopotamab deruxtecan (Dato-DXd) (PFS HR=0.63, ORR OR=1.94) demonstrated better efficacy in both PFS and ORR compared with chemotherapy...ADCs were superior to chemotherapy, with T-DXd showing the most favorable outcomes. Further studies are needed to guide treatment selection in specific subgroups."

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

Vepdegestrant, a PROteolysis Targeting Chimera (PROTAC) estrogen receptor (ER) degrader, induces greater ER degradation and antitumor activity relative to selective ER degraders (SERDs) in preclinical ER+ breast cancer models (AACR-NCI-EORTC 2025) - "Here, we report preclinical ER degradation and antitumor activity of vepdegestrant compared with FDA-approved (fulvestrant and elacestrant) and investigational oral SERDs (giredestrant, camizestrant, amcenestrant, and imlunestrant). Our results indicate that vepdegestrant induces greater maximal ER degradation than investigational oral SERDs, elacestrant, or fulvestrant in WT ER+ breast cancer cell lines. Vepdegestrant also demonstrated greater TGI and ER degradation in vivo compared with fulvestrant in a WT ER+ breast cancer CDX model."

Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

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 | "In this study of neoadjuvant oral SERD with monthly OFS, 7/38 (18.4%) preM pts had sE2 levels remain or rebound into the preM range. sE2 levels did not appear to impact Ki67 suppression on NA ET. Work up for ovarian cysts should be considered in pts with symptoms, or significantly elevated or persistent sE2 levels."

Clinical • Combination therapy • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

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