Fablyn (lasofoxifene) / Pfizer, Ligand, Sermonix, Fosun Pharma - LARVOL DELTA

Pharmacokinetics (PK), safety, and tolerability of lasofoxifene in healthy Chinese female adults: results from an open-label, single-dose phase I study (ESMO Asia 2025) - P | "LAS monotherapy was more effective than fulvestrant monotherapy at inhibiting tumour growth in mice bearing human breast carcinoma xenografts harbouring activating estrogen receptor 1 mutations, and so was LAS plus palbociclib versus fulvestrant plus palbociclib. There was no marked difference in drug exposure between premenopausal and postmenopausal healthy Chinese female adults following one dose of oral LAS 5 mg. No clinically relevant differences in PK of LAS were observed for the Chinese healthy females in this study when compared cross-trial to data from Japanese and Caucasian healthy females. LAS was safe and well tolerated."

Clinical • P1 data • PK/PD data • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation (SABCS 2025) - P3 | "In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival (PFS, median 5.6 mos vs 3.7 mos; HR: 0.669 [95% CI, 0.445‒1.125], P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), with a favorable safety profile (Goetz MP et al...Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an AI plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting...Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. Enrollment is currently ongoing to meet the target..."

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

Comparative transcriptomic and proteomic analysis of lasofoxifene and fulvestrant, in an ER-mutated metastatic breast cancer explant model, identifies potential molecular mechanisms underlying differential treatment efficacy (SABCS 2025) - "A combination of lasofoxifene (Las) and the CDK4/6 inhibitor abemaciclib has shown promising results in the ELAINE 2 trial, with significantly increased progression-free survival and good tolerability in mBC patients with activating ERα mutations who have progressed on endocrine/CDK4/6 therapy, including fulvestrant. In mouse studies, Las, as well as the Las plus palbociclib (Pal) combination, resulted in a significant reduction in primary tumor burden and metastasis compared to fulvestrant (Ful) and Ful plus Pal treatment. In this study, we used a mBC xenograft model with the ERα Y537S mutation (MCF7 ERα Y537S mutant) and GeoMx-DSP technology to investigate differences in transcriptional and protein expression levels between Las, Ful, and their combinations with Pal... Our data reveal the complexity of Las vs Ful treatment outcomes in the MCF-7 Y537S mBC explant model and provide potential insights into the molecular mechanisms underlying the differential efficacy of..."

Clinical • Metastases • Omic analysis • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • PCNA

Open-Label Study of Vaginal AZU-101 in Postmenopausal Women (clinicaltrials.gov) - P1/2 | N=35 | Not yet recruiting | Sponsor: Azure Biotech Inc. | Trial completion date: Dec 2024 ➔ Jun 2027 | Trial primary completion date: Sep 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date

Lasofoxifene acts as a selective agonist in the bone microenvironment (ENDO 2025) - P3 | "ELAINE-III [NCT05696626] is a clinical trial currently investigating the efficacy of lasofoxifene and abemaciclib compared to fulvestrant abemaciclib combination therapy for advanced or metastatic ER+ breast cancer with an ESR1-mutation...Additionally, drug synergism studies with lasofoxifene and the NCI NExT Oncology Interrogation Tools Set of 555 drugs were performed to identify pathways which were vulnerable in Elacestrant-treated cells. This data will translate into novel treatment combinations which are targeted to bone metastasis in pre-clinical models. This study has determined that lasofoxifene is protective in the bone microenvironment, unlike other new-generation endocrine therapies, and future directions include evaluating the ramifications of this activity on bone metastasis progression."

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

Lasofoxifene acts as a selective agonist in the bone microenvironment (ENDO 2025) - P3 | "ELAINE-III [NCT05696626] is a clinical trial currently investigating the efficacy of lasofoxifene and abemaciclib compared to fulvestrant abemaciclib combination therapy for advanced or metastatic ER+ breast cancer with an ESR1-mutation...Additionally, drug synergism studies with lasofoxifene and the NCI NExT Oncology Interrogation Tools Set of 555 drugs were performed to identify pathways which were vulnerable in Elacestrant-treated cells. This data will translate into novel treatment combinations which are targeted to bone metastasis in pre-clinical models. This study has determined that lasofoxifene is protective in the bone microenvironment, unlike other new-generation endocrine therapies, and future directions include evaluating the ramifications of this activity on bone metastasis progression."

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

Comparison of estrogens and selective estrogen receptor modulators (SERMs) used for menopausal hormone therapy. (PubMed, Menopause) - "Commonly used SERMs include tamoxifen, raloxifene, ospemifene, lasofoxifene, and bazedoxifene. Lastly, E4 has emerged as a novel estrogen with beneficial effects on VMS, GSM, and bone, and neutral effects on the breast and hemostatic factors. A personalized approach, based on each woman's biological profile, is recommended to guide the choice of MHT."

Clinical • Journal • Review • Breast Cancer • Cardiovascular • Hormone Receptor Breast Cancer • Oncology • Rheumatology • Solid Tumor • Venous Thromboembolism • Women's Health

PARP-1 as a novel target in endocrine-resistant breast cancer. (PubMed, J Exp Clin Cancer Res) - "Here, we show that Poly (ADP-ribose) polymerase-1 (PARP-1) may be considered as a novel therapeutic target in ERα-positive BC…We first demonstrated that the up-regulation of PARP-1 expression induced by estrogens is abrogated either by inhibiting or silencing ERα in MCF7 and T47D BC cells expressing ERα wild type or Y537S mutation…our results suggest that PARP-1 should be explored as a potential target in comprehensive therapeutic approaches in ET-resistant BC."

Journal • Breast Cancer • Endocrine Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • FOXA1 • PARP1

Circulating tumor DNA (ctDNA) in patients with stage 2/3 HR+HER2-negative breast cancer (BC) treated with neoadjuvant endocrine therapy (NET) in the I-SPY2 endocrine optimization pilot (EOP) trial. (ASCO 2025) - P2 | "Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET."

Circulating tumor DNA • 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 • HER-2

I-SPY2 endocrine optimization pilot (EOP): Neoadjuvant lasofoxifene (Laso) in molecularly selected patients with hormone receptor positive (HR+)/HER2 negative (HER2-) stage 2/3 breast cancer (BC). (ASCO 2025) - P2 | "Neoadjuvant laso demonstrates a favorable AE profile and promising anti-tumor activity in suppressing 3-wk Ki67 and MRI FTV change in pts with HR+ HER2-negative early BC. Ki67 suppression in premenopausal pts was seen in the absence of OFS. Ki67 expression at pre-treatment, and 3-wk time point.1Include the one male pt."

Clinical • Breast Cancer • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Hypertension • Immunology • Oncology • Solid Tumor • HER-2

ELAINE 3: Open-Label, Randomized, Multicenter, Phase 3 Study of the Efficacy and Safety of Lasofoxifene Plus Abemaciclib for Treating Locally Advanced or Metastatic, ER+/HER2–, Breast Cancer With an ESR1 Mutation (MBCC 2025) - P2, P3 | "The phase 2 ELAINE 1 trial (NCT03781063) showed numerically greater progression-free survival (PFS; median, 5.6 months vs 3.7 months; HR, 0.669; 95% CI, 0.445-1.125; P = .138), objective response rate (ORR, 13% vs 3%; P = .124), and clinical benefit rate (CBR, 37% vs 22%; P = .117) vs the ER degrader fulvestrant, with a favorable safety profile...Women (pre- and postmenopausal) and men were aged 18 years or older; and had ER+/HER2–, locally advanced breast cancer and/or metastatic breast cancer; 1 or more acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal therapy for advanced breast cancer/metastatic breast cancer; and 1 or fewer chemotherapy line in the advanced/ metastatic setting...Target sample size is up to 500 to provide 90% power with a 1-sided type I error rate of 0.025 after 285 PFS events. Status Recruitment has been initiated and is expected to occur over 18 months."

Clinical • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive 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

ELAINE 3: phase 3 study of lasofoxifene plus abemaciclib to treat ER+/HER2-, ESR1-mutated, metastatic breast cancer. (PubMed, Future Oncol) - P3 | "The phase 3, randomized ELAINE 3 trial will evaluate the efficacy and safety of lasofoxifene/abemaciclib versus fulvestrant/abemaciclib for locally advanced or metastatic, ER+/HER2- breast cancer with an ESR1 mutation that progressed after ET-CDK4/6i treatment. Enrollment is planned for up to 500 patients to evaluate progression-free survival as the primary endpoint.Clinical trial registration: www.clinicaltrials.gov identifier is NCT05696626."

Journal • P3 data • Breast Cancer • Estrogen Receptor Positive 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

Sermonix and Regor Announce Strategic Collaboration to Optimize Regor’s Proprietary rCARD Platform for Identification of Novel Targets and Therapeutics (GlobeNewswire) - "Sermonix Pharmaceuticals...and Regor Therapeutics Group...announced a strategic collaboration to optimize Regor’s proprietary, cutting-edge rCARD (Regor Computer Accelerated Rational Discovery) platform for identification of novel targets and therapeutics that fulfill unmet patient clinical needs and preferences in the breast oncology arena....With a Phase 3 asset – oral lasofoxifene – in development for the treatment of ESR1-mutated ER+ HER2- mBC, the Sermonix team has expertise within the clinical drug development and commercialization arena and understands the landscape and value proposition of new treatments, which are requirements for launch success and adoption by both patients and health care providers."

Licensing / partnership • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

ELAINEII: Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov) - P2 | N=29 | Completed | Sponsor: Sermonix Pharmaceuticals Inc. | Active, not recruiting ➔ Completed

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

Sermonix Announces Clinical Breast Cancer Publication of Article Examining Effects of Lasofoxifene Versus Fulvestrant on Urogenital Symptoms in Patients with ESR1-Mutated ER+/HER2- Metastatic Breast Cancer (GlobeNewswire) - P2 | N=100 | ELAINE-1 (NCT03781063) | Sponsor: Sermonix Pharmaceuticals Inc. | "Of 103 enrolled patients, 72 (70%) completed the mean vaginal (VAS) and vulvar (VuAS) assessment scales (mean age 61.5 years). Vaginal (40%)/vulvar (25%) dryness and vaginal pain (22%) were the most frequently reported symptoms; 26% reported ≥1 moderate/severe symptom. Lasofoxifene decreased the mean composite VAS/VuAS, VAS, and VuAS from baseline to week 16 by 74%, 74%, and 79%, respectively, while fulvestrant increased them by 36%, 15%, and 63%, respectively. Baseline vaginal/vulvar symptoms were more severe if patients were under age 40, had no visceral disease, used adjuvant tamoxifen previously, or had a longer duration of AI use in the adjuvant/metastatic settings."

P2 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Effects of Lasofoxifene Versus Fulvestrant on Vaginal and Vulvar Symptoms in Patients With ESR1-Mutated, ER+/HER2-, Metastatic Breast Cancer From the ELAINE 1 Study. (PubMed, Clin Breast Cancer) - "Oral lasofoxifene (5 mg/day), but not fulvestrant, appears to improve GSM vaginal symptoms in women with mBC. These preliminary findings suggest further study is needed; such will be explored in the phase 3, registrational, ELAINE 3 trial in patients with ESR1-mutated, ER+/HER2- mBC."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Pain • Solid Tumor • Vaginal Atrophy • Women's Health • ER • HER-2

Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation (SABCS 2024) - P3 | "In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival ([PFS] median, 5.6 mos vs 3.7 mos; HR 0.669 [95% CI, 0.445-1.125]; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), and a favorable safety profile (Goetz MP, et al...Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting...To achieve 90% power with a one-sided type I error rate of 0.025, the target sample size is 400 patients. Full recruitment is expected to occur over 18 mos."

Clinical • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive 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

ELAINE 3: Evaluation of Lasofoxifene Combined With Abemaciclib Compared With Fulvestrant Combined With Abemaciclib in Locally Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov) - P3 | N=500 | Recruiting | Sponsor: Sermonix Pharmaceuticals Inc. | Trial completion date: Jun 2026 ➔ Apr 2028 | Trial primary completion date: Jun 2025 ➔ Apr 2027

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

First Chinese Patient Dosed for Phase 3 MRCT on ER+/HER2- Breast Cancer of HLX78 (Henlius Press Release) - "Shanghai Henlius Biotech...announced that the first patient in China has been dosed in the international multi-centre Phase 3 clinical trial (ELAINE-3, NCT05696626) of HLX78 (oral lasofoxifene) in combination with abemaciclib (a CDK4/6 inhibitor) in patients with locally advanced or metastatic estrogen receptor-positive (ER+)/Human epidermal growth factor receptor 2-negative (HER2-) breast cancer who have disease progression on an aromatase inhibitor (AI) in combination with CDK4/6 inhibitor and have an estrogen receptor α gene (ESR1) mutation. ELAINE-3 is currently recruiting subjects in the United States, Canada, the European Union, in addition to other countries and regions."

Trial status • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Risk-reducing medications and primary breast cancer prevention: a network meta-analysis of randomized controlled trials. (SABCS 2024) - "These medications included tamoxifen, raloxifene, third-generation SERMs (arzoxifene, bazedoxifene, lasofoxifene), AIs (anastrozole, exemestane), statins (pravastatin, simvastatin, lovastatin), thiazolidinediones (rosiglitazone, pioglitazone), sulfonylurea, metformin, metformin plus sulfonylurea, fenretinide, tamoxifen plus fenretinide, calcium, and calcium plus vitamin D. For the secondary analysis, 16 studies evaluating AIs, tamoxifen, and raloxifene were included for invasive breast cancer...Conclusions These results offer a comprehensive comparative analysis of risk-reducing medications in relation to breast cancer. Findings can guide future research in breast cancer prevention as well as clinical considerations and guidelines on breast cancer chemoprevention."

Retrospective data • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

An Open Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of the Combination of Lasofoxifene and Abemaciclib to the Combination of Fulvestrant and Abemaciclib for the Treatment of Pre- and Postmenopausal Women and Men with Locally Advanced or Metastatic ER+/HER2− Breast Cancer with an ESR1 Mutation (ChiCTR) - P3 | N=400 | Not yet recruiting | Sponsor: Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

Metastases • New P3 trial • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer. (PubMed, J Med Chem) - "Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. 51 exhibited favorable pharmacokinetic properties and good brain penetration, with a brain/plasma ratio of 3.05, and significantly suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1 xenograft model. Overall, the study demonstrates 51 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

Sermonix Pharmaceuticals’ Lasofoxifene Is Well Tolerated, Demonstrates Promising Ki67 Suppression in Phase 2 I-SPY 2 Arm Evaluating Therapy in Neoadjuvant Breast Cancer Setting (GlobeNewswire) - P2 | N=5000 | I-SPY 2 (NCT01042379) | Sponsor: QuantumLeap Healthcare Collaborative | "Sermonix Pharmaceuticals Inc...and Quantum Leap Healthcare Collaborative today broadly announced that in the Phase 2 clinical trial evaluating lasofoxifene as a neoadjuvant endocrine therapy in molecularly selected HR+/HER2-, locally advanced breast cancer, the investigational drug was well tolerated and demonstrated promising early activity in suppressing the Ki67 protein in both premenopausal and postmenopausal patients....Median Ki67 expression went from 10% at baseline (range 1.0-40%) to 4% (1.0-18.0%) at Week 3. At three weeks, Ki67 expression was suppressed to <10% in 14 out of 16 (88%) patients, and to <2.7% in 6 out of 16 (38%) patients. Adverse events (AEs) were all grade 1-2. Most common AEs include hot flushes (65%), constipation (40%), fatigue (40%) and nausea (25%)."

P2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer. (PubMed, J Med Chem) - "ERD-1233 was developed based on Lasofoxifene as the ER binding moiety and a novel cereblon ligand through extensive optimization of the linker...Oral administration of ERD-1233 effectively reduces ER protein in ER+ tumors and achieves tumor regression in the ER wild-type MCF-7 xenograft tumor model and strong tumor growth inhibition in the ESR1Y537S mutated model in mice. Our data demonstrate that ERD-1233 is a promising ER PROTAC degrader for extensive evaluation as a new therapy for the treatment of ER+ human breast cancer."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CRBN • ER

Investigating Lasofoxifene Efficacy Against the Y537S + F404V Double-Mutant Estrogen Receptor Alpha Using Molecular Dynamics Simulations. (PubMed, Bioinform Biol Insights) - "These findings suggest a potential reduction in lasofoxifene efficacy due to the dual mutation. Further experimental validation is required to confirm these results and fully understand the impact of dual mutations on lasofoxifene's effectiveness in ERα + metastatic BC."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER