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

Lasofoxifene is a bone protective treatment option for estrogen receptor positive breast cancers (AACR 2026) - P3 | "Standard treatments like aromatase inhibitors and ER-antagonists, like fulvestrant, indiscriminately suppress ER signaling, in both breast and bone. Lasofoxifene, a selective ER modulator, exhibits tissue-selective ER-agonist activity in bone and is currently being evaluated in the ELAINE-III clinical trial [NCT05696626] in combination with abemaciclib for the treatment of ESR1-mutant advanced or metastatic ER+ breast cancer...Drug synergy screens have defined choices for rational combination with lasofoxifene to further potentiate its anti-tumor activity. Overall, this study supports the use of lasofoxifene-based treatment combinations which will concurrently protect bone architecture while suppressing ER+ metastasis progression in the bone niche."

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

Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors (ESMO 2022) - P2 | "Clinical trial identification NCT03781063. LAS may be a new treatment option following endocrine/CDK4/6i therapies if efficacy is confirmed in a larger, adequately powered clinical study. A phase 3 combination study of LAS and abemaciclib is planned based on encouraging efficacy/safety in ELAINE 2."

Clinical • Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2

Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. (ASCO 2022) - P2 | "LAS, a third-generation selective estrogen receptor modulator, as monotherapy or combined with a CDK4/6i, was shown to have superior efficacy over fulvestrant (FVT) in preclinical breast cancer models expressing ESR1 mutations. LAS combined with Abema in the ELAINE 2 trial was well tolerated and demonstrated robust and meaningful efficacy in women with ER+/HER2- mBC and an ESR1 mutation who had progressed on previous CDK4/6i therapies."

Clinical • P2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hematological Disorders • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Leukopenia • Oncology • Solid Tumor • ER • HER-2

Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2. (PubMed, Ann Oncol) - P2 | "Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need."

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

Trial in progress: Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating locally advanced or ER+/HER2- metastatic breast cancer with an ESR1 mutation (SABCS 2023) - P3 | "Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 years; ER+/HER2-, locally advanced and/or metastatic BC (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/metastatic BC; and ≤1 line of chemotherapy in the advanced/metastatic setting...Expected PFS is ≥10.3 months for lasofoxifene/abemaciclib and 7 months for fulvestrant/abemaciclib (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 months at 125 global sites."

Clinical • Metastases • P3 data • 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

Lasofoxifene (LAS) plus abemaciclib (Abema) for treating ESR1-mutated ER+/HER2- metastatic breast cancer (mBC) after progression on prior therapies: ELAINE 2 study update. (ASCO 2023) - P2 | "With longer ELAINE 2 follow up, LAS/Abema continues to be well tolerated with clinically meaningful efficacy in women with mESR1, ER+/HER2- mBC that had progressed on ET and CDK4/6is. Decreases in mESR1 ctDNA suggest effective target engagement of LAS. The PFS (median ~13 mos) and ORR (56%) with LAS/Abema are promising and a confirmatory phase 3 study (ELAINE 3) will begin in 2023."

Metastases • Breast Cancer • Cardiovascular • Estrogen Receptor Positive Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Respiratory Diseases • Solid Tumor • Venous Thromboembolism • CDK4 • ER • HER-2

Others (PROTAC, CERCA, Lasofoxifene, SERCA) and overcome of resistance (JSMO 2026) - No abstract available

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology

ELAINE 1: Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (clinicaltrials.gov) - P2 | N=100 | Completed | Sponsor: Sermonix Pharmaceuticals Inc. | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ May 2025 | Trial primary completion date: Dec 2024 ➔ May 2025

First-in-human • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial. (PubMed, Ann Oncol) - P2 | "Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation."

Journal • Metastases • P2 data • Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Musculoskeletal Pain • Oncology • Solid Tumor • 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 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

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 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