Fablyn (lasofoxifene)

P1/2, N=35, Not yet recruiting, Azure Biotech Inc. | Trial completion date: Dec 2024 --> Jun 2027 | Trial primary completion date: Sep 2024 --> Dec 2026

Overall, our results suggest that PARP-1 should be explored as a potential target in comprehensive therapeutic approaches in ET-resistant BC.

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.

P2, N=29, Completed, Sermonix Pharmaceuticals Inc. | Active, not recruiting --> Completed

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.

P3, N=500, Recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: Jun 2026 --> Apr 2028 | Trial primary completion date: Jun 2025 --> Apr 2027

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.

P3, N=400, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

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.

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.

P2, N=29, Active, not recruiting, Sermonix Pharmaceuticals Inc. | Trial completion date: May 2024 --> Dec 2024 | Trial primary completion date: May 2024 --> Dec 2024

In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.