Sermonix Pharmaceuticals Announces Breast Cancer Research Examining Lasofoxifene’s Preclinical Effects on Aromatase Inhibitor Resistant Non-ESR1 Mutated Breast Cancer

Sermonix Pharmaceuticals Inc. recently announced the publication of its scholarly article Lasofoxifene as a Potential Treatment for Aromatase Inhibitor-Resistant ER-Positive Breast Cancer, in the peer-reviewed journal Breast Cancer Research. The paper discusses positive findings observed during a preclinical study examining the effects of oral lasofoxifene, Sermonix’s lead investigational drug, on aromatase inhibitor-resistant, estrogen receptor-positive (ER+) breast cancer in the absence of ESR1 mutations.

The study investigated the activity of lasofoxifene in a letrozole-resistant breast tumor model that did not have ESR1 mutations. Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). The mice were randomized to vehicle – lasofoxifene alone or plus palbociclib, fulvestrant alone or plus palbociclib, or palbociclib alone – two to three weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements and histological analysis. The experiment was repeated with the same design and eight to nine mice in each treatment group.

Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene alone or combined with palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene alone or combined with palbociclib. The lasofoxifene plus palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment.

“We previously demonstrated that lasofoxifene effectively inhibits breast tumor growth in tumors bearing an ESR1 mutation that are resistant to endocrine therapy,” said Dr. Geoffrey Greene, MD, PhD, Chair of the Ben May Department for Cancer Research at the University of Chicago. “In this aromatase-resistant breast tumor model, we now show that lasofoxifene inhibits tumor growth in the absence of an ESR1 mutation and with low ESR1 expression, suggesting that lasofoxifene can be an effective therapy option for all hormone-treatment resistant breast tumors.”

Evidence of lasofoxifene’s antitumor activity in breast cancers with ESR1 mutations was previously demonstrated during the first two Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) trials. During ELAINE-1, lasofoxifene as a monotherapy led to numerically longer progression-free survival than fulvestrant (5.6 vs. 3.7 months; P=0.138) in patients with endocrine therapy-resistant, ESR1-mutated mBC who had prior CDK4/6i exposure. In ELAINE-2, the combination of lasofoxifene and abemaciclib was associated with a median progression-free survival of approximately 13 months.

ELAINE-3, A global registrational Phase 3 study, is currently enrolling, with clinical trial sites across the US, Europe, Asia-Pacific, Israel, and Canada. ELAINE-3 is assessing the efficacy of oral lasofoxifene and Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib (Verzenio) compared to fulvestrant and abemaciclib in 400 pre- and post-menopausal subjects with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation.

“The results of this new study demonstrate, for the first time, lasofoxifene’s anti-tumor activity in mouse models of ER-resistant breast cancer in the absence of ESR1 mutations, broadening its potential to become a valuable therapy regardless of ESR1 status,” said Barry Komm, PhD, Sermonix chief scientific officer and co-author of the article. “As we remain focused on completing the ELAINE-3 trial, we are excited to further examine this new avenue of investigation and the potentially broader promise of lasofoxifene.”

The open-access paper can be accessed online here.

Sermonix Pharmaceuticals Inc. is a privately held biopharmaceutical company focused on the development of female-specific oncology products and is currently undertaking a Phase 3 clinical study of lasofoxifene, its lead investigational drug. The Sermonix management team, led by founder Dr. David Portman, has significant experience in all stages of the drug development, regulatory and commercialization processes. Paul Plourde, MD, Vice President of Oncology Clinical Development, has many decades of experience at AstraZeneca in the breast cancer drug development arena. Barry Komm, PhD, Chief Scientific Officer, is recognized for his expertise in nuclear receptor biology. Miriam Portman, MD, is co-founder and Chief Operating Officer, with expertise in clinical trial conduct and patient recruitment. Elizabeth Attias, MMSc, ScD, Chief Strategy and Development Officer, has extensive experience in pharmaceutical drug commercialization. Simon Jenkins, PhD, Vice President of Operations, has over 30 years of experience in global drug development leadership. Sermonix non-executive chairman of the board is Anthony Wild, PhD, former President of both Parke-Davis Pharmaceuticals and Warner-Lambert’s Pharmaceutical Division. For more information, visit SermonixPharma.com.