289P - Results of the window-of-opportunity clinical trial D-BIOMARK: Study of biomarkers of the antitumor activity of denosumab and its role as a modulator of the immune response in early breast cancer

Background

Inhibitors of the Receptor Activator of NFkB (RANK) pathway, such as denosumab, have been shown to prevent breast cancer (BC) in preclinical models by reducing proliferation and tumor cell survival. Recent studies suggest that RANK pathway inhibition enhances the anti-tumor immune response. This study aimed to evaluate the antiproliferative, proapoptotic (primary endpoints), and immunomodulatory activity (exploratory endpoint) of denosumab in early BC.

Methods

D-BIOMARK study (NCT03691311) was a randomized window-of-opportunity trial designed to evaluate the biological effects of single-agent denosumab in early BC. Sixty patients with early HER2-negative BC were enrolled, 2:1 randomization to experimental (two doses of 120mg of denosumab separated by 7 days before surgery) or control (no treatment) group. Paired samples (core-biopsy and surgical specimen) were obtained from each patient for comparison of Ki67 (proliferation), Cleaved Caspase-3 (cell survival), and tumor infiltrating lymphocytes (TILS) according to international guidelines. Pre vs. post values were compared using a paired t-test.

Results

A total of 58 evaluable patients were analyzed, 10 with triple-negative breast cancer (TNBC), 27 premenopausal and 31 postmenopausal. Denosumab reduced free RANKL (sRANK) levels in patient’s serum but did not reduce tumor cell survival or proliferation. Denosumab increased TILS in all patients, except TNBC (n=6) while differences in the control group did not reach statistical significance. When considering clinically significant increases in TILS (5% or 10%), no differences were found between both groups. No associations were found between basal sRANKL and an increase in TILS. Table: 289P

Conclusions

Denosumab did not affect tumor cell survival nor proliferation in early BC but may have an immunomodulatory effect that warrants further investigation.

Clinical trial identification

NCT03691311.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Amgen.

Disclosure

A. Vethencourt: Financial Interests, Personal, Invited Speaker, Presentation in clinical or research sessions as a speaker: Novartis, Eisai; Non-Financial Interests, Project Lead, GEICAM Grant “Balil-Pelegrí” 2021-2022, sponsored by theSpanish breast cancer research group GEICAM.: GEICAM; Non-Financial Interests, Advisory Board: SOLTI; Non-Financial Interests, Leadership Role, Participation in the TransGEICAM group, which is part of the Spanish breast cancer research group GEICAM (Not Paid): GEICAM; Other, Travel, Accommodations, Support for attending meetings: Pfizer, Lilly, Novartis, Roche. A. Stradella: Financial Interests, Personal, Advisory Board, Advisory about CAPITELLO 291 trial: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory on new activities for residents: Novartis; Financial Interests, Personal, Invited Speaker, Trastu-Deruxtecan clinical case meeting: Daiichi; Financial Interests, Personal, Invited Speaker, meeting on new data on cyclin inhibitors: Novartis. M.J. Gil: Financial Interests, Personal, Advisory Board: Daiichi; Pfizer; Novartis, Gilead; Palex; Seagen; Roche y Pierre-Fabre. S. Pernas Simon: Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Member of Board of Directors: SOLTI. E. Gonzalez-Suarez: Financial Interests, Personal and Institutional, Coordinating PI: Amgen. All other authors have declared no conflicts of interest.