195P - Preclinical efficacy of the trastuzumab duocarmazine SYD985 as monotherapy or in combination with the PARP inhibitor niraparib in HER2-expressing endometrial cancer

Background

Recurrent and metastatic endometrial cancer (EC) has a poor prognosis due to limited response rates to conventional treatment. Trastuzumab duocarmazine SYD985 showed promising antitumour activity in various cancers, including endometrial cancer. In this study, we performed a mouse clinical trial to evaluate the combination of SYD985 alone and in combination with the PARP inhibitor niraparib to explore potential synergy.

Methods

A cohort of 15 HER2-expressing EC patient-derived xenograft (PDX) murine models was performed to assess the efficacy of SYD985 and Niraparib, in monotherapy or in combination. A non-binding isotype control ADC, SYD989 was also included. Treatment administration was: SYD985 and SYD989 (1 mg/kg, i.v single dose at day 1), Niraparib (40 or 50 mg/kg, oral gavage for 21 days); and Vehicle (ADC buffer plus methylcellulose [0.5%]). Plasma concentrations of total antibody, conjugated antibody and niraparib were determined at day 4. Treatment efficacy was determined by the comparing mean tumor volumes of the compound treated groups to the vehicle group throughout the duration of the study. Toxicity was evaluated by loss in body weight.

Results

Mice treated with SYD989 and niraparib as monotherapies showed the lowest response rate, with 53% (8/15) of PDX models exhibiting non-response (NR), and 40% (6/15) a partial response (PR). Importantly, PDX treated with SYD985 as monotherapy or in combination with Niraparib exhibited an enhanced response. Thirty-four (34%) of the PDX models showed a complete response to SYD985 as monotherapy, while combination with Niraparib shown an additive effect reaching up to 60% of complete response, of which 40% showed long-term CRs. Similarly, we observed an increased survival in animals treated with SYD985 alone or in combination with niraparib.

Conclusions

This study highlights a potential impact of targeted-treatment against HER2 in combination with PARP inhibitor for patients with HER2-expressing EC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vall d’Hebron Institute of Research.

Funding

Byondis B.V.

Disclosure

E. Colas: Financial Interests, Institutional, Research Funding: Byondis B.V.. A. Sotoca Covaleda, M. van der Vleuten, P. Groothuis: Financial Interests, Institutional, Full or part-time Employment, Employee in Byondis B.V.: Byondis B.V.. All other authors have declared no conflicts of interest.