Title: Anti-PD1 and Niraparib (PARPi) combination therapy in gynae carcinosarcoma: Identification of response-predictive biomarkers and resistance mechanisms
Isabelle Ray-Coquard (France), Centre Léon Bérard, Department of Medical Oncology, Lyon
Marc-Henri Stern (France), Institut Curie, Centre de Recherche, Insert U830, Paris
Elena Ioana Braicu (Germany), Charité Medizinische Universität - Department of Gynecology, Berlin
Sandro Pignata (Italy) Istituto Nazionale Tumori di Napoli "Fondazione G. Pascale” IRCSS, Naples
Carcinosarcomas (CS) are very rare and aggressive tumors. Gynecologic CS have a 5-year overall survival <10% and most patients relapsed after standard treatments. PARP inhibitor (PARPi) and anti-PD1/L1 independent trials showed some efficacy in relapsed CS. ROCSANbio translational program, merging with a phase III trial evaluating PARPi/anti-PD1 combination in relapsed CS, relies on 3 hypotheses:
- CS show high DNA damage response activity, driving PARPi as promising therapy;
- The high tumor mutation load observed in CS potentially results in neo-antigens, paving the way for immunotherapies;
- Such tumors, with an exhibited cell plasticity, represent a unique model to study its contribution in resistance to treatment.
The primary aim will be to define biomarkers within tumors (WP1) and blood (WP2) predicting anti-PD1/PARPi response in CS and to investigate the effect of this new therapeutic strategy on quality of life (QOL) and patient-reported outcome (PRO) in the whole population and by molecular subgroups (WP4). The secondary aim will be to identify resistance mechanisms (WP3). The unique access to materials at diagnosis, inclusion and progression will allow to compare responding and non-responding patients for numerous parameters: For WP1: 1) tumor immune infiltrate and immune checkpoint expression, 2) EMT signature, 3) homologous recombination deficiency signature and mutation burden and 4) tumor neo-epitopes and T cell response. For WP2: circulating 1) tumor DNA and 2) immune cells. For WP3: 1) EMT/tumor cell plasticity, 2) & 3) resistance pathways and 4) mutations in epigenetic modifiers and immune-related genes and their consequences. For WP4: 1) EORTC QOL disease-specific module, 2) Hospital Anxiety and Depression Scale and 3) PRO-CTCAE questionnaire.
We expect to identify biomarkers predicting anti-PD1/PARPi response, the impact on QOL and PRO for patients and to discover novel resistance targets representing better candidates for combination therapy.
(Project funded under JTC 2017)