Validation of circulating tumor DNA for prognostication and monitoring in metastatic endometrial carcinoma: Ancillary results from the phase II randomized GINECO trial UTOLA

BackgroundNo biomarker allows personalized prognostication and disease monitoring in metastatic endometrial carcinoma (EC). We investigated whether circulating tumor DNA (ctDNA) might be a relevant biomarker in patients included in the UTOLA trial.MethodsPatients with metastatic/advanced EC without progressive disease (PD) after a first line of chemotherapy with carboplatin-paclitaxel (CP) were randomized in UTOLA to receive either olaparib or placebo as maintenance until PD. Progression free survival (PFS) was similar between the two groups (intention-to-treat (ITT) population), but increased in patients affected by tumors with high levels of chromosomal instability (Joly et al. ESMO 2023). Plasma samples were collected at the end of CP and at three months (M3). Molecular group was characterized by mismatch repair and p53 immunostaining and NGS for POLE and TP53. The ctDNA was evaluated using a validated method based on detection of universally methylated genomic positions in EC by droplet based digital PCR (ddPCR, Beinse et al. Clin Chem 2022). ctDNA positivity was considered as detection beyond the limit of blank.ResultsAmong the 147 patients included in the ITT population, 128 had plasma at baseline, written consent for ancillary studies, and ddPCR success (3 technical fails). ctDNA was detected after CP in 24 (19%) patients, and was not associated with disease response after chemotherapy nor with tumor features. Median PFS in patients with or without ctDNA were 1.8 (95% confidence interval [1.7-1.9] and 7.4 [5.5-11] months, and median OS 10 [7.9-21] and 25 [22-28], respectively. ctDNA was associated with OS independently of molecular group and disease response after chemotherapy (adjusted hazard ratio 3.91 [2.31-6.65]). At M3, in patients with (N=18) and without (N=61) ctDNA, median PFS were 1.8 [1.7-NE] and 13 [9.0-15] months, and median OS 19 [16-NE] and 26 [23-32] months.ConclusionsOur results demonstrate the additional value of ctDNA in metastatic EC, for prognostication, evaluation of response to carboplatin, and monitoring, and should be evaluated as a surrogate for PFS/OS in clinical trials.Clinical trial identificationNCT03745950.Legal entity responsible for the studyARCAGY-GINECO.FundingAstraZeneca; GINECO.DisclosureG. Beinse: Financial Interests, Personal, Advisory Board: EISAI; Financial Interests, Institutional, Funding: GSK, AstraZeneca; Other, Personal, Other, Patent: MethysDX. V. Taly: Financial Interests, Personal, Other, Consultancy: Emulseo; Financial Interests, Personal, Other, President and CSO Board Member: Methys Dx; Financial Interests, Personal, Stocks/Shares: Emulseo, Methys Dx; Financial Interests, Institutional, Other, Co-inventor of 5 patents in exclusive licence to Methys Dx: Methys Dx; Financial Interests, Institutional, Funding, Collaborative funding: Institut de recherche Servier; Financial Interests, Institutional, Other, Collaboration agreement with University: Methys Dx. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape; Financial Interests, Personal, Writing Engagement, Educational: Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AZ, Clovis, Ability Pharma, MSD, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: AZ, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Other, consultancy: Owkin; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AZ; Financial Interests, Institutional, Funding, CI clinical trial: AZ; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE Immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AZ; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer; Non-Financial Interests, Member: GCIG. O. Tredan: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis-Sandoz, Lilly, MSD, AstraZeneca, Pierre Fabre Oncologie, Seagen, Daiichi Sankyo, Gilead, Eisai, Stemline-Menarini, Veracyte, Exact Sciences. B. You: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, GSK, Bayer, Roche, ESC Progastrine, Novartis, LEK, Amgen, Clovis Oncology; Financial Interests, Personal, Other, Travel: Roche, AstraZeneca, BMS, MSD Oncology, Bayer, Boehringer. M.J. Rodrigues: Financial Interests, Personal, Invited Speaker: Immunocore; Financial Interests, Personal, Advisory Board: GSK, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Johnson & Johnson; Non-Financial Interests, Institutional, Product Samples: MSD. L. Gladieff: Financial Interests, Personal, Other, Congress funding: Viatris, Roche; Financial Interests, Institutional, Invited Speaker: MSD, Clovis, GSK, Eisai; Financial Interests, Institutional, Advisory Board: Clovis, GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca. C. Lebreton: Financial Interests, Personal, Advisory Board: GSK, GSK, MSD, Eisai, Clovis Oncology. E. Kalbacher: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, Seagen; Financial Interests, Personal, Other, Travel: Sanofi, Roche, Tesaro, PharmaMar, Leopharma. P. Fournel: Financial Interests, Personal, Advisory Board: BMS, Sanofi, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Amgen; Financial Interests, Personal, Other, Congress invitation: Takeda; Financial Interests, Institutional, Local PI: BMS, Ipsen. J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen, Eisai; Financial Interests, Institutional, Advisory Board: Exactscience, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Financial Interests, Coordinating PI: AstraZeneca, Seagen; Financial Interests, Local PI: MSD, Daiichi; Non-Financial Interests, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi, MSD. F. Selle: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK Tesaro, MSD, AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK Tesaro, MSD, Eisai, Seagen. P. Laurent-Puig: Financial Interests, Personal, Invited Speaker: Amgen, Sanofi; Financial Interests, Personal, Advisory Board: Biocartis, Pierre Fabre; Financial Interests, Personal, Ownership Interest: Methys DX; Financial Interests, Institutional, Research Grant, PI of translational research: Federation Francophone de Cancerologie Digestive; Non-Financial Interests, Leadership Role: President of Canceropole Ile de France. F. Joly Lobbedez: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca, MSD, Janssen, Ipsen, Bayer, Astellas, Eisai, Seagen, Novocure, Pfizer; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, MSD, Janssen, Ipsen, Amgen, Novartis/3A, Eisai, Amgen, Eisai; Financial Interests, Institutional, Invited Speaker: Viatris; Financial Interests, Institutional, Coordinating PI: GSK, AstraZeneca; Financial Interests, Institutional, Research Grant: BMS, Astellas; Financial Interests, Institutional, Funding: Janssen; Non-Financial Interests, Member: GCIG; Other, travel and congress: MSD, Ipsen, Chugai; Other, travel: GSK, Eisai. J. Alexandre: Financial Interests, Personal, Advisory Board: Eisai, MSD, GSK, Janssen, Pfizer, Seagen; Financial Interests, Personal, Invited Speaker: Eisai, MSD, AstraZeneca, GSK, Novartis; Financial Interests, Institutional, Research Grant: Janssen, GSK, MSD; Financial Interests, Institutional, Local PI: MSD, Eisai, Agenus, GSK, ImmunoGen, Incyte; Financial Interests, Institutional, Coordinating PI: Kartos. All other authors have declared no conflicts of interest.