Abstract 1380P
Background
The androgen-receptor pathway inhibitors (ARPI) are standard treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the mechanisms of both primary and acquired resistance remain largely unknown.
Methods
In a prospective precision oncology trial, MATCH-R (NCT02517892), 55 mCRPC patients were included among whom 45 underwent whole exome sequencing (WES) and 52 RNA-sequencing (RNA-seq) of tumor tissue biopsies before starting ARPI. 16 patients who initially responded to the treatment underwent a second biopsy at resistance (WES=14, RNA-seq=14). Functional activity of signal transduction pathways was determined from RNA-seq data using OncoSIGNal (InnoSIGN, The Netherlands) and by gene set enrichment analysis. Associations of genomic and transcriptomic alterations with resistance were determined using Wilcoxon and Fisher's exact tests.
Results
22/55 patients had primary resistance. No genomic alteration detected on WES analysis was significantly associated with primary resistance. Analysis of sequential biopsies suggested that mCRPC follows mainly a parallel evolution model. At time of acquired resistance, most tumors have acquired new drivers affecting AR pathway (e.g, AR, NCOR1/2) or lineage switching (e.g, RB1, PTEN, TP53). AR gene alterations and AR expression were similar between responders and non-responders. Transcriptional analysis has demonstrated that multiple specific gene sets - including those linked to low AR-transcriptional-activity, stemness program, RB loss and homologous repair deficiency – were activated in both primary and acquired resistance. OncoSIGNal analysis has revealed that high HH and low AR pathways activity were associated with resistance to ARPI.
Conclusions
Multiple transcriptional programs already activated in pre-treated samples were associated with resistance to ARPI. Clonal evolution analysis along with RNA-seq data point to the role of genomic instability and lineage switching in driving acquired resistance. Specifically, the activity of the HH pathway may play a critical role in resistance to ARPI.
Clinical trial identification
NCT02517892.
Editorial acknowledgement
Legal entity responsible for the study
Institut Gustave Roussy.
Funding
Sanofi and Janssen.
Disclosure
C. Helissey: Financial Interests, Personal, Invited Speaker: Janssens, roche, Astellas, AstraZeneca, Sanofi; Non-Financial Interests, Principal Investigator: Janssen, Sanofi, roche, Astellas. P. Lavaud: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Sanofi, Janssen; Financial Interests, Personal, Other, Travel accommodation: Ipsen, Janssen, Astellas, Pfizer. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck KGaA, Pfizer, Gilead, Seattle Genetics, Taiho; Financial Interests, Personal, Other, Lectures, Advisory Boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, Lectures, Advisory Boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, MSD, Exelexis, AstraZeneca, Pfizer, Merck KGaA, BMS, Astellas, Gilead, Incyte; Financial Interests, Invited Speaker: MSD, Astellas, Gilead/Immunomedics, Taiho; Financial Interests, Personal, Invited Speaker: Basilea; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, Scientific Committee: ARC. All other authors have declared no conflicts of interest.