{"entity":{"id":"paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018","kind":"paper","name":"Circulating tumour DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer","aka":[],"tldr":"A blood test taken before the first tablet identified the men whose disease would resist both standard hormone drugs, which the clinical variables could not do.","summary":"Two hundred and two men with treatment-naive metastatic castration-resistant prostate cancer were randomised to abiraterone or enzalutamide and had whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA before therapy. Time to progression was similar for the two agents, which had never been directly compared. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and of circulating tumour DNA abundance. Somatic alterations in TP53, previously linked to reduced tumour dependency on androgen receptor signalling, were also independently associated with rapid resistance. Detection of AR amplification did not outperform standard prognostic biomarkers, but AR gene structural rearrangements truncating the ligand-binding domain were identified in several men with primary resistance.","asOf":"2026-09-25","links":[{"label":"Annala et al., Cancer Discov 2018: circulating tumour DNA genomics and resistance to abiraterone or enzalutamide in 202 randomised men with treatment-naive mCRPC","url":"https://doi.org/10.1158/2159-8290.CD-17-0937"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29367197/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["liquid-biopsy","wes-wgs"],"targets":["brca","atm","tp53","androgen-receptor"],"drugs":["abiraterone","enzalutamide"],"companies":[],"institutions":[],"pathways":["ar-signaling","homologous-recombination-repair","p53-cell-cycle","resistance-routes-map"],"terms":["ctdna","cfdna","liquid-biopsy","resistance","castration-resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2018,"doi":"10.1158/2159-8290.CD-17-0937","pmid":"29367197","authors":"Annala M, Vandekerkhove G, Khalaf D, et al.","paperType":"rct","findings":["BRCA2 and ATM defects independently associated with poor outcome on either hormonal agent.","TP53 alterations independently associated with rapid resistance.","AR amplification detection did not outperform standard prognostic biomarkers.","AR structural rearrangements truncating the ligand-binding domain found in men with primary resistance.","Time to progression was similar for abiraterone and enzalutamide."],"whatItMeans":"It shows that the useful information in a castration-resistant plasma sample is in the repair genes and TP53 rather than in the androgen receptor finding that dominates the report, and it is the closest thing the field has to a head-to-head comparison of abiraterone against enzalutamide.","caveats":["A randomised phase 2 trial, so the drug comparison is not definitive.","Two hundred and two men at Canadian centres.","The prognostic associations have not been used prospectively to assign treatment."],"changedPractice":false,"participants":202},"route":"/key-papers/paper-annala-ctdna-resistance-abiraterone-enzalutamide-cancer-discov-2018/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"cfdna","kind":"term","name":"Cell-free DNA (cfDNA)","route":"/terms/cfdna/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"}],"journal":[{"id":"cancer-discovery","kind":"journal","name":"Cancer Discovery","route":"/journals/cancer-discovery/"}],"biomarker":[{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","route":"/biomarkers/ar-amplification/"},{"id":"ctdna-tumour-fraction","kind":"biomarker","name":"Circulating tumour DNA fraction (and what a negative plasma result means)","route":"/biomarkers/ctdna-tumour-fraction/"}]}}