{"entity":{"id":"paper-antonarakis-ar-v7-resistance-nejm-2014","kind":"paper","name":"AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer","aka":["Antonarakis 2014","AR-V7","androgen receptor splice variant 7"],"tldr":"A short form of the androgen receptor, missing the part that the hormone drugs grab onto, can be detected in tumour cells circulating in the blood. Not one man whose cells carried it responded to either enzalutamide or abiraterone.","summary":"Emmanuel Antonarakis, Jun Luo and colleagues at Johns Hopkins used a quantitative reverse-transcriptase polymerase chain reaction assay for the androgen receptor splice variant 7 messenger RNA in circulating tumour cells from 62 men with metastatic castration-resistant prostate cancer starting enzalutamide or abiraterone.\n\nAR-V7 lacks the ligand-binding domain, which is exactly what both drugs target, so the prediction was mechanical and the result was categorical: 0 percent of AR-V7-positive men had a prostate-specific antigen response on either drug, against 53 percent and 68 percent of AR-V7-negative men. Every survival endpoint followed. A decade on, AR-V7 testing is available but little used, partly because a negative result does not guarantee response and partly because the alternatives the test would send a man to, taxanes and radioligand therapy, are used in the same sequence anyway.","asOf":"2026-09-25","links":[{"label":"N Engl J Med 2014","url":"https://doi.org/10.1056/nejmoa1315815"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25184630/"},{"label":"Antonarakis et al., N Engl J Med 2014: AR-V7 in circulating tumour cells and resistance to enzalutamide and abiraterone (62 patients)","url":"https://doi.org/10.1056/NEJMoa1315815"}],"tags":["prostate-evidence"],"related":["paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","paper-mu-sox2-lineage-plasticity-science-2017","idea-bio1-arv7-degrader","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["diagnostics","hormonal"],"technologies":["liquid-biopsy"],"targets":["androgen-receptor"],"drugs":["enzalutamide","abiraterone"],"companies":[],"institutions":["johns-hopkins"],"pathways":["ar-signaling","rna-splicing","resistance-routes-map","intravasation-ctc-survival"],"terms":["castration-resistance","psa","ctdna","radiographic-progression-free-survival","neuroendocrine-differentiation","ar-v7","liquid-biopsy","resistance","psa50"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2014,"doi":"10.1056/nejmoa1315815","pmid":"25184630","authors":"Antonarakis ES, Lu C, Wang H, et al.","paperType":"observational","findings":["AR-V7 was detectable in circulating tumour cells from 39 percent of 31 enzalutamide-treated patients and 19 percent of 31 abiraterone-treated patients.","Among men receiving enzalutamide, AR-V7-positive patients had a prostate-specific antigen response rate of 0 percent against 53 percent in AR-V7-negative patients (P equals 0.004).","Among men receiving abiraterone, the prostate-specific antigen response rate was 0 percent against 68 percent (P equals 0.004).","Median prostate-specific antigen progression-free survival on enzalutamide was 1.4 against 6.0 months, clinical or radiographic progression-free survival 2.1 against 6.1 months, and overall survival 5.5 months against not reached (P equals 0.002).","The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA."],"whatItMeans":"The first predictive resistance biomarker in prostate cancer, and a mechanism rather than a correlation: a receptor with no ligand-binding domain cannot be blocked by a drug that binds the ligand-binding domain. It is also the origin of the case for androgen receptor degraders, which destroy the protein rather than blocking a site the protein no longer has.","caveats":["62 patients, prospectively enrolled but not randomised, and the authors state that large-scale prospective validation is required.","A negative AR-V7 result does not predict response, only the absence of this particular resistance mechanism; most non-responders are AR-V7-negative.","Assay-dependent: messenger RNA and protein-based AR-V7 assays do not identify the same patients, and the test is not standardised across laboratories."],"changedPractice":false,"participants":62},"route":"/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/","neighbours":{"paper":[{"id":"paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","kind":"paper","name":"Molecular determinants of resistance to antiandrogen therapy","route":"/key-papers/paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004/"},{"id":"paper-mu-sox2-lineage-plasticity-science-2017","kind":"paper","name":"SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer","route":"/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/"}],"idea":[{"id":"idea-bio1-arv7-degrader","kind":"idea","name":"Destroy the truncated androgen receptor that hormone drugs cannot touch","route":"/ideas/idea-bio1-arv7-degrader/"},{"id":"idea-prostate-randomise-the-sequence-not-only-the-drugs","kind":"idea","name":"Randomise the order of treatment, not only the drugs: a strategy platform for metastatic prostate cancer","route":"/ideas/idea-prostate-randomise-the-sequence-not-only-the-drugs/"},{"id":"idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2","kind":"idea","name":"Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint","route":"/ideas/idea-prostate-bipolar-androgen-therapy-phase-3-on-pfs2/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch","route":"/roadmaps/prostate-roadmap/"}],"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/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"hormonal","kind":"section","name":"Hormonal Therapy","route":"/fronts/hormonal/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"}],"drug":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"}],"institution":[{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"intravasation-ctc-survival","kind":"pathway","name":"Intravasation & circulating tumour cells","route":"/pathways/intravasation-ctc-survival/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"},{"id":"rna-splicing","kind":"pathway","name":"RNA splicing","route":"/pathways/rna-splicing/"}],"term":[{"id":"ar-v7","kind":"term","name":"AR-V7 splice variant","route":"/terms/ar-v7/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"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/"},{"id":"neuroendocrine-differentiation","kind":"term","name":"Neuroendocrine differentiation in prostate cancer","route":"/terms/neuroendocrine-differentiation/"},{"id":"psa","kind":"term","name":"PSA (prostate-specific antigen)","route":"/terms/psa/"},{"id":"psa50","kind":"term","name":"PSA50 / PSA90 response","route":"/terms/psa50/"},{"id":"radiographic-progression-free-survival","kind":"term","name":"Radiographic progression-free survival (rPFS)","route":"/terms/radiographic-progression-free-survival/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"biomarker":[{"id":"ar-v7-splice-variant","kind":"biomarker","name":"AR-V7 splice variant","route":"/biomarkers/ar-v7-splice-variant/"}]}}