{"entity":{"id":"paper-attard-abiraterone-phase-1-cyp17-jco-2008","kind":"paper","name":"Phase 1 trial of abiraterone acetate confirms that castration-resistant prostate cancer commonly remains hormone driven","aka":["Attard 2008 abiraterone phase 1","CYP17 inhibition abiraterone first-in-human"],"tldr":"Twenty-one men whose prostate cancer had already stopped responding to every hormone treatment available were given a drug that shuts off the last remaining source of androgen. Two thirds had their PSA fall, which proved the cancer had never stopped depending on the hormone.","summary":"Gerhardt Attard, Johann de Bono and colleagues at the Royal Marsden and the Institute of Cancer Research ran the first-in-human study of abiraterone acetate, a selective inhibitor of cytochrome P450 17A1 (CYP17), the enzyme that makes androgen in the adrenal gland and in the tumour itself. Twenty-one chemotherapy-naive men whose disease was resistant to multiple hormonal therapies were dosed through five levels from 250 mg to 2,000 mg.\n\nThe result settled a twenty-year argument about what castration-resistant prostate cancer is. If the disease were genuinely hormone-refractory, removing the residual androgen would do nothing. It did a great deal, and the secondary mineralocorticoid excess that the drug produces (hypertension, hypokalaemia, lower-limb oedema) was managed with a mineralocorticoid receptor antagonist, which is why abiraterone is still given with a steroid today.","asOf":"2026-09-25","links":[{"label":"J Clin Oncol 2008","url":"https://doi.org/10.1200/jco.2007.15.9749"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/18645193/"}],"tags":["prostate-evidence"],"related":["paper-cou-aa-301-abiraterone-de-bono-nejm-2011","paper-abiraterone-acetate-prostate-n-engl-j-med-2013","paper-chen-androgen-receptor-overexpression-antiandrogen-resistance-nat-med-2004","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["hormonal","targeted-therapy"],"technologies":[],"targets":["androgen-receptor"],"drugs":["abiraterone"],"companies":[],"institutions":["royal-marsden","icr-london"],"pathways":[],"terms":["castration-resistance","psa"],"trials":[],"people":["gerhardt-attard","johann-de-bono"],"bottlenecks":["b-resistance","b-translational-valley"],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2008,"doi":"10.1200/jco.2007.15.9749","pmid":"18645193","authors":"Attard G, Reid AH, Yap TA, et al.","paperType":"rct","findings":["Declines in prostate-specific antigen of at least 30 percent in 14 of 21 patients (66 percent), at least 50 percent in 12 (57 percent) and at least 90 percent in 6 (29 percent).","Responses lasted between 69 and at least 578 days.","1,000 mg was selected for cohort expansion (9 further patients) because of a plateau in pharmacodynamic effect above that dose.","Administration suppressed serum testosterone, downstream androgenic steroids and estradiol in all patients, and raised adrenocorticotropic hormone and the steroids upstream of CYP17.","The anticipated toxicities of secondary mineralocorticoid excess (hypertension, hypokalaemia and lower-limb oedema) were managed with a mineralocorticoid receptor antagonist."],"whatItMeans":"The proof, in people, that castration-resistant prostate cancer is usually still androgen-driven. It renamed the disease (hormone-refractory became castration-resistant) and it opened the line of drugs that now dominate treatment at every stage from first diagnosis of metastatic disease onwards.","caveats":["21 patients in a dose-escalation study with no control arm; the survival evidence came from COU-AA-301 and COU-AA-302.","Prostate-specific antigen decline is a pharmacodynamic signal, not a survival endpoint.","The mineralocorticoid excess is intrinsic to CYP17 blockade and is the reason abiraterone must be given with prednisolone or a mineralocorticoid antagonist, which carries its own long-term cost."],"changedPractice":true,"participants":21},"route":"/key-papers/paper-attard-abiraterone-phase-1-cyp17-jco-2008/","neighbours":{"paper":[{"id":"paper-abiraterone-acetate-prostate-n-engl-j-med-2013","kind":"paper","name":"Abiraterone in metastatic prostate cancer without previous chemotherapy","route":"/key-papers/paper-abiraterone-acetate-prostate-n-engl-j-med-2013/"},{"id":"paper-cou-aa-301-abiraterone-de-bono-nejm-2011","kind":"paper","name":"COU-AA-301: abiraterone and increased survival in metastatic castration-resistant prostate cancer after docetaxel","route":"/key-papers/paper-cou-aa-301-abiraterone-de-bono-nejm-2011/"},{"id":"paper-latitude-nejm-2017","kind":"paper","name":"LATITUDE: abiraterone plus prednisone in newly diagnosed high-risk metastatic castration-sensitive prostate cancer","route":"/key-papers/paper-latitude-nejm-2017/"},{"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/"}],"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":"hormonal","kind":"section","name":"Hormonal Therapy","route":"/fronts/hormonal/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"}],"drug":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"}],"institution":[{"id":"icr-london","kind":"institution","name":"The Institute of Cancer Research","route":"/institutions/icr-london/"},{"id":"royal-marsden","kind":"institution","name":"The Royal Marsden","route":"/institutions/royal-marsden/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"psa","kind":"term","name":"PSA (prostate-specific antigen)","route":"/terms/psa/"}],"person":[{"id":"gerhardt-attard","kind":"person","name":"Gerhardt Attard","route":"/people/gerhardt-attard/"},{"id":"johann-de-bono","kind":"person","name":"Johann de Bono","route":"/people/johann-de-bono/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-translational-valley","kind":"bottleneck","name":"The valley of death between lab and product","route":"/bottlenecks/b-translational-valley/"}],"journal":[{"id":"jco","kind":"journal","name":"Journal of Clinical Oncology","route":"/journals/jco/"}]}}