Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance

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dc.contributor.authorSharifi, N.
dc.contributor.authorDiaz, R.
dc.contributor.authorLin, H.-M.
dc.contributor.authorRoberts, E.
dc.contributor.authorHorvath, L.G.
dc.contributor.authorMartin, A.
dc.contributor.authorStockler, M.R.
dc.contributor.authorYip, S.
dc.contributor.authorSubhash, V.V.
dc.contributor.authorPortman, N.
dc.contributor.authorDavis, I.D.
dc.contributor.authorSweeney, C.J.
dc.date.issued2024
dc.description.abstractBACKGROUND. Metastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes. METHODS. Our prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes. RESULTS. Patients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide. CONCLUSION. These data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.
dc.description.statementofresponsibilityNima Sharifi, Robert Diaz, Hui-Ming Lin, Evan Roberts, Lisa G. Horvath, Andrew Martin, Martin R. Stockler, Sonia Yip, Vinod V. Subhash, Neil Portman, Ian D. Davis, and Christopher J. Sweeney
dc.identifier.citationJournal of Clinical Investigation, 2024; 134(18):e183583-e183583
dc.identifier.doi10.1172/jci183583
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.orcidSweeney, C.J. [0000-0002-0398-6018]
dc.identifier.urihttps://hdl.handle.net/2440/143630
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigation
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2016274
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1196225
dc.rights© 2024, Sharifi et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License
dc.source.urihttp://dx.doi.org/10.1172/jci183583
dc.subjectMetastatic hormone-sensitive prostate cancer (mHSPC); androgen deprivation therapy (ADT)
dc.subject.meshAdrenal Glands
dc.subject.meshHumans
dc.subject.meshProstatic Neoplasms
dc.subject.meshNeoplasm Metastasis
dc.subject.meshBenzamides
dc.subject.meshNitriles
dc.subject.meshPhenylthiohydantoin
dc.subject.meshMultienzyme Complexes
dc.subject.meshAndrogen Antagonists
dc.subject.meshSteroid Isomerases
dc.subject.meshProgesterone Reductase
dc.subject.meshNeoplasm Proteins
dc.subject.meshSurvival Rate
dc.subject.meshAged
dc.subject.meshMiddle Aged
dc.subject.meshMale
dc.titleSurvival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance
dc.typeJournal article
pubs.publication-statusPublished

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