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

Autor: Sharifi N; Desai Sethi Urology Institute and.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA., Diaz R; Desai Sethi Urology Institute and.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA., Lin HM; Advanced Prostate Cancer Group, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; School of Clinical Medicine, UNSW, Sydney, New South Wales, Australia., Roberts E; Desai Sethi Urology Institute and.; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA., Horvath LG; Advanced Prostate Cancer Group, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; School of Clinical Medicine, UNSW, Sydney, New South Wales, Australia.; Chris O'Brien Lifehouse, Sydney, New South Wales, Australia.; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia., Martin A; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.; Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia., Stockler MR; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia., Yip S; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia., Subhash VV; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia., Portman N; Advanced Prostate Cancer Group, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; School of Clinical Medicine, UNSW, Sydney, New South Wales, Australia.; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia., Davis ID; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.; Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia.; Department of Cancer Services, Eastern Health, Melbourne, Victoria, Australia., Sweeney CJ; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, New South Wales, Australia.; South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Sep 17; Vol. 134 (18). Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1172/JCI183583
Abstrakt: BACKGROUNDMetastatic 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.METHODSOur 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.RESULTSPatients 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.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.
Databáze: MEDLINE