Inheritance of the adrenal-permissive HSD3B1 genotype in men with low-volume metastatic castration-sensitive prostate cancer (mCSPC) is associated with development of earlier castration-resistant disease and shorter overall survival, according to a new study.

The genotype augments extragonadal dihydrotestosterone synthesis, and previous research has suggested an association between the adrenal-permissive allele and early development of castration-resistant prostate cancer (CRPC), investigators involved in the new study noted in a paper published in JAMA Oncology.

The new findings may enable clinicians to identify patients more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression, a team led by Nima Sharifi, MD, of Cleveland Clinic, concluded.

Dr Sharifi and colleagues analyzed the association between HSD3B1 (1245A) allele and early development of CRPC using prospective data from CHAARTED (E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer), a multicenter phase 3 trial of androgen deprivation therapy with or without docetaxel therapy in men with newly diagnosed mCSPC. Of 790 men randomized in the trial, 527 had available DNA samples. Dr Sharifi’s team retrospectively determined the HSD3B1 germline genotype in 475 white men (in whom the frequency of the adrenal-permissive allele is highest) and analyzed clinical outcomes by genotype.


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Of the 475 men, 270 (56.8%) inherited the adrenal-permissive genotype allele, whereas 205 had the adrenal-restrictive genotype, which limits extragonadal dihydrotestosterone synthesis. Among men with low-volume disease, the proportion of patients without CRPC at 2 years was significantly smaller among those with the adrenal-permissive than adrenal-restrictive genotype (51% vs 70.5%), Dr Sharifi’s team reported. The overall survival rate at 5 years also was significantly worse in the group with the adrenal-permissive genotype (57.5% vs 70.8%).

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Compared with the adrenal-restrictive genotype, the adrenal-permissive genotype was significantly associated with a nearly 1.9-fold increased risk of CRPC and 1.7-fold increased risk of death. The investigators found no associated between genotype and outcomes among men with high-volume disease.

“Taken together, our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume metastatic prostate cancer,” Dr Sharifi’s team concluded. “Those with the adrenal-permissive genotype have a worse prognosis inasmuch as they develop CRPC sooner and have shorter overall survival than men with the adrenal-restrictive genotype. This information could assist clinicians in counseling patients and guide researchers in identifying those for whom escalated androgen receptor axis inhibition beyond mere gonadal testosterone suppression is most warranted.”

Reference

Hearn JWD, Sweeney CJ, Almassi N, et al. HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer. JAMA Oncol. 2020;6(4):e196496. doi:10.1001/jamaoncol.2019.6496