As reported in JAMA Oncology, Nima Sharifi, MD, and colleagues have found that the adrenal-permissive HSD3B1 genotype is associated with earlier onset of castration resistance and poorer overall survival in men with low-volume metastatic prostate cancer.
Nima Sharifi, MD
As noted by the investigators, the adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments synthesis. Available data indicate an association between the adrenal-permissive allele, which is most common in white men, and earlier development of castration-resistant prostate cancer.
Study Details
The study involved a subgroup of 474 white males with DNA samples from the phase III CHAARTED trial. In the trial, 790 patients with castration-sensitive metastatic prostate cancer were randomly assigned to castration plus docetaxel or castration alone.
Among the 475 men, 270 (56.8%) carried the adrenal-permissive genotype; of these, 173 had high-volume disease and 97 had low-volume disease. A total of 205 carried the adrenal-restrictive genotype; of these, 128 had high-volume disease, and 77 had low-volume disease. Median follow-up among surviving patients was 64.4 months for the low-volume group and 42.6 months for the high-volume group.
Among men with low-volume disease, rates of freedom from castration-resistant prostate cancer at 2 years were 51.0% for those with the adrenal-permissive genotype vs 70.5% for those with the adrenal-restrictive genotype (P = .01). On multivariate analysis, the hazard ratio was 1.89 (95% confidence interval [CI] = 1.13–3.14, P = .02).
Among men with low-volume disease, overall survival at 5 years was 57.5% vs 70.8% (P = .03). On multivariate analysis, the hazard ratio was 1.74 (95% CI = 1.01–3.00, P = .045).
“Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.”— Nima Sharifi, MD, and colleagues
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Among men with high-volume disease, there were no significant differences between those with adrenal-permissive vs adrenal-restrictive genotypes in 2-year freedom from castration-resistant prostate cancer (26.6% vs 27.3%, P = .89; multivariate hazard ratio = 1.10, 95% CI = 0.82–1.47, P = .52) or in 5-year overall survival (37.3% vs 33.1%, P = .65; multivariate hazard ratio = 0.89, 95% CI = 0.65–1.22, P = .48).
No interaction between genotype and benefit from docetaxel was observed. For both outcomes, patients with low-volume disease did not significantly benefit from docetaxel, whereas those with high-volume disease derived benefit regardless of HSD3B1 genotype.
The investigators concluded, “Inheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.”
Dr. Sharifi, of the Genitourinary Malignancies Research Center, Cleveland Clinic, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the National Cancer Institute, U.S. Department of Defense Congressionally Directed Medical Research Programs, a Conquer Cancer, the ASCO Foundation Merit Award, and others. For full disclosures of the study authors, visit jamanetwork.com.
