In metastatic castration-sensitive prostate cancer, both progression to castration-resistant disease and overall survival are negatively impacted by the adrenal-permissive genotype of HSD3B1, according to a new analysis of data from the phase 3 CHAARTED trial.
Androgen deprivation therapy (ADT) almost always produces an initial response in metastatic prostate cancer; over time, however, the cancer inevitably develops a resistance to castration. One major way in which this happens is when the tumor synthesizes testosterone or dihydrotestosterone from extragonadal precursor steroids, restimulating the androgen receptor. The gene HSD3B1 encodes the enzyme 3β-hydroxysteroid dehydrogenase-1, which catalyzes the rate-limiting step in the metabolic conversion of dehydroepiandrosterone into testosterone and dihydrotestosterone. A germline variation can affect this process: HSD3B1(1245A), an adrenal-restrictive allele, encodes for an enzyme that degrades rapidly and limits conversion of dehydroepiandrosterone into dihydrotestosterone, whereas HSD3B1(1245C), an adrenal-permissive allele, encodes for a stable enzyme that enables increased conversion to dihydrotestosterone.
Retrospective studies have associated HSD3B1(1245C), which occurs disproportionately frequently in white men, with poorer outcomes in terms of time to development of castration-resistant prostate cancer (CRPC), metastasis-free survival, and overall survival. The current analysis sought to prospectively validate these findings.
The phase 3 E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter study of castration with or without docetaxel in men with newly diagnosed metastatic prostate cancer. Of the 790 patients randomized for the trial, 527 had available DNA samples. The current publication analyzed data from the 475 white men with DNA samples, for whom the HSD3B1 germline genotype was retrospectively determined.
Of the 475 patients, who had a mean age of 63 years, 56.8% inherited the adrenal-permissive genotype, having at least one HSD3B1(1245C) allele. Among men with low-volume disease, those with the adrenal-permissive genotype were less likely to still be free of CRPC at two years compared with those who had the adrenal-restrictive genotype (51.0% vs 70.5%). In addition, they had a worse rate of five-year overall survival (57.5% vs 70.8%). Among patients with high-volume disease, genotype was not associated with any outcomes. There was no association between genotype and docetaxel benefit for either high-volume or low-volume disease.
"This expanded analysis of a large randomized trial appears to demonstrate that the adrenal-permissive genotype… is associated with early development of CRPC and worse overall survival in white patients with low-volume metastatic prostate cancer treated with ADT regardless of the use of docetaxel [and] despite any subsequent therapies received after the development of CRPC. To our knowledge, these results represent the first prospective apparent support of the importance of the HSD3B1 genotype with respect to clinical outcomes," write the researchers in their publication in JAMA Oncology, led by first author Jason W. D. Hearn, MD, Assistant Professor of Radiation Oncology at Michigan Medicine, and senior author Nima Sharifi, MD, Director of the Center for Genitourinary Malignancies Research at the Cleveland Clinic's Lerner Research Institute. "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."
For More Information
Hearn JWD, Sweeney CJ, Almassi N, et al (2020). HSD3B1 genotype and clinical outcomes in metastatic castration-sensitive prostate cancer. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2019.6496
Image credit: National Institutes of Health