HSD3B1 genotype linked to worse outcomes in low-volume metastatic prostate cancer
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The adrenal-permissive HSD3B1 genotype appeared associated with earlier castration resistance and shorter OS among men with low-volume metastatic prostate cancer, according to results of a retrospective analysis of a randomized phase 3 study published in JAMA Oncology.
Genetic testing for the variant may help identify men who are more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression, researchers noted.
“These findings lay the groundwork for more personalized and effective treatments for prostate cancer,” Nima Sharifi, MD, director of the Center for GU Malignancies Research at Cleveland Clinic Lerner Research Institute, said in a press release. “If men carry this specific testosterone-related genetic abnormality, we may be able to individualize their therapy.”
Other retrospective studies among at least seven different groups of men with nonmetastatic and metastatic prostate cancer suggested that inheritance of the adrenal-permissive HSD3B1(1245C) allele, more frequent among white men, correlated with earlier progression to castration-resistant prostate cancer and lower rates of metastasis-free survival and OS.
Sharifi and colleagues retrospectively analyzed outcomes of 475 white men with metastatic prostate cancer enrolled in the randomized phase 3 E3805 CHAARTED study to determine if the HSD3B1(1245C) allele has the greatest consequences for men with low-volume disease.
In E3805 CHAARTED, men underwent random assignment to castration in combination with docetaxel dosed at 75 mg/m2 every 3 weeks for six cycles or castration alone.
Two-year freedom from castration-resistant prostate cancer and 5-year OS, with results stratified according to disease volume, served as the current study’s primary endpoint. Researchers evaluated overall outcomes associated with genotype by combining men across study groups according to genotype. They also conducted secondary analyses by treatment group to assess any variations in docetaxel outcomes by genotype.
Among the 475 men, 270 (mean age, 63 years) inherited the adrenal-permissive HSD3B1 genotype.
Results showed freedom from castration-resistant prostate cancer at 2 years diminished among men with low-volume disease with the adrenal-permissive genotype compared with adrenal-restrictive genotype (51% vs. 70.5%; P = .01). Men with low-volume disease and the adrenal-permissive genotype also had worse 5-year OS than those with the adrenal-restrictive genotype (57.5% vs. 70.8%; P = .03).
Multivariable analysis adjusting for known prognostic factors also showed associations between the adrenal-permissive genotype and higher risk for castration-resistant prostate cancer (HR = 1.89; 95% CI, 1.13-3.14) and higher risk for death (HR = 1.74; 95% CI, 1.01-3).
Researchers observed no association between genotype and outcomes among men with high-volume disease, and no interaction between genotype and benefit from docetaxel.
The study’s restriction to men in the E3805 CHAARTED study, which lacked a diverse patient population, served as a limitation.
“These findings represent a 7-year research story that started at the lab bench and has now reached the patient bedside,” Sharifi said in the release. “As the team has shown here, incorporating genetic testing in prostate cancer as part of routine care has significant potential to improve treatment success and quality and length of life for men with prostate cancer who carry the HSD3B1(1245C) variant. This work is another step in that direction.” – by John DeRosier
Disclosures: Sharifi reports personal fees from Janssen and Pfizer outside the study and a patent issued to HSD3B1. Please see the study for all other authors’ relevant financial disclosures.
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