Inheriting the adrenal-permissive HSD3B1 genotype may be associated with earlier development of castration resistant disease and shorter overall survival (OS) among white men with low-volume metastatic castration-sensitive prostate cancer (mCSPC), according to a new study published in JAMA Oncology.1

The findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume metastatic prostate cancer, investigators concluded.

A team led by Nima Sharifi, MD, Director of the Genitourinary Malignancies Research Center at the Case Comprehensive Cancer Center in Cleveland examined whether the inheritance of the adrenal-permissive HSD3B1(1245C) allele is associated with probable worse clinical outcomes in men treated with androgen deprivation therapy (ADT) with or without docetaxel for mCSPC. They examined clinical outcomes in a phase 3 clinical trial of castration compared with castration plus docetaxel.

“We found that Caucasian men with low-volume metastatic prostate cancer who inherit the adrenal-permissive HSD3B1 allele develop castration-resistant prostate cancer more rapidly and have shorter overall survival from the time of castration therapy, with or without docetaxel,” said corresponding author.


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In a series of previous studies, investigators found that a more active inherited version of the adrenal-permissive HSD3B1 allele was associated with conversion of adrenal precursor steroids to potent androgens (testosterone and dihydrotestosterone). For the current study, Dr Sharifi and colleagues looked at 475 genotyped white men with mCSPC treated in the E3805 CHAARTED (Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial.2

While the study showed that the adrenal-permissive genotype was associated with significantly shorter time to castration-resistant disease and significantly lower OS in men with low-volume disease, it did not show any association between genotype and outcomes in men with high-volume disease. E3805 CHAARTED was conducted from July 2006 to December 31, 2012 and included 790 men (of whom 527 had available DNA samples). All men were randomized to castration plus docetaxel 75 mg/m2 every 3 weeks for 6 cycles, or castration alone. The mean age was 63 years.

The current analysis included 475 white men with DNA samples and it showed that 270 (56.8%) of them had inherited the adrenal-permissive genotype. Among men with low-volume disease, freedom from castration-resistant prostate cancer (CRPC) at 2 years was reduced in men with the adrenal-permissive genotype compared with those who had the adrenal-restrictive genotype (51% vs 70.5%). OS at 5 years also was lower among men with the adrenal-permissive genotype (57.5% vs 70.8%). The adrenal-permissive genotype was significantly associated with a nearly 1.9-fold increased risk for CRPC and 1.7-fold increased risk for death.

“Right now, we do not use genetic information to determine the time and type of hormonal therapy used for the treatment of advanced prostate cancer,” Dr Sharifi told Renal & Urology News. “Our study, which shows a clear inherited genetic determinant of clinical outcomes after castration therapy and has a clearly defined mechanism, is a step toward distinguishing between different types of prostate cancer and determining the best treatment for each genetic group.”

The median follow-up time was 64.4 months for the low-volume group and 42.6 months for the high-volume group. As far as they are aware, the results represent the first prospective apparent support of the importance of the HSD3B1 genotype with respect to clinical outcomes, and they are concordant with previous retrospective studies, Dr Sharifi and colleagues noted.

Michael Whalen, MD, Assistant Professor of Urology at the George Washington University School of Medicine and Health Sciences in Washington, DC, said given these new findings and the fact that an inhibitor of adrenal androgens exists in the armamentarium, this allele should certainly continue to be examined as part of the germline analysis in future prospective clinical trials. Still, based on the purported mechanism of HSD3B1, he said, it would have been interesting and meaningful for the authors of the current study to have reported on the patients’ circulating levels of adrenal androgens, DHEA, and androstenedione, or even intratumoral levels of these hormones to assess their impact in the tumor microenvironment.

“The findings of the study dovetail well with the recent National Comprehensive Cancer Network Prostate Cancer Guidelines 2020 to recommend germline testing to all de novo metastatic prostate cancer patients,” Dr Whalen said. “Although more work has to be done, this is certainly a step in the right direction toward precision medicine to tailor treatments based on expectations for success as derived by analysis of a patient’s genetic code.”

Heather H. Cheng, MD, PhD, Associate Professor of Genitourinary Medical Oncology at the University of Washington in Seattle, said the new findings will need to be confirmed in prospective trials with a much more diverse cohort. “Given the preponderance in white men, the study highlights the need for a collective effort in identifying similarly promising findings in diverse populations,” Dr Cheng said. “Incorporating the HSD3B1 allele as a stratification factor for low-volume metastatic prostate cancer in future prospective randomized trials will be a key step in confirming these findings and in further defining its clinical utility.”

Prostate cancer is complex, and this complexity increases as the disease progresses, observed Maha Hussain, MD, Professor of Medicine in the Division of Hematology Oncology at Northwestern University Feinberg School of Medicine, where she is Director of the Robert H. Lurie Comprehensive Cancer Center. “While over 90% of men will respond to androgen deprivation therapy, we also know that outcomes are variable in metastatic hormone sensitive prostate cancer and that disease burden and location clearly matter,” Dr Hussain said. In addition, aside from disease burden and location it is still unclear what specifically impacts the magnitude and duration of response, she said. 

“The results from this prospective study are very interesting and certainly provide some insights into the biology [of mCSPC] and why we see variable outcomes even in patients with low-volume disease,” Dr Hussain said.  Nevertheless, even though the freedom from CRPC at 2 years and OS at 5 years was lower in men with low-volume disease with the adrenal-permissive versus adrenal-restrictive genotype, these differences do not justify therapy change at this time outside of clinical trials.

References

  1. 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
  2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080-1087. doi: 10.1200/JCO.2017.75.3657