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ASCO 2019 Annual Meeting

ASCO 2019: HSD3B1 and OS in Men with Low-Volume Metastatic Prostate Cancer Treated with ADT or Chemohormonal Therapy in the CHAARTED Randomized Trial

Chicago, IL (UroToday.com) The HSD3B1(1245A > C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. A common germline variant affects steady-state levels of HSD3B1 and results in different metabolic phenotypes: (i) H HSD3B1(1245A) is the adrenal restrictive allele and encodes for a more rapidly degraded enzyme that limits conversion of DHEA to DHT, and (ii) HSD3B11245C is the adrenal permissive allele that encodes for a stable enzyme that enables even greater conversion from DHEA to DHT. Several retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. Furthermore, HSD3B1(1245C) allele varies greatly by race and is much more common in Caucasians. At the ASCO 2019 prostate cancer session, Jason Hearn, MD and colleagues presented results of their validation study with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) study.1 The objectives of the study were to (i) validate the clinical significance of HSD3B1(1245C) allele on time to CRPC and OS by genotyping men included in CHAARTED, and (ii) to analyze outcomes in Caucasian men, particularly those with low volume disease. 

In CHAARTED, men with newly metastatic prostate cancer were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). The investigators determined germline HSD3B1 genotype in a subset of Caucasian men stratified by volume of disease (low volume disease: < 4 bone metastases, no visceral metastases). Furthermore, they analyzed 2-year freedom from CRPC (an early endpoint) and 5-year OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. 

There were 475 Caucasian men in CHAARTED that were genotyped, including 174 low volume and 301 high volume disease patients. The median follow-up was 64.4 months for low volume mean and 42.6 months for high volume men. For low-volume men, freedom from CRPC at 2-years was 70.5% for HSD3B1(1245A) and 51.0% for HSD3B1(1245C) (p=0.01); 5-year OS was 70.8% for HSD3B1(1245A) and 57.5% for HSD3B1(1245C) (p=0.03). For high-volume men, freedom from CRPC at 2-years was 27.3% for HSD3B1(1245A) and 26.6% for HSD3B1(1245C) (p=0.89); 5-year OS was 33.1% for HSD3B1(1245A) and 37.3% for HSD3B1(1245C) (p=0.65).
Figure1_CRPC_HSD3B1_genotype.png
For low-volume men, multivariable analysis of the impact of HSD3B1(1245C) genotype demonstrated (i) shorter time to CRPC: HR 1.89 (95% CI 1.13-3.14), and (ii) lower overall survival: HR 1.74 (95% CI 1.01-3.00). For high volume men, there was no association between genotype and clinical outcomes. Additionally, there was no interaction between treatment arm (receipt of docetaxel) and genotype.

The conclusion from this study is that inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with more rapid development of CRPC and lower OS in Caucasian men treated with ADT with or without docetaxel for low volume newly metastatic prostate cancer. Additional study is warranted in patients with high volume disease.

Clinical trial information: NCT00309985

Presented by: Jason W.D. Hearn, MD, University of Michigan, Ann Arbor, MI

Co-Authors: Christopher Sweeney, Nima Almassi, Chad A. Reichard, Chandana A. Reddy, Brian Hobbs, David Frazier Jarrard, Yu-Hui Chen, Robert Dreicer, Jorge A. Garcia, Michael Anthony Carducci, Robert S. DiPaola, Nima Sharifi; University of Michigan, Ann Arbor, MI; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; UT MD Anderson Cancer Center, Houston, TX; Cleveland Clinic, Cleveland, OH; Taussig Cancer Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH; University of Wisconsin Hosp and Clinics, Madison, WI; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; University of Virginia, Charlottesville, VA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Sidney Kimmel Cancer Center At Johns Hopkins, Baltimore, MD; University of Kentucky, Lexington, KY

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.