HSD3B1 variant & Abiraterone (Zytiga).

[pjoshea13]

New study below.

Some might benefit from watching this brief video first.

contactcenterworld.com/vide...

"... abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor."

"Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone"

"Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients"

-Patrick

Link to Full Text: jci.org/articles/view/98319

J Clin Invest. 2018 Aug 1;128(8):3333-3340. doi: 10.1172/JCI98319. Epub 2018 Jun 25.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

Alyamani M1, Emamekhoo H2,3, Park S4, Taylor J1, Almassi N5, Upadhyay S6, Tyler A3, Berk MP1, Hu B4, Hwang TH4, Figg WD7, Peer CJ7, Chien C8, Koshkin VS3, Mendiratta P3, Grivas P3, Rini B3, Garcia J3, Auchus RJ6, Sharifi N1,3,5.

Author information

1

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

2

Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.

3

Department of Hematology and Oncology, Taussig Cancer Institute.

4

Department of Quantitative Health Sciences, Lerner Research Institute, and.

5

Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.

6

Division of Endocrinology and Metabolism, Department of Internal Medicine and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

7

Clinical Pharmacology Program, NCI, Bethesda, Maryland, USA.

8

Janssen Research & Development, Spring House, Pennsylvania, USA.

Abstract

BACKGROUND:

A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients.

METHODS:

First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics.

RESULTS:

Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002).

CONCLUSION:

Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition.

FUNDING:

Prostate Cancer Foundation Challenge Award, National Cancer Institute.

KEYWORDS:

Endocrinology; Oncology; Prostate cancer; Sex hormones

PMID: 29939161 DOI: 10.1172/JCI98319

Free full text

[Schwah]

Thanks so much for posting but for most of us who are not on the field it is unintelligible. Can you please summarize the pertinent aspects for us and what we should ask our MO as it relates to this new info ? Greatly appreciated!

Schwah

[pjoshea13 in reply to Schwah]

Well, the paper provides an explanation why some men will have a shortened response to Zytiga. That's not a reason to have HSD3B1 tested & perhaps not use Zytiga at all.

I don't know if the drug company are looking at inhibiting 3-keto-5α-abiraterone.

The paper describes the variant as being common, so the issue should be a concern for patients & drug company alike.

-Patrick