Gene Variant May Affect Response to Abiraterone in Certain Men with Prostate Cancer

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The breakdown of the medication abiraterone, which can be accelerated by the presence of a specific gene variant, produces drug metabolites that are suspected to play a role in the progression of pros
The breakdown of the medication abiraterone, which can be accelerated by the presence of a specific gene variant, produces drug metabolites that are suspected to play a role in the progression of pros

Abiraterone is an antiandrogen medication approved by the US Food and Drug Administration (FDA)  in combination with prednisone for patients with high-risk metastatic castration-sensitive and metastatic castration-resistant prostate cancers (CRPCs).

A new study has shown that a genetic anomaly found in certain men with prostate cancer — a variant in HSD3B1 — may affect their response to abiraterone.1

Men who undergo androgen deprivation therapy (ADT) for their prostate cancer often experience recurrence and are classified as having castration-resistant prostate cancer. In men with CRPC, the cancer cells have adapted and are using an alternative source of androgens produced intratumorally from extragondal precursors that originate primarily in the adrenal glands.

Abiraterone is designed to block these extragonadal androgens, called DHEA, explained study researcher Nima Sharifi, MD, of Cleveland Clinic in Ohio.

In previous studies, Dr Sharifi and colleagues established that men with advanced prostate cancer treated with ADT who have a variant in the HSD3B1 gene had worse outcomes than patients who lacked the variant.2-4 HSD3B1 encodes an enzyme that allows the prostate cancer cells to use adrenal androgens as fuel for growth, but the study showed that in men with the variant HSD3B1 (1245C) — this enzyme becomes overactive, allowing the tumor to turn to extragonadal hormones earlier in the disease process than usual.

Based on these results, it appeared as though men with the HSD3B1 variant would benefit from blocking extragonadal androgens upfront using abiraterone. The benefit of this upfront administration of abiraterone to treat men with prostate cancer, regardless of the presence of this variant, was proven in two large clinical trials — LATITUDE and STAMPEDE — in which abiraterone plus prednisone added to ADT increased overall survival and progression-free survival in men with castration-sensitive disease.3,4 However, abiraterone is metabolized differently in different men.

In the current study, Dr Sharifi and colleagues found that patients with the HSD3B1 variant had high levels of a metabolite called 5-α abiraterone — which is structurally very similar to androgens, stimulates the androgen receptor, and is known to promote tumor progression in xenograft models.5

“Basically the same enzyme that becomes overactive with the HSD3B1 variant is the first enzyme that converts abiraterone to multiple steroidal metabolites,” Dr Sharifi explained. “One of the metabolites is a modest androgen agonist that can act as an androgen and stimulate the androgen receptor.”

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