August 29, 2019
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Androgen-deprivation therapy yields risk for QT prolongation, torsades de pointes

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Joe-Elie Salem

Men receiving androgen-deprivation therapies for prostate cancer, who are at high risk for hypogonadism, often had elevated risk for QT prolongation and torsades de pointes, which confer heightened sudden death odds, researchers reported in Circulation.

In a review of 6,560,565 individual case safety reports, the researchers found that seven of 10 androgen-deprivation therapy drugs were associated with disproportionately high odds of acquired long QT syndrome, torsades de pointes or sudden death (OR range = 1.4-4.7; P < .05 for all).

“The paper addresses something that we have known for some time — that women (after puberty) have a longer QTc than men, partly due to testosterone. This issue becomes important when one considers the millions of men who receive androgen deprivation therapy (antagonizing effects of testosterone),” Joe-Elie Salem, MD, PhD, assistant professor in the department of pharmacology at Pitié-Salpétrière Hospital, Paris, told Healio. “Here, we provided clinical data that men with ADT are at risk for QT prolongation and a particular form of ventricular arrhythmias (ie, torsades de pointes) but also provided pre-clinical and mechanistic evidence for this phenomenon.”

In the case safety reports, the researchers found 184 patients with acquired long QT syndrome and/or torsades de pointes — 11% of the torsades de pointes cases were fatal — and 99 patients who had sudden death (minimum time to sudden death, 0.25 days; median time to sudden death, 92 days).

Among the drugs studied, the androgen receptor agonist enzalutamide (Xtandi, Astellas/Pfizer) was associated with more deaths than the other prostate cancer drugs (17% vs. 8.1%; P < .0001), Salem and colleagues wrote.

When the researchers conducted experiments in induced pluripotent stem cells, they found acute and chronic enzalutamide (25 µm) prolonged action potential durations (P < .0001 for both).

Enzalutamide also inhibited delayed rectifier potassium current and boosted late sodium current, Salem and colleagues found.

“In men developing acquired long QT syndrome or torsades de pointes, diagnostic workup should include evaluation of testosterone blood level, androgen deprivation therapy intake, and evaluation for endocrine conditions associated with hypogonadism,” Salem said in an interview. “In men treated with androgen deprivation therapy, other risk factors for torsades de pointes should be sought and corrected, to avoid accumulation of risks. In men treated with androgen-deprivation therapy, the role of electrocardiographic monitoring to detect QT prolongation requires further evaluation.”

The findings do not necessarily change ideas about who should receive androgen-deprivation therapy, “but risks should require more monitoring,” he said. – by Erik Swain

For more information:

Joe-Elie Salem, MD, PhD, can be reached at joe-elie.salem@aphp.fr.

Disclosure: Salem reports no relevant financial disclosures. Please see the study for the other authors’ relevant financial disclosures.

Editor’s Note: This article was updated on August 30, 2019 to clarify that androgen-deprivation therapies are a treatment for prostate cancer, not hypogonadism. The Editors regret the error.