Intermittent ADT Upped Risk for Ischemic, Thrombotic Events

Men with prostate cancer assigned to intermittent androgen deprivation therapy (ADT) experienced more ischemic and thrombotic events than did men assigned to continuous ADT, according to the results of a substudy of the SWOG S9346 trial presented by Dawn L. Hershman, MD, MS, from Columbia University Medical Center, at the 2015 ASCO Annual Meeting (abstract 5008).

“Given the failure of S9346 to prove noninferiority, clinicians should be cautious about using intermittent ADT,” Hershman said.

Previous research has shown that ADT may lead to both short- and long-term consequences, including sexual dysfunction, osteoporosis, cardiovascular disease and more. To compare the late effects of intermittent vs continuous ADT, Hershman and colleagues analyzed a subset of 1,134 patients taken from the SWOG S9346 trial, which randomly assigned patients with metastatic prostate cancer to continuous or intermittent ADT.

Results of the larger study, published in 2013 in the New England Journal of Medicine, showed that intermittent ADT failed to prove noninferiority compared with continuous therapy. There was higher median survival on continuous therapy compared with intermittent therapy (5.8 vs 5.1 months).

For this analysis, the researchers linked data between the trial and corresponding Medicare claims in order to identify and track late-effects by treatment arm. They hypothesized that late cardiovascular and endocrine effects would be lower in patients on intermittent ADT.

For intermittent ADT, treatment was reinitiated when PSA increase to 20 or returned to baseline, or for symptoms. If the PSA after 7 months was 4 or less, then patients started another observation period off of ADT. If the PSA at month 6 or 7 increased to greater than 4, then the patients received continuous therapy until progression.

Hershman and colleagues found that there was an increase of ischemic and thrombotic events at both 5 years (25% vs 14%) and 10 years (33% vs 23%) for patients assigned to intermittent ADT compared with continuous therapy (hazard ratio [HR] = 0.68; P = .02). Looking only at ischemic events, patients assigned intermittent therapy had an increased rate of events at both 5 and 10 years (HR = 0.55; P = .005).

The researchers did not find a significant difference for dementia, sexual dysfunction, depression, or endocrine events between the two treatment arms.

“Why would ischemic/thrombotic events be lower for patients on continuous ADT?” Hershman asked.

This risk is highest during the first 6 months after ADT initiation, said Hershman, so there is an increased risk with each initiation. Estrogen changes that occur with ADT discontinuation could also increase coagulation, as could testosterone levels, which may stay suppressed after ADT withdrawal.