Greater long-term side effect risk with intermittent ADT

New York-In men with metastatic prostate cancer, those assigned to intermittent androgen deprivation therapy (ADT) have more ischemic and thrombotic events than those assigned to continuous androgen deprivation, according to Columbia University researchers.  

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Dr. HershmanThe finding comes from linking data from the randomized SWOG 9346 clinical trial to corresponding Medicare claims. This method has the advantage of random assignment for study-specific comparisons of late effects, which limits confounding, said first author Dawn L. Hershman, MD.

Observational studies have linked ADT to sexual dysfunction, osteoporosis and bone fracture, cardiovascular disease, metabolic complications, diabetes, and cognitive changes. Much of these data come from linked databases such as the Surveillance, Epidemiology, and End Results Medicare database, in which a tumor registry is combined with claims-based data.

“Our objective was to evaluate the late effects by treatment arm on men randomized to intermittent versus continuous androgen deprivation therapy who were enrolled in SWOG 9346 for metastatic prostate cancer,” Dr. Hershman said of the study, which was presented at the 2015 American Society of Clinical Oncology annual meeting in Chicago and subsequently published in JAMA Oncology (2016; 2:453-61).

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SWOG 9346 had a non-inferiority study design in which men with newly diagnosed metastatic hormone-sensitive prostate cancer and a PSA level ≥5.0 ng/mL received induction therapy with goserelin acetate (Zoladex) plus bicalutamide (Casodex) for 7 months. If the PSA level declined to <4.0 ng/mL, patients were randomized to either continuous or intermittent ADT. Men randomized to the intermittent-therapy group discontinued ADT and had monthly PSA, and resumed ADT based on pre-specified criteria.

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Intermediate ADT failed to reach non-inferiority with respect to median overall survival.  The median duration of protocol therapy was 19 months in the intermittent arm and 17 months in the continuous arm. Intermittent therapy was associated with better erectile function and mental health at month 3 but not thereafter. There was no significant difference between the groups in the number of treatment-related high-grade adverse events.

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“Only patients without a given prior toxicity were considered at risk for experiencing new toxicity. That means that if a patient had a prior bone fracture, it would not be included in the bone fracture analysis,” said Dr. Hershman, professor of epidemiology at Columbia University’s Mailman School of Public Health and professor of medicine at Columbia University Medical Center, New York.

Toxicity was determined for any hospital claim or at least two outpatient claims at least 30 days apart. The toxicities evaluated were ischemic thrombotic events, endocrine/sexual dysfunction, dementia, and depression.

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Of the overall SWOG 9346 study population, 636 (56%) of trial participants had ≥1 year of continuous Medicare Parts A and B coverage. Of these, 311 received continuous ADT and 325 received intermittent ADT. Their mean age was approximately 71 years.

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At 5 years, the cumulative incidence of ischemic/thrombotic events was 25% in the intermittent group and 14% in the continuous group, and at 10 years, the cumulative incidence was 33% and 23%, respectively, for a hazard ratio (HR) of 0.68 (p=.02) with continuous ADT on multivariable regression analysis.

For ischemic events alone, the 5-year cumulative rates were 9% and 4% in the intermittent versus continuous arms, and the 10-year rates were 12% and 7%, respectively, for an HR of 0.55 (p=.005) on multivariable regression.

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The results were unchanged when two sensitivity analyses were conducted by treatment duration variability.

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Cycling of coag. cascade may increase risk

“One might ask, why would ischemic-thrombotic events be lower for patients on continuous ADT? We know there is an increased risk of diabetes and certain cardiovascular diseases with any exposure to ADT. Consulting with my hematology colleagues, they pointed out that the cycling of the coagulation cascade may increase risk, as it does for women on hormone replacement therapy or on birth control pills. The risk is highest in the first 6 months, after initiation of ADT. So, it may increase with each initiation of treatment,” Dr. Hershman said.

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Compared with no ADT, the incidence of vertebral fractures increased by 40% in men taking ADT. Prospective studies of bone mineral density in men on intermittent ADT have shown heterogeneity in bone mineral density recovery as patients go off treatment. Many patients enrolled in SWOG 9346 have been followed with bone density measurements and may have been treated with bisphosphonates for any change in bone density, she said.

“Given the failure of SWOG 9346 to prove non-inferiority, clinicians should be cautious about using intermittent ADT,” Dr. Hershman said.

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