Data May Ease Concerns About Risks From GnRH Agonists

SAN FRANCISCO — Adjuvant androgen deprivation therapy with a gonadotropin-releasing hormone agonist did not increase deaths from cardiovascular causes in a randomized, controlled clinical trial that enrolled 945 men with locally advanced prostate cancer from 1987 to 1992.

“There's been growing concern about potential adverse effects from the use of hormonal therapy in prostate cancer,” said Dr. Jason A. Efstathiou, lead author of a new analysis that made the finding. “This study perhaps provides some evidence to put at ease some of those concerns.”

Dr. Efstathiou of Harvard Medical School, Boston, has no association with companies that make gonadotropin-releasing hormone (GnRH) agonists.

He presented the study at a symposium on genitourinary cancers sponsored by the American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology.

He and his associates analyzed data from the Radiation Therapy Oncology Group (RTOG) 85–31 study, a large, multicenter, prospective, randomized, controlled trial that compared radiotherapy for locally advanced prostate cancer to radiotherapy plus adjuvant goserelin. The 477 patients randomized to combination therapy took goserelin for a median of 4 years. In the radiotherapy-alone arm, 64% of 468 patients received salvage GnRH agonist therapy for a median of 3 years after the end of radiotherapy.

During a median follow-up of 8 years, 574 men died in the trial, 117 (20%) of them from cardiovascular-related causes. The treatment groups did not differ significantly in the rate of cardiovascular-related deaths, Dr. Efstathiou reported. In the combination therapy group, 65 (14%) men died from cardiovascular causes; meanwhile, there were 52 (11%) cardiovascular-related deaths in the radiotherapy-alone group.

The 9-year cumulative cardiovascular mortality rates were 8% for men who received adjuvant goserelin, and 11% for men treated without adjuvant goserelin. The 5-year cumulative incidence of cardiovascular mortality was 6.5% with adjuvant goserelin and 4.1% without it. These differences between groups were not statistically significant.

The study's finding of no increase in cardiovascular-related mortality remained even when excluding patients from the radiotherapy-only group who received salvage GnRH agonist therapy, or when applying alternative definitions of cardiovascular mortality, or when imputing missing data, or when limiting the analysis to high-risk subjects.

Traditional cardiac risk factors—including the presence of cardiovascular disease or diabetes mellitus—were significantly associated with increased cardiovascular mortality.

GnRH agonist therapy has been shown to decrease the risk of death from prostate cancer in men with locally advanced prostate cancer; in some studies it decreased the all-cause mortality risk. Use of GnRH agonist therapy has increased markedly for men with prostate cancer, including those with lower-stage disease and in older men with significant competing causes of mortality, Dr. Efstathiou noted.

Two separate, large, claims-based analyses have suggested that men with prostate cancer who are treated with GnRH agonists may be at greater risk for new coronary heart disease, myocardial infarction, or diabetes (J. Clin. Oncol. 2006;24:4448–56;Cancer 2007;110:149–500). Little has been known about the potential effect of GnRH therapy on cardiovascular-related mortality, which inspired the current study.

Although it found no increase in cardiovascular-related deaths from GnRH agonist therapy, this does not exclude the possibility that GnRH agonist therapy may be associated with other problems that could lead to deaths, including diabetes, anemia, or fractures, Dr. Efstathiou said.

He received a merit award for his poster and oral presentation at the meeting.