Continuous Androgen-Deprivation Therapy Remains Standard of Care for Metastatic Prostate Cancer

In an international collaborative phase III clinical trial in patients with hormone-sensitive metastatic prostate cancer, intermittent androgen-deprivation therapy (IAD) was not shown to be noninferior to continuous AD (CAD) (Abstract 4).

Maha Hussain, MD

"Therefore, CAD continues to be the standard of care" for this population, Maha Hussain, MD, of the University of Michigan Comprehensive Cancer Center, said at Sunday’s Plenary Session.

Dr. Hussain described the results of SWOG 9346 (INT-1062), a collaboration among five cooperative groups in the United States, Canada, and Europe, which she referred to as an "intergalactic study." Discussant William K. Oh, MD, of The Tisch Cancer Institute at Mount Sinai School of Medicine, called the study a "Herculean effort," spanning 17 years, enrolling more than 3,000 patients, and demonstrating the importance of cooperative groups for clinical research.

In a secondary analysis, IAD was noninferior to CAD in patients with extensive disease but was inferior to CAD in patients with minimal disease.

Noninferiority Design

The trial accrued 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer between 1995 and 2008. Those included had a prostate-specific antigen (PSA) level of 5 ng/mL or greater before initiation of AD and a Southwest Oncology Group (SWOG) performance status of 0 to 2.

Patients were stratified by performance status, extent of disease, and prior hormone therapy. Eligible patients were treated with goserelin and bicalutamide for 7 months, and those who achieved a PSA of 4 ng/mL or less were randomly assigned to CAD (765 patients) or IAD (770 patients).

In the IAD arm, therapy was reinitiated when PSA increased to 20 ng/mL or, for those who had a baseline value less than 20 ng/mL, when PSA returned to baseline.

If the PSA after another 7-month course met the normalization criteria, the patient started another observation period. If it was greater than 4 ng/mL at 6 or 7 months, the patient received CAD until progression.

The trial was designed to assess whether overall survival (OS) with IAD was noninferior to CAD. The design of the trial specified that survival with IAD would be noninferior to CAD if the 95% confi dence interval for the hazard ratio (HR; IAD versus CAD) excluded 1.2. This specification would rule out the possibility of a 20% or greater increase in the relative risk of death with IAD, Dr. Hussain explained, with an alpha of 0.05 and 90% power, adjusting for stratifications in a proportional hazards model.

The mean OS was 5.8 years for patients receiving CAD and 5.1 for patients receiving IAD (Fig. 1), representing a 9% increase in relative risk of death for IAD (HR 1.09, 95% CI [0.95 - 1.24]). Because the upper limit of the CI did not exclude 1.2, the noninferiority criterion was not met.

Therefore, IAD was not found to be noninferior to CAD based on the prespecifi ed defi nition of survival comparability. Dr. Hussain and Dr. Oh both referred to IAD as "inferior" to CAD in their presentations, and they were challenged on the use of this terminology during a later question-and-answer session.

In her presentation, Dr. Hussain noted that when the trial was designed, it was assumed that the median survival in the control arm would be 3 years. With actual median survival of more than 5 years in the study, "an HR of 1.2 translates into a larger difference in survival, which is certainly inferior and clinically concerning," she said.

In his discussion of the paper, Dr. Oh noted that a previous study, NCIC PR7, showed that either CAD or IAD are appropriate standards of care in patients with nonmetastatic prostate cancer.

However, all previous trials have been underpowered to evaluate survival in metastatic prostate cancer.

"Neither this nor any randomized trial has ever shown a superior cancer outcome with intermittent AD therapy," he said, "and we must really stop propagating this concept based on animal studies performed 2 decades ago."

The cooperative groups involved in the study, in addition to SWOG, were the Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), and the European Organisation for Research and Treatment of Cancer (EORTC).