Continuous Androgen Deprivation Therapy Continues to Be Standard of Care for Newly Diagnosed Metastatic Prostate Cancer


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Based on a prespecified definition of survival comparability, intermittent androgen deprivation proved to be inferior to continuous androgen deprivation for men with newly diagnosed hormone-sensitive metastatic prostate cancer in the phase III SWOG 9346 intergroup trial. The data were presented at the 2012 ASCO Annual Meeting Plenary Session,1 where lead author Maha Hussain, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, concluded, “continuous therapy continues to be the standard of care.”

Intermittent androgen deprivation therapy is used in the United States as a first-line treatment option for newly diagnosed metastatic prostate cancer, based on evidence suggesting that it was feasible, with no obvious harm and more tolerable than continuous androgen deprivation. SWOG 9346 suggests that men treated with intermittent androgen therapy could have a shorter survival, and the findings favoring continuous androgen therapy were more pronounced in a subgroup analysis of men with minimal disease. ASCO dedicated a special session for a post-plenary discussion of this abstract (see sidebar below).

Study Details

Between 1995 and 2008, the study enrolled 3,040 men with newly diagnosed metastatic disease and prostate-specific antigen (PSA) levels ≥ 5 ng/mL. Almost two-thirds were white, and 14% were black. All patients received hormone therapy for 7 months. If PSA level fell to ≤ 4 ng/mL (the study population was preselected for hormone sensitivity), they were randomized to either intermittent therapy (n = 770)—stopping treatment at that point until a rise in PSA level was observed (an increase to 20 ng/mL, or for those with baseline value < 20 ng/mL, when PSA returned to baseline) or for symptoms—or continuous therapy (n = 765). Hormone therapy consisted of goserelin (Zoladex) and bicalutamide, which was in use in 1995 when the study was launched. At randomization, patients were stratified according to performance status, extent of disease, and prior exposure to hormone therapy.

At a median follow-up of 9.2 years, median overall survival was 5.1 years with intermittent androgen deprivation and 5.8 years with continuous androgen deprivation, an absolute difference of slightly more than 6 months favoring continuous androgen deprivation therapy in the entire study population.

The study design specified that survival with intermittent androgen deprivation therapy would be noninferior to continuous androgen therapy if the upper 95% confidence bound for the hazard ratio did not reach or include 1.2. This specification would rule out with high confidence the possibility of a 20% or greater increase in the relative risk of death with intermittent androgen therapy, Dr. Hussain explained. The difference between the two treatments resulted in a hazard ratio of 1.09 in favor of continuous therapy, but the upper boundary of the 95% confidence interval was 1.24, so the conclusion was that the two treatments could not be called equivalent.

“Because the confidence interval included 1.2, we conclude that survival with intermittent androgen therapy is inferior to continuous androgen therapy,” Dr. Hussain stated. “Survival in both arms was much better than expected; we expected a 3-year median overall survival,” she added.

Subgroup Analysis

In all examined subgroups, continuous androgen therapy was slightly better than intermittent androgen therapy, with the exception of extensive disease (disease extent was a prespecified protocol stratification), where intermittent androgen therapy achieved comparable survival. In line with the noninferiority endpoint, Dr. Hussain said, “intermittent androgen therapy was not inferior in extensive disease.”

In this subgroup analysis, patients with minimal disease had a median overall survival of 5.2 years in the intermittent androgen therapy group vs 7.1 years with continuous androgen therapy, suggesting that the loss of almost 2 years of life in the intermittent group could not be ruled out. “Continuous androgen therapy was significantly better in the minimal disease group, with a 23% relative increase in risk of death with intermittent androgen therapy, which was unexpected and quite striking,” Dr. Hussain commented.

 In the group with extensive disease, median overall survival was 5 years on intermittent androgen therapy vs 4.4 years on continuous androgen therapy.■

Disclosure: Dr. Hussain has received research funding from Abbott Laboratories, Astellas Pharma, Merck Serono, Millennium, NCCN, Pfizer, and Lilly.

Reference

1. Hussain M, Tangen CM, Higano CS, et al: Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer patients: Results of S9346 (INT-0162), an international phase III trial. 2012 ASCO Annual Meeting. Abstract 4. Presented June 3, 2012.


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