Androgen Deprivation for Rising PSA Level

Following the discovery in 1941 that prostate cancer is dependent on androgen, the mainstay treatment for metastatic disease has been androgen deprivation. Since then, indications for androgen deprivation have been expanded to include nonmetastatic disease as well.

In the early 1990s, prostate-specific antigen (PSA) testing offered an objective evaluation of the efficacy of definitive treatment; biochemical failure became an accepted end point. However, possibility of early diagnosis created a dilemma for clinicians because the justification for continuous androgen deprivation is more obvious in patients with symptomatic disease than in men with a slowly rising PSA level without symptoms of disease.

The use of intermittent androgen deprivation for PSA elevation following radiotherapy may improve quality of life and delay hormone resistance. Researchers recently conducted a phase 3 noninferiority randomized trial to assess intermittent versus continuous androgen deprivation therapy in men with a rising PSA level after definitive radiotherapy and or evidence of metastatic disease. Results were reported in the New England Journal of Medicine [2012;367(10):895-903].

The primary end point was overall survival. Secondary end points included time to castration-resistant disease and quality of life. For patients in the intermittent-therapy group, additional end points included the duration of off-treatment intervals, time to testosterone recovery, and time to potency recovery.

The study enrolled 1386 patients with a PSA level >3 ng per milliliter more than 1 year following primary or salvage radiotherapy for localized prostate cancer. Of those, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Intermittent therapy was provided in 8-month cycles, with nontreatment periods determined according to the PSA level.

Analyses of pretreatment characteristics and efficacy were performed with data from the intention-to-treat population (all 1386 patients who underwent randomization) and with data from the per-protocol population (the 1364 patients who underwent randomization and received at least 1 dose of the assigned treatment; there were no notable differences between the 2 sets of results.

Overall survival was calculated from the date of randomization to the date of death. At the median follow-up (6.9 years), 525 patients had dies (268 in the intermittent-therapy group and 256 in the continuous-therapy group). Median overall survival was 8.8 years in the intermittent-therapy group and 9.1 years in the continuous-therapy group (hazard ratio for death with intermittent therapy vs continuous therapy, 1.02; 95% confidence interval [CI], 0.86-1.21).

The P value for noninferiority (hazard ratio, <1.25) was .009, supporting the hypothesis that intermittent therapy was not inferior to continuous therapy.

Because there was a high proportion of deaths that were unrelated to prostate cancer (59%), the researchers added an unplanned retrospective analysis to determine whether a significant difference in treatment effect was obscured by the data on deaths from causes other than prostate cancer. A total of 214 patients died from prostate cancer or related causes (120 in the intermittent-therapy group and 94 in the continuous-therapy group). Following adjustment for stratification and confounding factors, the estimated disease-specific hazard ratio was 1.23 (95% CI, 0.94-1.60; P=.13).

Time to testosterone recovery during the first nontreatment interval in the intermittent-therapy group was defined as the time until a return to the pretreatment level. Full testosterone recovery in 35% of patients in the intermittent-therapy group; testosterone recovery to the trial-entry threshold occurred in 79%.

Quality of life was assessed at fixed time points, regardless of the phase of treatment. At baseline quality-of-life scores were similar in the 2 groups. Intermittent therapy provided benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function.

For functional domains (physical role and global health), scores in the intermittent-therapy group were slightly better compared with the continuous-therapy group, but the differences were not statistically significant. For items pertaining to symptoms, intermittent therapy was associated with significantly better scores for hot flashes (P<.001), desire for sexual activity (P<.001), and urinary symptoms (P=.006), with a trend toward improvement in the level of fatigue (P=.07).

In summary, the researchers stats, “Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy.”