Intermittent versus Continuous Androgen Deprivation in Prostate Cancer

Abstract

BACKGROUND Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. METHODS Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone–releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. RESULTS A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P = 0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. CONCLUSIONS Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.)

Androgen-deprivation therapy in men with metastatic prostate cancer: less may not necessarily be more

“…This trial recruited men without evidence of metastatic disease, and patients assigned to intermittent ADT were on therapy only 27% of the time. As expected with earlier stage prostate cancer, median survival was longer (9 years), and prostate cancerspecific mortality (14.2%) lower in this trial 5 compared to the randomized controlled trial in men with metastatic prostate cancer by Hussain et al 4 While the trial by Crook et al 5 showed non-inferiority for overall survival, intermittent therapy was associated with a non-significant increase (9%) of prostate cancer-specific mortality, with a trend towards reduced overall survival in those with a Gleason score of 8-10. Because of the relatively low number of prostate cancer-related deaths, the trial may have been underpowered to show inferiority of intermittent therapy.…”

“…In summary, because the confidence interval limits crossed both unity and the prespecified delta, the findings by Hussain et al 4 were statistically inconclusive. Thus, the results do not imply that intermittent therapy is inferior; rather, the possibility that intermittent therapy is inferior cannot be discounted.…”

“…Collectively, these two pivotal trials 4,5 do not support the hypothesis from preclinical data 3 that intermittent ADT delays the emergence of castrate resistance disease, but they do inform about patient characteristics predicting suitability for either continuous or intermittent ADT. Clearly, treatment needs to be individualized for a men with prostate cancer, based on potential benefits, and risks with intermittent versus continuous ADT, and the patient should be, where appropriate, involved in decision making.…”

“…While several smaller randomized controlled clinical trials have compared the use of intermittent with continuous ADT, no definitive information is available for patients with metastatic prostate cancer. To fill this evidence gap, a large multinational randomized controlled trial led by Hussain et al 4 was designed in 1993, and outcomes have been published recently in the New England Journal of Medicine. In a coprimary end point, the authors tested the hypotheses that (i) intermittent ADT is not inferior to continuous ADT with respect to survival in men with metastatic, hormonesensitive prostate cancer; and (ii) compared to continuous therapy, intermittent ADT improves quality of life.…”

“…The study by Hussain et al 4 enrolled 3040 men from the Unite States, Canada and UK who had newly diagnosed prostate cancer with lymph node, visceral or bone metastases and a prostate-specific antigen (PSA) . 5 ng ml 21 .…”