Characteristics of the Patients

Of the 1386 patients who underwent randomization, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. 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 one dose of the assigned treatment), with no notable differences between the two sets of results. The safety analysis was based on data from the as-treated population (the 1381 patients who began treatment per protocol). The Supplementary Appendix provides details regarding patient accrual according to cooperative group (Table S1 in the Supplementary Appendix) and reasons for ineligibility (Table S2 in the Supplementary Appendix).

Table 1. Table 1. Baseline Characteristics of the Patients.

The median follow-up was 6.9 years (range, 2.8 to 11.2). Patients in the intermittent-therapy group completed one to nine 8-month treatment cycles. A total of 49 patients were lost to follow-up at a median of 4.0 years (range, 1 day to 9.6 years), with an equal distribution between the treatment groups. Baseline characteristics were balanced between the two groups (Table 1).

Overall Survival

Figure 1. Figure 1. Overall Survival in the Intention-to-Treat Population. The per-protocol analysis yielded very similar results to the analysis presented here, with an estimated hazard ratio for death with intermittent androgen-deprivation therapy (IAD), as compared with continuous androgen-deprivation therapy (CAD), of 1.03 (95% CI, 0.86 to 1.23). The P value for noninferiority (hazard ratio, <1.25) was 0.01.

Table 2. Table 2. Investigator-Reported Causes of Death (Intention-to-Treat Population).

Overall survival was calculated from the date of randomization to the date of death, with data censored at the last known date that the patient was alive. At a median follow-up of 6.9 years, a total of 524 patients had died (268 in the intermittent-therapy group and 256 in the continuous-therapy group). Figure 1 shows the Kaplan–Meier curve for overall survival according to treatment group. The causes of death, which were reported by the investigators and were not audited, are summarized in Table 2. The median overall survival was 8.8 years in the intermittent-therapy group and 9.1 years in the continuous-therapy group. The hazard ratio for death with intermittent therapy versus continuous therapy was 1.02 (95% CI, 0.86 to 1.21). The P value for noninferiority (hazard ratio, <1.25) was 0.009, supporting the hypothesis that intermittent therapy was not inferior to continuous therapy.

A multivariable Cox proportional-hazards model was used to adjust for potential prognostic factors, including age (<75 years vs. ≥75 years), Eastern Cooperative Oncology Group performance status (0 vs. 1, with 0 indicating that the patient is fully active and able to carry on all predisease activities without restriction, and 1 that the patient is restricted in physically strenuous activity but is ambulatory and able to carry out work of a light or sedentary nature), time since completion of radiotherapy (1 to 3 years vs. >3 years), baseline PSA level (3 to 15 ng per milliliter vs. >15 ng per milliliter), and neoadjuvant androgen-deprivation therapy (no vs. yes; maximum length of therapy allowed, 12 months), yielding an adjusted hazard ratio with intermittent therapy versus continuous therapy of 1.03 (95% CI, 0.86 to 1.22). A Cox regression model that included study treatment and Gleason score (≤6, 7, or 8 to 10, on a scale of 1 to 10, with higher scores indicating a worse prognosis) showed that there was no differential treatment effect among the three Gleason-score groups (Fig. S3 in the Supplementary Appendix).

Disease-Specific Survival

Table 3. Table 3. Hazard Ratio for Death from Prostate Cancer or Treatment Complication in the Intention-to-Treat Population.

In view of the high proportion of deaths that were unrelated to prostate cancer (59%), disease-specific survival was added as 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. Disease-specific survival was calculated from the date of randomization to the date of death from prostate cancer or a complication of cancer treatment. 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 (hazard ratio with intermittent therapy, 1.18; 95% CI, 0.90 to 1.55; P=0.24 by the log-rank test). After adjustment for stratification and confounding factors, the estimated disease-specific hazard ratio was 1.23 (95% CI, 0.94 to 1.60; P=0.13) (Table 3). The 7-year cumulative disease-related death rates were estimated at 18% and 15% for the intermittent-therapy and continuous-therapy groups, respectively (Fig. S4 in the Supplementary Appendix).

Time to Castration-Resistant Disease

Castration-resistant disease developed in a total of 445 patients (202 patients in the intermittent-therapy group and 243 in the continuous-therapy group). On the basis of a Cox regression analysis with adjustment for the stratification factors, the estimated hazard ratio for castration-resistant disease with intermittent therapy, as compared with continuous therapy, was 0.80 (95% CI, 0.67 to 0.98; P=0.02). With adjustment for potential prognostic factors, the estimated hazard ratio was 0.81 (95% CI, 0.68 to 0.98; P=0.03).

For patients in the intermittent-therapy group, there was an inherent delay in the identification of castration-resistant disease, because treatment had to be restarted in these patients and they had to have a “castrate-range” testosterone level and an additional three increases in the PSA level before being classified as having castration-resistant disease. This difference between the groups biased the result against continuous androgen-deprivation therapy in time to castration resistance by an unknown magnitude but probably accounted for the 4-month gain in survival after the diagnosis of castration-resistant disease in that group (Fig. S5 in the Supplementary Appendix).

Drug Exposure

The duration of androgen deprivation was calculated as the sum of the periods of treatment with LHRHa on the basis of the depot formulation. Patients in the continuous-therapy group received treatment with LHRHa for a median of 43.9 months (interquartile range, 19.5 to 74.5). Patients in the intermittent-therapy group received treatment for a median of 15.4 months (interquartile range, 8.5 to 23.9) and had a cumulative nontreatment period of 37.6 months (interquartile range, 20.0 to 59.6). Patients who withdrew from the per-protocol treatment were followed until death.

Treatment-Phase Dynamics

Figure 2. Figure 2. Numbers of Patients Completing Treatment Cycles and the Median Duration of Off-Treatment Periods in the Intermittent-Therapy Group. The maximum number of nontreatment intervals observed was nine, with 95% of patients entering the first nontreatment period, 58% the second, and 32% the third.

The duration of the nontreatment intervals and the number of patients in the intermittent-therapy group who completed each interval are shown in Figure 2. The maximum number of nontreatment intervals was nine, with 95% of patients entering the first nontreatment period, 58% the second, and 32% the third. Attrition was due to an off-treatment interval of 2 or fewer months or the development of castration-resistant disease. The median duration of nontreatment periods decreased progressively; the first nontreatment period lasted for a median of 20.1 months, the second for 13.2 months, and the third for 9.1 months, with periods 4 through 7 lasting for approximately 4 to 5 months each.

Quality of Life

Quality of life was assessed at fixed time points, regardless of the phase of treatment. Baseline quality-of-life scores were similar in the two groups for most items, with no clinically meaningful differences.20 Responses were assessed with the use of an area-under-the-curve analysis; individual scores at each assessment between baseline and 5 years were multiplied by the duration of the interval and then summed and compared between groups with the use of the Wilcoxon rank-sum test. For functional domains (physical, role, and global health), the intermittent-therapy group had scores that were slightly better than those in the continuous-therapy group, but the differences were not significant. For items pertaining to symptoms, intermittent therapy was associated with significantly better scores for hot flashes (P<0.001), desire for sexual activity (P<0.001), and urinary symptoms (P=0.006), with a trend toward improvement in the level of fatigue (P=0.07).

Testosterone and Potency Recovery

The 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. Although only 35% of patients in this group had a return to pretreatment levels within 2 years after completing the first period of treatment, 79% had a level of at least 5 nmol per liter (144 ng per deciliter; the threshold for study entry). Data from patients who never had a recovery were censored on the date that treatment was restarted. A Cox regression model showed that patients who were older than 75 years of age were less likely than younger patients to have a return to the pretreatment level (P=0.001). Only 29% of the men who were potent at baseline had a recovery of potency.