Intermittent androgen deprivation was not associated with inferior survival for men with a rising prostate-specific antigen level after definitive radiotherapy in a study reported in the Sept. 6 issue of the New England Journal of Medicine.
The findings from the phase III National Cancer Institute of Canada (NCIC) Clinical Trials Group study appear to conflict with those of another international phase III clinical trial reported in June at the annual meeting of the American Society of Clinical Oncology, and as such may fuel rather than extinguish the longstanding debate regarding the proper use and timing of endocrine therapy with androgen antagonists.
In the NCIC trial, 696 of 1,386 men with a PSA level greater than 3 ng/mL more than 1 year after primary or salvage radiotherapy for localized prostate cancer were randomized to continuous androgen suppression therapy consisting of a luteinizing hormone–releasing hormone agonist (LHRHa), combined with a minimum of 4 weeks of a nonsteroidal antiandrogen, or orchiectomy.
Another 690 men were randomized to intermittent androgen deprivation in 8-month cycles, with periods of nontreatment determined by PSA level. Each treatment cycle for the latter group began with the administration of LHRHa injections combined with a nonsteroidal antiandrogen for a minimum of 4 weeks and ended after 8 months if there was no evidence of clinical disease progression and if the patient’s PSA level was less than 4 ng/mL and not more than 1 ng/mL above the previous recorded value.
"During the treatment interval, the PSA level was monitored every 2 months until it reached 10 ng/mL, provided there was no intervening evidence of disease progression," stated lead investigator Dr. Juanita M. Crook of the British Columbia Cancer Agency, Kelowna, and her colleagues. (N. Engl. J. Med. 2012;367:895-903).
Overall survival was the primary end point of the study, and time to castration-resistant disease and quality of life were secondary end points, the authors wrote. Duration of off-treatment intervals, time to testosterone recovery, and time to potency recovery were additional end points for patients randomized to intermittent therapy.
At a median follow-up of 6.9 years, 524 patients had died, including 268 in the intermittent group and 256 in the continuous group, the authors reported. Median overall survival in both arms was statistically similar, at 8.8 years in the intermittent group and 9.1 years in the continuous therapy group.
"The hazard ratio for death with intermittent therapy versus continuous therapy was 1.02," the authors wrote, and the P value for noninferiority, at.009, supported the investigators’ initial hypothesis that intermittent therapy was not inferior to continuous therapy. A nonsignificant increase in deaths from other causes was observed in the continuous therapy group.
Because most of the deaths (59%) were unrelated to prostate cancer, the investigators retrospectively analyzed disease-specific survival "to determine whether a significant difference in treatment effect was obscured by the data on deaths from causes other than prostate cancer," they said. The estimated disease-specific hazard ratio after adjustment for stratification and confounding factors was 1.23, and the estimated 7-year cumulative disease-related death rates were 18% and 15%, respectively, for the intermittent and continuous groups.
With respect to time to castration-resistant disease, based on a Cox regression analysis adjusted for stratification and prognostic factors, the estimated hazard ratio for intermittent versus continuous therapy was 0.81, the authors reported, noting, however, that the study design contributed to a bias "by an unknown magnitude" against continuous androgen-deprivation therapy.
"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," the investigators wrote.
In quality of life measures, the intermittent therapy group had nonsignificantly better scores for functional domains (physical, role, and global health) and significantly better scores for symptoms, including hot flashes, desire for sexual activity, and urinary symptoms, the authors reported. Full testosterone recovery in the intermittent group occurred in 35% of the patients, while recovery to the trial entry threshold occurred in 79%, they said.
The authors concluded that their trial "raises provocative questions" and cautioned that their results "cannot be extrapolated to other intermittent-treatment schedules or disease characteristics."
The article did not address the apparent contradiction between the NCIC trial results and the findings of the Southwest Oncology Group (SWOG) 9346 trial reported earlier in the year at the ASCO annual meeting.
The latter trial randomized 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer with a PSA level of at least 5 ng/mL before androgen deprivation and a SWOG performance status of 0-2 to intermittent or continuous therapy. The investigators reported a 9% increase in the relative risk of death associated with intermittent therapy, which did not meet the prespecified criteria for noninferiority.