Intermittent androgen deprivation fell short of proving its noninferiority in a 10-year study comparing survival outcomes for intermittent and standard continuous androgen deprivation in men with metastatic hormone-sensitive prostate cancer.
In the international randomized clinical trial designed to test the noninferiority of intermittent androgen deprivation, the findings were "statistically inconclusive," according to a report published online April 3 in the New England Journal of Medicine.
In short, "the trial results are inconclusive," said Dr. Maha Hussain of the division of hematology/oncology, University of Michigan, Ann Arbor, and her associates. "The median survival after randomization was 5.1 years in the intermittent-therapy group, as compared with 5.8 years in the continuous-therapy group."
The researchers also cautioned that "the lack of a significant difference between the groups does not imply similar survival."
Intermittent therapy might even compromise survival, they said, as a 10% relative increase in the risk of death was associated with that treatment approach. And statistically, a possible 20% relative rise in mortality risk could not be ruled out.
It was hoped that intermittent androgen deprivation would improve patients’ quality of life by reducing adverse effects from the treatment and would improve survival by staving off the androgen resistance, which eventually develops in most patients.
Dr. Hussain and her colleagues compared intermittent with continuous androgen deprivation in 1,749 men enrolled during 1995-2008 at multiple sites across the United States, the United Kingdom, and Canada.
The study subjects all had newly diagnosed, metastatic, hormone-sensitive prostate cancer and a prostate-specific antigen (PSA) level of 5 ng/mL or higher. All had responded to a 7-month induction course of goserelin, bicalutamide, or a similar agent.
The study subjects were stratified by their performance status, prior hormone therapy, and the extent of their metastatic disease. Cancer confined to the spine, pelvic bones, or lymph nodes was considered minimal while that involving the ribs, long bones, or visceral organs was considered extensive.
The subjects were then randomly assigned to receive either intermittent or standard, continuous androgen-deprivation therapy.
In intermittent therapy, treatment was suspended until PSA values returned to baseline levels or to 20 ng/mL. At the discretion of the researchers, androgen deprivation also could be resumed when PSA levels reached 10 ng/mL or when symptoms developed. If patients responded to a subsequent 7-month course of the therapy, another off-treatment interval was begun.
The study subjects were followed for a median of 9.8 years.
Overall median survival was 3.7 years. There were 445 deaths in the continuous-therapy group and 483 deaths in the intermittent-therapy group. Deaths were cancer-related in approximately 80% of the members of both groups, the investigators reported (N. Engl. J. Med. 2013 April 3 [doi: 10.1056/NEJMoa1212299]).
The researchers were unable to show that intermittent androgen-deprivation therapy was either noninferior or inferior to continuous androgen-deprivation therapy.
Treatment effects were "generally consistent" across all subgroups of patients in a post hoc analysis of the data. For example, there was no significant difference in survival between patients who were alive before 2004, when treatment with docetaxel was approved, and those who were alive in 2004 or later. However, "caution should be taken not to overinterpret the results of the subgroup analyses," Dr. Hussain and her associates noted.
The two study groups differed in quality-of-life measures at 3 months after randomization. Men assigned to intermittent therapy were significantly less likely to report impotence and had significantly better mental health scores than did those assigned to continuous androgen deprivation. The intermittent-therapy group also tended to have higher scores for libido, but that difference did not reach statistical significance.
The advantage in quality-of-life measures persisted at 9 months after randomization but gradually declined. By 15 months, the only quality-of-life measure that scored better in the intermittent-therapy group was overall physical functioning.
There was a "remarkably similar" number of grade 3 and grade 4 adverse events in both study groups, the researchers said.
This study was funded by the U.S. National Cancer Institute, the U.S. Public Health Service, and AstraZeneca. AstraZeneca donated goserelin and bicalutamide used in this study but had no role in the study design, data collection or analysis, or writing the manuscript. Dr. Hussain reported ties to AstraZeneca, and her associates reported ties to numerous industry sources.