ORLANDO – Periodic breaks from androgen suppression therapy did not impact survival in men with prostate-specific antigen progression after radical therapy for prostate cancer.
Dr. Laurence Klotz
In a phase III study involving 1,386 men, median overall survival was 9.1 years with continuous androgen deprivation and 8.8 years with intermittent androgen suppression (P value .009, hazard ratio 1.02), lead author Dr. Laurence Klotz said at the Genitourinary Cancers Symposium. Median follow-up was 6.9 years.
"Based on this study, which is really, I think a pivotal, definitive trial of this question, IAS [intermittent androgen suppression] should be the standard of care for most patients with PSA [prostate-specific antigen] recurrence after radiation, who are initiating androgen deprivation therapy," he said.
The inter-group study, which was stopped early based on the interim analysis, answers the long-standing question of survival for a therapeutic approach that is increasingly popular among clinicians and patients.
Intermittent androgen suppression was first described in a report by Dr. Klotz in 1986 and since then has been the subject of 17 phase II and nine phase III studies. Although previous studies reported favorable results, they were either too small to determine survival non-inferiority or included patients with both metastatic and non-metastatic disease, he said.
The current study included men without metastatic disease who had a rising serum prostate-specific antigen of more than 3 ng/ml and serum testosterone of more than 5 nmol/L at one year after undergoing radiation therapy, either as primary management or post radical prostatectomy. PSA testing was performed every 2 months.
In the randomized multi-center trial, 696 patients received initial flare blockade with an anti-androgen (AA) and therapy with a luteinizing hormone-releasing hormone (LHRH) analog until castrate resistance and 690 patients received initial AA and LHRH for 8 months, at which time therapy was stopped if PSA levels became normal. If PSA rose to more than 10 mg/ml, the 8 months of therapy was repeated. Patients were switched to continuous androgen deprivation at disease progression or with a PSA of more than 10 ng/ml within 2 months of discontinuing therapy.
Dr. Christopher Logothetis, chair of genitourinary medical oncology at MD Anderson Cancer Center in Houston, said in an interview that another trial is unlikely to be conducted and that the current findings make intermittent therapy the preferred treatment. He has been using intermittent androgen suppression for more than 5 years in his patients and said the difference in quality of life is striking for these men.
"I’m not sure that the side effect profile he [Dr. Klotz] described captures the degree of benefit that patients feel when they have a normal testosterone – this general sense of well-being, a sort of equanimity they experience and return to life and engagement," he said. "My own view of life is that the benefits are underestimated."
Significant adverse events were similar between the intermittent androgen suppression and continuous androgen deprivation patients, including erectile dysfunction (86% vs. 88%), libido (79% both groups), urine frequency/urgency (61% vs. 57%), fatigue (59% both groups), myocardial ischemia/infarction (10% vs. 11%), and osteoporotic fracture (4% vs. 3%). The only real difference was in hot flashes, favoring the intermittent androgen suppression arm at 90% vs. 93% (P = .04), said Dr. Klotz, chief of urology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
Quality-of-life studies, which will address off-treatment events, will be reported at a future meeting.
The median time to castration resistance was 10 years with continuous androgen deprivation and 9.8 years with intermittent androgen suppression, although a stratified log-rank analysis favored the intermittent arm (P = .024, HR 0.80). This finding may reflect the study design, which was biased toward a longer time of castrate resistance in the intermittent arm because patients off treatment had to be retreated before they could be defined as castrate resistant, he said.
There were 9% more prostate cancer deaths on intermittent androgen suppression and 8% more non-prostate cancer deaths on continuous androgen deprivation. Seven-year disease-specific mortality was 18% in the intermittent androgen suppression arm vs. 15% in the continuous arm (P = .24, HR 1.18).
Dr. Klotz suggested that the increase in non-prostate cancer deaths in the continuous androgen deprivation arm may be related to the metabolic effects of long-term continuous androgen deprivation. The increase in prostate cancer deaths in the intermittent arm "is going to be a matter, I think, for some discussion and controversy," even though it was statistically insignificant and "a very secondary point compared to the observation of no difference in overall survival," he added.
Surprisingly, the average on-treatment time was only 27% on average in the intermittent arm, with men spending a median of 15.4 months on therapy and 37.6 months off therapy. Dr. Klotz pointed out that this contrasts with an on-treatment time of 50% observed in most of the phase II studies.