CHICAGO—Intermittent androgen deprivation therapy (ADT) has some quality-of-life (QOL) benefits for men with metastatic prostate cancer (PCa), but overall survival times are inferior to those seen with continuous ADT, according to the findings of a 17-year study (SWOG9346) presented at the American Society for Clinical Oncology 2012 annual meeting.

“Some doctors recommend intermittent hormonal therapy to men with metastatic prostate cancer, believing it will reduce their risk of side effects without compromising their outcome, but these findings demonstrate a downside to this approach for certain men,” said lead researcher Maha Hussain, MD, Professor of Medicine and Urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. “The findings clearly demonstrate that intermittent hormonal therapy is not as effective for all patients with metastatic prostate cancer. These findings are likely practice changing for many doctors in the U.S. and abroad who routinely use intermittent therapy; specifically, physicians must counsel interested patients regarding the potential negative impact on survival with intermittent therapy.”

The study enrolled 3,040 men with hormone-sensitive, metastatic prostate cancer between 1995 and 2008.  All men received an initial course of androgen-deprivation treatment for seven months. The 1,535 eligible men whose PSA level dropped to 4 ng/mL or less by the end of those seven months were then assigned at random to stop therapy (the intermittent therapy group) or continue therapy (the continuous therapy group).

Those randomized to the intermittent therapy arm had their treatment suspended until their PSA rose to a predetermined level, at which time they started another seven-month course of ADT. The patients cycled on and off therapy in this way as long as their PSA levels continued to respond appropriately during the “on” cycle.

The 1,535 eligible patients had a median age of 70 years; 48% had extensive disease and 12% had received prior neoadjuvant ADT. A total of 765 were randomized to continuous therapy and 770 patients were randomized to the intermittent arm. Men on continuous therapy had a median overall survival time of 5.8 years from the time of randomization, with 29% of these men surviving at least 10 years. Those on intermittent therapy had a median overall survival time of 5.1 years, with 23% surviving at least 10 years from randomization. Men with minimal disease (disease that had not spread beyond the lymph nodes or the bones of the spine or pelvis) did significantly better on continuous therapy, whereas men with extensive disease seemed to do about as well using either treatment approach.

“In the past when it came to using hormone therapy in this disease, doctors viewed the disease as one entity and adopted a ‘one size fits all' approach,” Dr. Hussain said. “Based on this study's findings, it seems that one size does not necessarily fit all.”

Intermittent hormonal therapy appeared to be safe in prior studies, but those studies generally included either men whose only evidence of prostate cancer progression was an increase in PSA level (as opposed to radiographic evidence of disease spread), or men with wide-ranging stages of disease (not just metastatic cancer).

Additional exploratory subgroup analyses of these new data indicated that after a median follow-up of 9.2 years, the median overall survival time for those with minimal disease was 7.1 years on continuous ADT compared with only 5.2 years on intermittent treatment. Patients with extensive disease had median overall survival times of 4.4 years on continuous therapy and 5.0 years on intermittent therapy. There was no evidence that the treatment effect differed by race. The study showed that Grade 3/4 related adverse events were similar for intermittent and continuous treatment (30.3% vs. 32.6%).

With respect to QOL measures, which were compared during the first 15 months following randomization, more men receiving intermittent rather than continuous therapy had significant improvements in the  level of sexual functioning..

“There is some improvement in aspects of quality of life, but the durability is the issue,” Dr. Hussain told Renal & Urology News. “Our study demonstrates that what may appear safe may not be completely so and it sometimes takes a large study to determine this. It's important to look beyond PSA responses when evaluating hormone therapy approaches and also it's important to have a control group in performing the trials.”

Even though these data showed potential QOL improvements with intermittent therapy, the primary findings of the study demonstrate that intermittent therapy is inferior with regard to overall survival, which should be the primary consideration when counseling all patients interested in intermittent therapy, particularly those with minimal disease, she said. 

“This clinical trial will change the use of intermittent therapy,” said study co-investigator E. David Crawford, MD, Professor of Surgery/Urology/Radiation Oncology at the University of Colorado in Denver. “This is the largest study to date and one we have all been waiting for. It shows that intermittent therapy is inferior to standard continuous androgen ablation. There were flaws in other trials such as not powered to show equivalence or even slight but significant differences.”

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