SIDEBAR: How Should SWOG 9346 Be Interpreted?

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The findings of Southwest Oncology Group (SWOG) 9346 sparked controversy at the ASCO Annual Meeting, and the interpretations were debated at an official postpresentation discussion. At the Best of ASCO Boston meeting, William K. Oh, MD, of Mount Sinai School of Medicine, New York—who also served as the invited discussant at ASCO—had a definite opinion.

“My conclusion is that intermittent androgen deprivation therapy is inferior to continuous therapy,” he said. “Neither this, nor any randomized trial has ever shown a superior cancer outcome with intermittent therapy. This concept, based on preclinical studies from 20 years ago, must no longer be propagated.”

Why Treat Intermittently?

The practice of intermittent androgen deprivation therapy has been widely adopted as a means of reducing adverse events, cost of treatment, and patient inconvenience. The practice is backed by preclinical data from long ago, and also by nearly two dozen phase II trials and a few phase III trials that found this strategy safe and effective.

However, most of the trials have not been designed appropriately, or powered adequately, to show survival effects, and certainly none has shown that intermittent therapy is superior to continuous, Dr. Oh said. Only the National Cancer Institute of Canada (NCIC) PR7 trial in nonmetastatic disease with rising prostate-specific antigen (PSA) after radiation therapy showed equivalent survival between continuous and intermittent therapy.

Questions Remain

The findings of SWOG 9346, a “Herculean effort,” still leave questions unanswered, he said. For one thing, the study only randomly assigned the most androgen-sensitive patients, the “optimal” 64% of the initial cohort who responded to 7 months of induction. In addition, patients on the intermittent arm nevertheless spent about two-thirds of their time on treatment, once the 7-month induction is figured in. That said, “How intermittent was this?” he asked.

Prior studies have suggested that testosterone recovery can take at least 4 months, and some older patients never fully recovery. This particular study reported only a minimal impact on side effects with the intermittent approach, he said. But the real question, he continued, is this: “If there is a survival benefit, how much difference in quality of life would you need to see in order to justify a worse survival with intermittent therapy?” The study showed a 9% higher mortality risk with intermittent treatment.

Additional Concerns

Dr. Oh further stated that he is bothered by the lack of a biologic rationale for the subgroup differences. “This finding is speculative and not necessarily intuitive, especially according to the definitions used in this study,” he said, adding that subgroup analyses must always be interpreted with caution.

Posing another widely raised question, Dr. Oh asked, “Is ‘not noninferior,’ which is the statistically correct term for what the study showed, equal to ‘inferior’? From a statistical point of view, they are not the same. But clinically, I question whether this makes a difference. To us as clinicians and to our patients, is a 9% difference in survival, which was over 8 months, meaningful to patients? In the castration-resistant setting, drugs are approved based on this. I think it might be meaningful to many patients.”

The bottom line from this expert: “Intermittent androgen deprivation therapy is inferior to continuous therapy, but of course we should consider intermittent therapy for patients with a poor quality of life on continuous therapy. It’s not unreasonable to give these patients a break,” he said. “But the standard of care in metastatic prostate cancer should be continuous treatment.” ■

Disclosure: Dr. Oh reported no potential conflicts of interest.

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