A new study supports the growing consensus that intermittent androgen suppression is no less effective than continuous androgen suppression at treating prostate cancer that recurs after radiotherapy. According to Laurence Klotz, MD, chief of urology, Sunnybrook Health Sciences Centre, and professor of surgery at the University of Toronto, "Intermittent androgen suppression should be the standard of care for most patients with prostate-specific antigen [PSA] recurrence after radiation therapy" regardless of whether they have had radical prostatectomy. Klotz was lead investigator for the PR7 trial and presented findings at the 2011 Genitourinary Cancers Symposium in Orlando.
The phase III trial enrolled 1386 men with nonmetastatic prostate cancer who experienced rising PSA and testoerone levels 1 year after radiotherapy, suggesting recurrence. Patients were randomized to receive androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) continuously until they developed resistance (n = 696) or intermittently (n = 690) until progression, at which point they were switched to continuous ADT.
The phase III trial enrolled 1386 men with nonmetastatic prostate cancer who experienced rising PSA and testoerone levels 1 year after radiotherapy, suggesting recurrence. Patients were randomized to receive androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) continuously until they developed resistance (n = 696) or intermittently (n = 690) until progression, at which point they were switched to continuous ADT.
Median overall survival (OS) reached 9.1 years for the continuous arm versus 8.8 years for the intermittent group (hazard ratio [HR], 1.02), which translated to statistical significance for the noninferiority of the study's intermittent protocol (P = .009). At 7 years' follow-up, disease-specific mortality was 18% in the intermittent group compared with 15% in the continuous arm, which Klotz said was not statistically significant (HR, 1.18; P = .24).
Castration resistance occurred at a median of 10 years' follow-up for men who received continuous ADT compared with 9.8 years for men in the intermittent arm (HR, 0.80; P = .024). The fact that the median duration of OS was shorter than the median time to castration resistance in both groups points to the fact that several men died from causes other than prostate cancer.
The rate of deaths unrelated to prostate cancer was 9% higher in the continuous arm than the intermittent group. Klotz theorized that the known metabolic effects of continuous ADT might account for some of the non-cancer deaths.
In most phase II studies comparing intermittent ADT with continuous ADT, Klotz said men in the intermittent group were on treatment 50% of the time. On average, men randomized to intermittent ADT in Klotz's study were actively treated 27% of the time, spending a median of 15.4 months on an LHRH and 37.6 months off.
At baseline, all the men had nonmetastatic disease with a PSA level >3 ng/ml and a serum testosterone level >5 nmol/L. After randomization and an initial flare blockade with an anti-androgen, patients in the intermittent group took an LHRH for 8 months. Treatment was halted for those with a normal PSA level and resumed for another 8 months if subsequent testing indicated a PSA level >10 ng/ml. If the PSA level rose above 10 ng/ml within 2 months of treatment discontinuation, the patient was switched to continuous therapy.
Similar proportions of patients in each group experienced the most common adverse events, including erectile dysfunction, loss of libido, incontinence issues, fatigue, myocardial ischemia/infarction, and osteoporotic fracture. Patients in the intermittent ADT arm were significantly less likely to experience hot flashes than patients in the continuous arm (90% vs 93%; P = .04). The investigators are currently analyzing the data for quality-of-life issues, including off-treatment events.
Unless the cause of non-cancer deaths for men in the continuous ADT group is confirmed as treatment-related, neither treatment confers a survival advantage. The primary benefits associated with intermittent therapy appear to be cost savings and less inconvenience for patients. Oliver Sartor, MD, medical director, Tulane Cancer Center, New Orleans, Louisiana, was a discussant at the meeting, and said he already uses intermittent therapy for his patients. He cautioned that proper monitoring was essential and noted that he monitors his patents on intermittent therapy every 2 months.