E. David Crawford, MD
Men given the gonadotropin-releasing hormone (GnRH) antagonist degarelix (Firmagon) because their prostate-specific antigen (PSA) level rose after primary therapy fared at least as well on an intermittent medication schedule as on a continuous schedule, researchers have found.
The study compared intermittent degarelix dosing against a continuous schedule of either degarelix or leuprolide (Lupron).
About one-quarter of the men taking degarelix on a 7-months-on/7-months-off schedule needed to resume the drug during their off period to control their PSA levels. However, even in those cases, patients using the intermittent strategy took less medication overall to keep their PSA levels below 4 ng/mL than did those patients on continuous therapy, reported E. David Crawford, MD, on May 20, 2014, during the Annual Meeting of the American Urological Association (AUA) in Orlando, Florida.
The concept of an intermittent dosing schedule to reduce the costs and side effects of androgen deprivation therapy (ADT) and to maintain sensitivity to such drugs has been around for decades, according to Crawford, lead author of the study and professor of Surgery, Urology, and Radiation Oncology and head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus. Most clinical explorations of the dosing strategy have involved luteinizing hormone-releasing hormone agonists, with results often showing intermittent and continuous dosing strategies running neck and neck, Crawford said. The study he presented during the AUA meeting was one of the first looking at a hormone antagonist on an intermittent dosing schedule, he said.
“There was not a long follow-up in this trial, so we can’t talk about survival or progression,” Crawford said. “We can say that the drug was safe and effective, and that recovery of testosterone was pretty rapid afterwards.”
Men whose PSA levels had risen after primary definitive therapy and who had testosterone levels Ëƒ150 ng/mL were eligible for the degarelix study. Participants were separated into an intermittent degarelix arm (n=177), a continuous degarelix arm (n=50), and a continuous leuprolide arm (n=182).
All patients received their respective medications for 7 months, and then the men in the intermittent arm stopped degarelix for 7 months while the patients in the other two cohorts continued therapy.
The primary endpoint was the proportion of patients with PSA levels ≤4 ng/mL at 14 months.
While 2.4% and 1.3% of the men in the continuous degarelix and leuprolide arms, respectively, had PSA levels Ëƒ4 ng/mL at month 14, none of the men in the intermittent arm did, the authors reported.
However, 35 patients (26%) in the intermittent arm experienced a PSA rise to Ëƒ2 ng/mL during months 7-14, and resumed doses of degarelix during that time, staying on the treatment until their PSA levels dropped appropriately and stayed down for a couple of months, according to Crawford.
The need to treat patients who were on an off cycle does not mean that the intermittent strategy failed, Crawford said. There will always be questions about when to restart therapy when dosing is intermittent, he said; possibilities include restarting therapy when PSA reaches its baseline level, when it has gone up 50%, or when a patient starts experiencing symptoms.
In this study, he said, “The bottom line is that people on intermittent therapy got less drug.”
Crawford and his colleagues also tracked median time to testosterone recovery (TËƒ50 ng/mL) in the intermittent degarelix group, which was 112 days, counting from 28 days after the last degarelix dose. Testosterone recovery occurred in 116 (85%) of those patients within 6 months of discontinuing degarelix.
Being less than 65 years of age was predictive of testosterone recovery, the authors wrote.
Testosterone recovery could not be tracked in the other groups, because those participants remained on hormonal therapy throughout the study period.
Preclinical Degarelix Data Presented
In a Sunday poster session during AUA, an author presented the results of a Canadian preclinical study indicating that degarelix, when compared against GnRH analogues and orchiectomy, contributes less to weight gain, metabolic syndrome (MS), and cardiovascular disease (CVD).
“Motivated by the observation that the incidence of adiposity, metabolic syndrome and cardiovascular disease accompanies the incremental increase in serum FSH [follicle-stimulating hormone] levels in menopause, we hypothesize that GnRH antagonists which maximally inhibit FSH levels will associate with reduced adiposity and development of MS and CVD compared to GnRH analogues and orchiectomy,” Duivenvoorden et al wrote.
The investigators divided mice into four cohorts of 12 and studied the effects of orchiectomy, sham surgery, sham surgery plus degarelix, and sham surgery plus the GnRH agonist enantone. The mice were also stratified by either a normal or a high-fat diet.