Kate Johnson

March 26, 2013

MILAN, Italy — In patients with prostate cancer and cardiovascular disease, degarelix (Firmagon, Ferring Pharmaceuticals) is associated with fewer serious adverse events and less all-cause death compared to luteinizing hormone-releasing hormone (LHRH) agonists, according to 2 pooled analyses of 6 clinical trials.

"In light of the toxicities that have emerged with the chronic administration of agonists, these are very significant findings," said investigator Bertrand Tombal, MD, from the Cliniques Universitaires Saint-Luc in Brussels, Belgium.

The US Food and Drug Administration mandated cardiovascular safety warnings for LHRH agonists in 2010. Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist and might have a different effect on the cardiovascular system because of a different mode of action, Dr. Tombal explained here at the European Association of Urology 28th Annual Congress.

The investigators pooled data from 6 prospective phase 3 studies that compared various doses of degarelix with the LHRH agonists leuprolide or goserelin. The analysis involved 2328 patients. The duration of half the studies was 12 months and of the remaining half was 3 months.

The investigators found that risk for serious cardiovascular events or all-cause death was significantly lower with degarelix than with the LHRH agonists (= .0383). The risk was also significantly lower for the subgroup of those with baseline cardiovascular disease (= .0066).

In light of the toxicities that have emerged...these are very significant findings.

"The overall result is mainly driven by the results of the group with baseline cardiovascular disease," explained session moderator Levent Turkeri, MD, PhD, from Marmara University School of Medicine in Istanbul, Turkey, who was asked by Medscape Medical News to comment on the 2 analyses.

After adjustment for the most common variables affecting risk for serious cardiovascular events or death, degarelix was associated with more than a 50% risk reduction in men with baseline cardiovascular disease (hazard ratio [HR], 0.414; = .0040).

After only 12 months of treatment, significantly fewer patients in the degarelix group than in the LHRH group experienced a serious cardiovascular event or death. "Men in need of androgen-deprivation therapy, especially those with a history of cardiovascular disease, may have a significantly lower risk of cardiovascular disease sequealae with the GnRH antagonist degarelix than with an LHRH agonist," Dr. Tombal explained.

A separate analysis of the same data showed a significantly decreased risk for urinary tract adverse events (< .0001), joint-related signs and symptoms (P = .0116), and the probability of fracture (= .0234), "indicating improved clinical response," reported investigator Kurt Miller, MD, from Charité-Universitätsmedizin in Berlin, Germany.

Both degarelix and LHRH-treated patients showed significant and sustained suppression in testosterone and prostate-specific antigen (PSA) at day 28. However, for the 21% to 23% of patients with baseline PSA levels above 50 ng/mL, degarelix was associated with significantly better PSA progression-free survival (= .0255).

Although there were changes from baseline in the serum alkaline phosphatase level in both groups, there was significantly greater suppression in the degarelix group than in the LHRH agonist group.

Overall survival was similar in the 2 groups, although it was statistically superior in the degarelix group (98.3% vs 96.7%; = .0329).

Overall Survival

"All these advantages are not huge in number, but they add to the growing body of evidence that antagonists offer better disease control with fewer disease-related adverse events and fewer side effects than LHRH agonists," Dr. Miller said.

Dr. Turkeri emphasized that these results must be interpreted with caution.

Flare protection was not mandatory in the LHRH agonist groups, he noted. "If you don't prevent flare initially, disease progression can occur early, and this minute factor — by itself — can explain at least part of the results."

"We know that LHRH analogs initially cause an increase in testosterone levels, which come down by the end of 1 month. If you don't prevent that, your patients progress," he said. "We know that flare protection can, in fact, change the course of the disease, at least for some patient populations," Dr. Turkeri noted.

"Also, these are pooled analyses of data, so do not possess the same level of scientific evidence as a randomized phase 3 clinical trial.... This question would be best answered by a randomized prospective phase 3 clinical trial that compares agonists with antagonists."

The trials were sponsored by Ferring Pharmaceuticals. The investigators report receiving funding from the trial's sponsor. Dr. Turkeri has disclosed no relevant financial relationships.

European Association of Urology (EAU) 28th Annual Congress: Abstracts 677 and 678. Presented March 17, 2013.