In Advanced Prostate Cancer, Degarelix Offers Advantages Over LHRH Agonists

OncologyLive, October 2013, Volume 14, Issue 10

Men with advanced prostate cancer who took the GnRH antagonist degarelix experienced improved disease control, fewer instances of urinary infections, and a lower risk of cardiovascular events than did those patients who took LHRH agonists.

Neal D. Shore, MD

Medical Director

Carolina Urologic Research Center

Myrtle Beach, SC

E. David Crawford, MD

Head, Section of Urologic Oncology

University of Colorado Anschutz Medical Campus

Aurora, CO

Men with advanced prostate cancer who took the gonadotropin-releasing hormone (GnRH) antagonist degarelix experienced improved disease control, fewer instances of urinary infections, and a lower risk of cardiovascular events than did those patients who took luteinizing hormone-releasing hormone (LHRH) agonists, according to recent retrospective analyses of six clinical trials.

The analyses compared data pooled from randomized trials that included 2328 patients who took either degarelix or an LHRH agonist—leuprolide acetate or goserelin—for three months to a year. Findings were presented in separate abstracts during the annual meeting of the American Urological Association (AUA), held in San Diego in May.

The two groups of patients were balanced for age, disease stage, and levels of testosterone and prostate-specific antigen (PSA), said Neal D. Shore, MD, medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, who presented findings that compared disease control-related outcomes.1

Shore and colleagues found that muscle or bone pain was more likely to occur among those on the LHRH arm, with 12% of those patients reporting such symptoms, compared with 9% of those on the degarelix arm (P = .0822). Degarelix patients faced a <1% probability of bone fracture versus a 2% probability for LHRH patients (P = .0411), and a 4% rate of joint-related adverse events (AEs) versus a 6% rate for LHRH patients (P = .0116).

Among men with metastatic disease who were treated for a year, those who took degarelix experienced a greater reduction in alkaline phosphatase (ALP) (P = .0373), the authors wrote.

In a 2006 study, investigators found that, when controlling for other prognostic variables amongmen with hormone-refractory metastatic prostate cancer, higher levels of serum bone-specific ALP were associated with shorter survival.2

The pooled analysis comparing the GnRH antagonist to LHRH agonists also demonstrated that “there was a significantly lower overall probability of urinary tract AEs (P <.0001) and a significantly longer time to first urinary infection (P = .0010) in men treated with degarelix,” according to the abstract. Five percent of degarelix patients experienced urinary infections, as compared with 8% of those taking LHRH agonists.

Finally, in men with a baseline PSA >50 ng/mL, those treated with degarelix demonstrated significantly better PSA progression-free survival at one year versus patients treated with LHRH agonists (66% vs 54.7%; P = .0245). Across all participating patients, overall survival in the first year of treatment was significantly higher for those taking degarelix (98.3% vs 96.7%; P = .0329).

In an interview, Shore also noted that patients in the pooled analysis who were treated with LHRH agonists experienced a statistically significant increase in cardiovascular events and cardiovascular mortality. Data on those outcomes, presented during the AUA meeting by Albertsen, et al,3 showed that treatment with degarelix instead of an LHRH agonist decreased the risk of subsequent serious cardiovascular events by greater than 50% for men with a history of cardiovascular disease; in patients with no baseline cardiovascular disease, there was no difference between groups.

“It’s very interesting, and it’s certainly hypothesis- generating, that the antagonists may have less impact on cardiomyocytes, less impact on certain types of white blood cells which could be impacting coronary plaque,” Shore said. “We need to do more investigation, but the data are the data, and the degarelix population had fewer cardiovascular events and deaths. Additionally, we saw data that showed a delay in the degarelix patients in converting from the androgen-sensitive state to the castration-resistant state.”

The phase III study that led to the FDA’s approval of degarelix in 2008 compared its safety and efficacy against that of leuprolide in achieving and maintaining testosterone suppression in patients with prostate cancer for up to one year.4 Among its findings was that degarelix sparked a more rapid suppression of testosterone and PSA than leuprolide.

E. David Crawford, MD, head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus, put those results into context in a recent interview.

The study “took men eligible for hormone therapy and randomized them to a loading dose and a maintenance dose of degarelix versus monthly leuprolide acetate, mainly Lupron, and basically, at the end of one year, both of those drugs were equivalent in maintaining castration and suppression way above 95%,” Crawford said. “Looking at some of the stratifications in the study and outcomes, what was shown is that degarelix—as far as PSA, suppression, and alkaline phosphatase are concerned—was better. With degarelix, you didn’t get a flare in testosterone or PSA; in fact, you kept testosterone levels down fairly low. The FDA says these men should be able to achieve serum testosterone levels of <50 ng/dL on these treatments, and both drugs were able to do that.”

The study also demonstrated that follicle-stimulating hormone (FSH) dropped more rapidly in patients on degarelix, and remained at lower levels, than in those who took leuprolide. The authors wrote that the significance of that finding was undetermined, but Crawford suggested that elevated FSH could be a risk factor for disease.

“It wasn’t studied in this study, but FSH might actually be a stimulus of cancer growth,” he said. “A study that was in The New England Journal of Medicine5 looked at staining for FSH in prostate cancer and found that it was there in the vasculature, so if you lower FSH, that may have an effect on prostate.”

References

  1. Shore N, Miller K, Tombal B. Analysis of disease control-related outcomes from six comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists. Presented at: American Urological Association Annual Meeting: May 4-8, 2013; San Diego, CA. Abstract 716.
  2. Cook RJ, Coleman R, Brown J, et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res. 2006;12(11 Pt 1):3361-3367.
  3. Albertsen P, Tombal B, Wiegel T, et al. Androgen deprivation therapy by a gonadotropin releasing hormone antagonist, degarelix, lowers the risk of cardiovascular events or death when compared to luteinising hormone-releasing agonists. Presented at: American Urological Association Annual Meeting; May 4-8, 2013; San Diego, CA. Abstract 781.
  4. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11):1531-1538.
  5. Radu A, Pichon C, Camparo P, et al. Expression of follicle- stimulating hormone receptor in tumor blood vessels. N Engl J Med. 2010;363(17):1621-1630.