Study: Degarelix Before Leuprolide Can Eliminate Testosterone Surge

Robert Given, MD

Patients who undergo androgen deprivation therapy (ADT) to manage advanced prostate cancer will often face the prospect of a potentially dangerous testosterone surge before the downregulation of leuteinizing hormone (LH) secretion occurs and, within about 3 weeks, testosterone drops to castration-like levels. While some patients might consider orchiectomy, the emotional and psychological issues, and the permanence of this surgery, make it unacceptable to most.

Based on the results of a recent study, however, there is an alternative to surgery in this patient population: initiating ADT through the administration of gonadotropin-releasing hormone (GnRH) antagonist degarelix, followed by LHRH agonist leuprolide.

“Initiation of ADT using degarelix followed by leuprolide can be done safely and with little concern for a clinically significant testosterone surge in the majority of patients,” the investigators wrote in a poster presented at the annual meeting of the American Urological Association in May.

Robert Given, MD, associate professor of Urology at Eastern Virginia Medical School, and Jack Zuckerman, MD, also of Eastern Virginia Medical School, conducted the prospective, single- arm, open-label safety study because a testosterone surge can have serious complications for some patients, especially those with increasing severity of bone pain from metastasis or ureteral or bladder outlet obstruction, or in whom neurologic compromise is imminent from metastatic disease of the spine. To counteract this effect, the authors wrote, patients are often pretreated with an anti-androgen. But the usefulness of initiating ADT with degarelix and then switching to leuprolide, they wrote, had not been explored.

The 6-month study involved 48 men with prostate cancer, aged 59 to 86 years (mean 73 years). Nineteen percent had received prior ADT; however, all the men had been off hormonal therapy for at least 6 months prior to enrolling in the study. Ten percent of patients had evidence of metastatic disease and 44% had undergone prior attempted curative treatment. Participants had a base testosterone level of >150 ng/dl. To reach castration levels, that number had to drop to <50 ng/dl.

In the study, patients received subcutaneous degarelix 240 mg (day 0), then two monthly 80 mg doses (days 30 and 60). Leuprolide was administered on day 90 of the trial. Testosterone levels and PSA values were measured throughout the study.

Given emphasized the importance of ensuring that each patient’s testosterone was at castration levels before moving on to the LHRH agonist. Three patients were excluded from analysis because they did not reach castration levels of testosterone prior to transition to leuprolide, and all three had a significant rise in testosterone from a mean of 88.7 to 225 ng/dl at day 93, the researchers noted.

Among the remaining cohort, mean serum testosterone and PSA were reduced from a baseline of 374.6 ± 155.7 ng/ dl and 23.8 ± 55.8 ng/ml, respectively, to 16.5 ± 8.1 ng/dl and 1.6 ± 3.7 ng/ml following 3 months of treatment with degarelix.

Upon the transition from degarelix to leuprolide at day 90, there was a rise in testosterone from the lowest point of 16.5 ng/dl to a peak of 25.8 ng/dl recorded on day 93 (P = .0005), the researchers reported. Four patients (8.9%) experienced a clinically significant surge with a mean peak serum testosterone of 80.7 ng/dl; all four returned to castration levels within 7 days.

The authors noted that none of these patients had symptomatic flare, and that this amount of rise in testosterone would not be relevant in clinical practice. In counter distinction to this, patients who are not castrate at conversion may run a risk of symptomatic flare, and administering an anti-androgen should be considered.

Side effects for degarelix and LHRH agonists were found to be comparable from a hypogonadal standpoint, Zuckerman said. “What differs is the likelihood for a local injection-site reaction,” he said. “For degarelix, the initial injection is a loading dose, with a larger-volume subcutaneous injection. Once the loading dose is administered, subsequent doses of degarelix require a smaller injection volume and are much better tolerated.”

Degarelix and LHRH agonists are also comparable from a financial standpoint, depending on a patient’s drug-benefit coverage, Giv en added.

Reference

Zuckerman J, Given R. Degarelix induction followed by leuprolide maintenance: a new treatment paradigm? Presented at: the American Urological Association Annual Meeting; May 4-8, 2013; San Diego, California. Poster 783.