Investigational GnRH Antagonist Reduces PSA Without Hormonal Surge

ANAHEIM, California—Abarelix, an injectable gonadotropin-releasing hormone (GnRH) antagonist, reduces serum prostate-specific antigen (PSA) levels and testosterone levels more than standard therapy, with less hormonal "surge," according to several studies presented at the American Urological Association (AUA) annual meeting.

Abarelix depot is currently under priority review by the FDA for the treatment of prostate cancer. "Abarelix represents a completely unique hormonal therapy for prostate cancer. It is rapid acting, without a testosterone surge," commented Dennis Pessis, MD, associate professor of urology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago. Dr. Pessis reported the findings for the Abarelix Study Group.

No Need for Combination Therapy

Antiandrogens are frequently coadministered with luteinizing hormone-releasing hormone (LHRH) agonists to mitigate the effects of the androgen and gonadotropin surge and the consequent potential clinical flare associated with the use of LHRH agonists alone.

Abarelix monotherapy is devoid of this initial surge and, therefore, could potentially eliminate the cost, noncompliance, and inconvenience associated with combined therapies, Dr. Pessis pointed out.

At the meeting, he reported the results of a head-to-head phase III trial (abstract 685) of 251 early- and late-stage prostate cancer patients randomized to abarelix (n = 168) or leuprolide acetate (Lupron) plus bicalutamide (Casodex) (n = 83) for 24 weeks. Abarelix and the leuprolide combination were administered every 4 weeks by intramuscular injection, with an additional injection of abarelix given on day 15.

Serum levels of testosterone, dihydrotestosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured throughout the course of the study.

Efficacy measures included (1) avoidance of testosterone surge, (2) rapidity of achieving medical castration (testosterone level of 50 ng/dL or less), and (3) reduction in PSA concentration.

After 1 week of therapy, 68% of abarelix-treated patients achieved the targeted testosterone level, compared with none of the patients treated with leuprolide plus bicalutamide.

All patients receiving abarelix avoided testosterone surge, compared with 14% of patients receiving the combination (P < .001). All patients in each treatment arm achieved a 50% reduction from baseline in serum PSA at 24 weeks, Dr. Pessis reported.

Second Head-to-Head Study

In a second head-to-head, randomized, multicenter, phase III trial of 271 patients with early- and late-stage prostate cancer (abstract 850), patients given abarelix (n = 180) demonstrated a median percent reduction from baseline in serum PSA of 50% after 2 weeks of treatment and 75% after 4 weeks.

The comparator, leuprolide acetate (n = 91), produced a median percent reduction in serum PSA of 15% after 2 weeks and 61% after 4 weeks, reported Norman Zinner, MD, of Western Clinical Research, Inc., Torrance, California.

At day 85, both patient groups had achieved a greater than 90% reduction in serum PSA levels.

Abarelix-treated patients also reached target testosterone levels (50 ng/dL or less) sooner. By day 8, 72% of these patients had achieved target reduction vs none of the leuprolide-treated patients. None of the abarelix patients experienced a surge of testosterone, compared with 82% of the leuprolide patients, Dr. Zinner reported.

Median changes from baseline by day 2 were as follows in abarelix patients: 84% reduction in testosterone, 80% reduction in LH, and 38% reduction in FSH. For leuprolide patients, these figures were: 45% increase in testosterone, 369% increase in LH, and 100% increase in FSH. From day 29 through day 85, both patient groups achieved the targeted testosterone level.

"Testosterone fuels the growth of prostate cancer cells," Dr. Zinner said. "A surge in testosterone may stimulate tumor cell growth, elevate PSA levels, and potentially worsen the symptoms of cancer during the first weeks of treatment."

Both treatments were well tolerated in both trials. The incidence of allergic reactions requiring medical intervention was similar between the arms.

Single-Arm Study

A single-arm study reported at the meeting (abstract 1185) confirmed these findings in advanced symptomatic prostate cancer patients with bone pain from skeletal metastases (31 patients), enlarged prostate gland or pelvic mass (25 patients), urinary tract obstruction (9 patients), or impending neurological compromise (6 patients).

Among these patients, 57 (79%) achieved targeted testosterone levels after 1 week on abarelix, and 68 (94%) achieved the target after 4 weeks.

Serum levels of PSA, LH, and FSH were suppressed from baseline throughout treatment, and pain scores (by Visual Analog Scale) declined from a median of 4.4 (out of 10) at baseline to 0.7 on day 85.

The frequency, dose, and/or potency of analgesic use decreased in 13 of the 19 patients who were using analgesics at study entry, Michael Koch, MD, professor of urology, University of Indiana School of Medicine, Indianapolis, reported at the AUA meeting.