TORONTO, CanadaA multicenter phase III trial involving more than 250 prostate cancer patients confirmed earlier trials demonstrating that abarelix, a GnRH antagonist, achieved more rapid reduction of testosterone to castrate levels than leuprolide acetate (Lupron) and bicalutamide(Drug information on bicalutamide) (Casodex), but did not produce a testosterone surge and clinical flare.
These findings by the Abarelix-Depot Study Group at the University of Toronto were reported at the ASCO meeting by John Trachtenberg, MD.
The researchers randomized 255 prostate cancer patients to 100 mg abarelix-depot or to 50 mg leuprolide acetate plus 50 mg bicalutamide.
Abarelix and leuprolide were administered via intramuscular injection on days 1, 29, and 57 (with an additional abarelix injection on day 15). Oral doses of bicalutamide were given daily. In the 2:1 allocation, 170 patients received abarelix and 85 received leuprolide/bicalutamide.
All participants were candidates for initial hormonal therapy. The patient population (median age, 73 years) was 80% white.
Serum levels of testosterone, dihydrotestosterone, and gonado-tropins were assessed throughout, Dr. Trachtenberg said.
Efficacy measures included avoidance of testosterone (T) surge (T not more than 10% of baseline); rapidity of achieving medical castration in the first week of treatment (T 50 ng/dL or less on day 8); and achievement and maintenance of castration from day 29 through 85 (T greater than 50 ng/dL on two consecutive readings at least 2 weeks apart counted as failures).
Suppression of Testosterone
The primary endpoints were rates of avoidance of testosterone surge during the first week following the first dose of study drug and rapidity of reduction of testosterone to castrate levels (percent attaining medical castration on day 8).
In an interview with ONI, Dr.Trachtenberg noted an immediate suppression of testosterone production in men receiving abarelix such that by day 8, 68% of these men had achieved castrate levels, compared with 0% in the leuprolide/bicalutamide group. The difference was highly significant.
What also was rather amazing and perhaps predictable was that by day 8, the vast majority of men (86%) receiving leuprolide had a testosterone surgemeaning more than a 10% increase over baselinewhile no men given abarelix had any surge, Dr. Trachtenberg stated.
Among men with prostate cancer, the basic premise is that you want to decrease androgen production as soon as possible, he said. So if one looks at the timeline to androgen suppression, it looks like there is between a 1 and 2 month more rapid achievement of castration by abarelix than by leuprolide. And I think thats important.
Dr. Trachtenberg noted that more than 90% of patients in the study achieved and maintained medical castration through 12 weeks.
An unexpected finding, Dr. Trachtenberg said, was that in addition to suppressing testosterone, dihydrotestosterone, and LH, abarelix also suppressed follicle-stimulating hormone (FSH), which was not suppressed by leuprolide.
In addition to a report that FSH will cause stimulation of prostate cancer cell growth in cell culture, Dr. Trachtenberg noted that there has been some speculation that continuous exposure of prostate cancer cells to FSHeven in the absence of androgensmay cause some ultimately to become hormone independent.
This is something that needs to be explored further, but clearly could be of great clinical benefit, he said.
Dr. Trachtenberg concluded, Abarelix-depot represents the first hormonal therapy for prostate cancer that completely eliminates the testosterone surge and more rapidly achieves castration.