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 (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
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
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.
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
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
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.