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DUTASTERIDE/BICALUTAMIDE -
An alternative to Lupron? Where's The Meat?
(June 2008)
The combination of
dutasteride, 0.5 mg/qd, combined with bicalutamide, 50 mg/qd, has
surreptitiously crept into clinical practice as a potentially legitimate
alternative to Lupron as hormonal therapy for prostate cancer in all
phases of the disease. A fair question is: on the basis of what
evidence? Answer: the published evidence to support the substitution is
fairly sparse and largely inferential. But the drive to adopt such a
regimen is strongly driven by the fervent desire to find a hormonal
therapy with quality of life consequences substantially more tolerable
compared to the major side effects of Lupron.
The incompletely
satisfied logical syllogism in support of the substitution involves the
following elements:
1) Bicalutamide, 50 mg/qd,
is superior to flutamide, 125 mg/tid, with respect to dosing and
toxicity. Diarrhea and elevation of liver enzymes are frequent with
flutamide.
2) In a small study
flutamide 125 mg/tid, combined with finasteride, 5 mg/qd, with
castration (medical or surgical) administered upon PSA relapse, was
estimated to be equivalent to Lupron alone in patients with metastatic
disease. Combined therapy yielded a period of hormone responsiveness of
more than 4 years (Oh, WK and Kantoff, PW, UROLOGY, July, 2003).
3) In regimens of
peripheral androgen blockade the addition of the 5-alpha-reductase
inhibitor, finasteride, compared to an antiandrogen alone extended PSA
control:
In men with advanced
prostate cancer, 150 mg/qd bicalutamide reduced PSA levels by 96.5% with
a nadir at 3.7 weeks, and the subsequent addition of finasteride, 5 mg/qd,
induced a second nadir in 5.8 weeks for a total PSA reduction from
baseline of 98.5%. The median period of disease control was 21.3 months,
"comparable to castration," Yay, MH and Oh, WK, Ann Oncol, 2004
June.
Additional support for
a combined treatment regimen comes from Drs.
Bañez,
Crawford, and Moul in an abstract presented at the SESAUA meeting, March
2008, and is being expanded for a paper to be titled "Phase II Trial of
Combination of Low-Dose Flutamide plus Finasteride versus Low-Dose
Flutamide Monotherapy for Recurrent Prostate Cancer: Long-Term
Follow-up."
Thirty-six asymptomatic
men with rising PSA (PSA >0.4ng/ml) following prostatectomy or
beam radiotherapy were treated with flutamide, 125 mg/bid plus
finasteride 5 mg/bid, and 20 received flutamide alone. Median follow-up
was 54 months for combined therapy and 43.5 months for monotherapy.
"Multivariate analysis revealed that men on combination therapy had
significantly less risk of progression compared to men on monotherapy
(hazard ratio=0.21). The authors concluded that Phase III trials are
warranted comparing the flutamide/finasteride regimen against Lupron as
first line therapy for recurrent prostate cancer. In personal
communication Dr. Bañez allowed that a third trial arm could be
bicalutamide/dutasteride.
4) Basic science
studies suggest dutasteride, an inhibitor of both types I
and II 5-alpha-reductase (5-AR), offers optimal reduction of
intracellular DHT compared to finasteride. An indirect comparison
of the efficacy of the two inhibitors in prostate cancer prevention will
be suggested when the results of the REDUCE (dutasteride vs. placebo)
trial can be viewed against the completed finasteride prostate
prevention trial. The higher activity of type I 5-AR in metastatic
prostate cancer suggests that dual inhibition by dutasteride may be
superior to finasteride, which only inhibits 5-AR type II.
For in depth discussion
of dutasteride see Testosterone-Based LHRH Dosing; Intraprostatic
Androgens During Androgen Suppression; Dutasteride and Intraprostatic
Androgens, and Intermittent Androgen Deprivation Combined with
Finasteride (Sept 2007), in the PCa Commentary indexed under
"Hormone Therapy."
5) The first published report of the
combination of bicalutamide, 50 mg/qd, plus dutasteride, 5 mg/qd
appeared in UROLOGY, 2006, July: "Efficacy of neoadjuvant
bicalutamide and dutasteride as a cytoreductive regimen before prostate
brachytherapy" by Merrick, GS, and Wallner, KE, et al. Their study of
31 men found that after a 3-month course of therapy the volumetric
reduction in prostate size was 34.6%, which was "comparable to previous
reports of volume reduction using a luteinizing hormone-releasing agonist
with or without an antiandrogen."
BOTTOM LINE: Indirect evidence allows that a peripheral
androgen blockade regimen of bicalutamide/dutasteride (with Lupron upon
PSA relapse) may serve as an acceptable substitute to Lupron as hormonal
therapy for prostate cancer. The side effect profile is clearly superior
to that of Lupron, which is with associated castrate levels of
testosterone, whereas the combination leaves the testosterone levels
unchanged or slightly higher than baseline. However, currently there are
no reports of head-to-head comparison trials of Lupron and the
combination regimen and none are in progress.
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