650132

research-article2016
TAU0010.1177/1756287216650132Therapeutic Advances in UrologyC Olesovsky and A Kapoor

Therapeutic Advances in Urology Review

Evidence for the efficacy and safety of

Ther Adv Urol

2016, Vol. 8(4) 257271

tadalafil and finasteride in combination DOI: 10.1177/

1756287216650132

for the treatment of lower urinary tract

The Author(s), 2016.
Reprints and permissions:
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symptoms and erectile dysfunction in men

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with benign prostatic hyperplasia

Chris Olesovsky and Anil Kapoor

Abstract: Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated

with prostatic enlargement and bladder outlet obstruction that can cause significant lower
urinary tract symptoms (LUTS). These LUTS have a negative impact on an individuals quality
of life, which is why treatment of symptomatic BPH has become a major priority. Although
surgical interventions exist for treating BPH, pharmacological therapies are often preferred
due to their minimal invasiveness and high degree of effectiveness. The three classes of
drugs approved for treating BPH include -blockers, 5--reductase inhibitors (5-ARIs) and
phosphodiesterase 5 (PDE-5) inhibitors. Individually, each class of drug has been studied and
shown to improve symptom relief through a variety of different mechanisms. A more recent
focus has been on the development of combinatorial therapies that combine classes of drugs
in order to provide maximal benefit. The mTOPS and CombAT studies were the first of their
kind to examine whether the combination of 5-ARIs and -blockers was more effective than
monotherapy alone. Both studies found similar results in that the combinatorial therapy was
superior to monotherapy. Over the last decade other combinatorial therapies have been at the
forefront of investigation. One in particular is the combination of tadalafil, a PDE-5 inhibitor,
with finasteride, a 5-ARI. Studies have shown that the combination of tadalafil and finasteride
is a safe, effective, and well tolerated treatment for BPH. Evidence suggests that this
combination may be particularly effective in reducing treatment-related sexual adverse events
associated with 5-ARI treatments. The following review will explore in detail the current
evidence surrounding treatment of BPH LUTS using tadalafil and finasteride.

Keywords: benign prostatic hyperplasia (BPH), finasteride, tadalafil, lower urinary tract
symptoms (LUTS), erectile function

Introduction hesitancy, straining, weak stream, and incomplete Correspondence to:

Anil Kapoor, BSc, BEngr,
Benign prostatic hyperplasia (BPH) is a condition emptying, whereas irritative symptoms include MD, FRCS
histopathologically characterized by hyperplasia of frequency, urgency, nocturia, and dysuria. BPH is McMaster Institute of
Urology, 50 Charlton
stromal and epithelial elements in the periurethral an age-related phenomenon and has been found Avenue, G344 Mary Grace
transitional zone of the prostate. The develop- to occur in approximately 5060% of men in their Wing, Hamilton, ON,
Canada L8N 4A6
ment of prostatic hyperplasia may or may not be 60s and 80% of men in their 80s in autopsy stud- akapoor@mcmaster.ca
associated with increases in urethral resistance, ies [Girman, 1998]. The main area of prostatic Chris Olesovsky, BHSc
causing bladder outlet obstruction (BOO) and enlargement in BPH is the transitional zone of the McMaster University,
Hamilton, ON, Canada
characteristic lower urinary tract symptoms prostate, or the periurethral area, which is a likely
(LUTS) [Roehrborn, 2005]. LUTS can be contributing factor to BOO [Berry et al. 1984].
divided into two categories: obstructive and irrita- Traditional therapies for BPH included watchful
tive symptoms. Obstructive symptoms include waiting, transurethral resection of the prostate

http://tau.sagepub.com 257
Therapeutic Advances in Urology 8(4)
(TURP), as well as open prostatectomy, however
surgical intervention for BPH is invasive and has
considerable associated morbidity. There has
since been an emergence of targeted medical ther-
apy for the treatment of symptomatic BPH.
There are currently three major classes of medi-
cations available for the treatment of BPH. These
classes include -blockers, 5--reductase inhibi-
tors (5-ARIs) and phosphodiesterase 5 (PDE-5)
inhibitors. -Blockers are the most widely used
class of medication for LUTS related to BPH
[Roehrborn, 2005]. Relaxation of the resting
smooth muscle tone in the prostate is mediated
through 1-adrenergic receptor blockade and can
lead to reduced LUTS score indexes and
improved urinary flow rates [Roehrborn, 2005].
Unfortunately, this class of medication does not
affect the progressive natural history of BPH
since they do not influence prostate growth
[Roehrborn, 2005]. The second major class of
medications are the 5-ARIs, which will be dis-
cussed later in this review. These medications
target the 5--reductase (5-AR) enzyme, respon-
sible for catalyzing the conversion of testosterone
to dihydrotestosterone (DHT) [Roehrborn,
2005]. A more recently approved third class of
medication are PDE-5 inhibitors such as tadalafil
(Cialis, Eli Lilly, Toronto, Ontario, Canada).
This class of drugs promotes smooth muscle
relaxation and arterial dilation by inhibiting the
degradation of cyclic guanosine monophosphate
(cGMP) [Corbin, 2004]. Studies have shown
that treatment with tadalafil is safe and can statis-
tically significantly improve International
Prostate Symptom Score (IPSS) among subjects
[Donatucci et al. 2011; Porst et al. 2011].
Consequently, it was approved for the treatment
of BPH-associated LUTS as well as for the treat-
ment of combined BPH and erectile dysfunction
(ED) in October 2011. Although the exact link
between LUTS related to BPH and ED is not yet
completely understood, numerous studies have
shown there is a high comorbidity between ED
and LUTS. In fact, one study which analyzed
over 4000 randomly selected men between the
ages of 30 and 80 showed that the prevalence of
LUTS in men suffering from ED was 72.2%
compared with just 37.7% in men who did not
report ED [Braun etal. 2003]. In another study
investigating sexual function in men with symp-
tomatic BPH, it was found that approximately
60% of men with LUTS reported low scores for
erections on a sexual function questionnaire
[Namasivayam et al. 1998]. Taken together,
258 http://tau.sagepub.com
these studies show that ED affects a significant
number of men experiencing symptomatic BPH.
The role of androgens has been implicated in
BPH as men castrated before puberty do not
develop BPH. As well, even though circulating
levels of androgens decrease in aging men,
intraprostatic DHT levels remain high [Andriole
et al. 2004]. The androgen-signaling cascade
begins with the production of androgens predom-
inantly from the testes and from the adrenals to a
lesser extent. 5-AR is a nuclear membrane bound
enzyme that catalyzes the NADPH-dependent
reduction of testosterone to DHT. In animal
studies, DHT has been found to be twice as
potent as testosterone, with a greater affinity for
the androgen receptor (AR) [Wright etal. 1996].
Upon binding, the DHT-AR complex then dis-
sociates from heat shock proteins within the
nuclear membrane and binds to androgen
response elements to induce androgen-responsive
genes such as prostate specific antigen (PSA),
platelet-derived growth factor, and epidermal
growth factor [Rittmaster, 2008; Bartsch et al.
2000]. Though the exact role of testosterone and
DHT in BPH is unknown, one hypothesis is
through the modulation of prostatic stromal cell
insulin-like growth factor axis and paracrine
effects on prostatic epithelial cells [Le etal. 2006].
Benign prostatic hyperplasia management
Lifestyle changes and herbal medicine
Lifestyle modifications may help improve BPH-
related symptoms. These include decreasing alco-
hol and caffeine consumption as well as decreasing
fluids before bedtime to improve nocturia symp-
toms, and timed voiding. One meta-analysis
[Boyle etal. 2000] suggested that the herbal med-
ication saw palmetto may result in a small
improvement in BPH-related symptoms, but
more recent studies have suggested the benefit is
no better than placebo [Bent et al. 2006]. Saw
palmetto has minimal side effects and it appears
to be a harmless herbal remedy that may result in
a slight benefit in a few patients.
Pharmacotherapy
-Blockers.The -blockers work to relax the
smooth muscle at the prostate and bladder neck by
blocking 1a-adrenergic receptors. By relaxing the
smooth muscle at the prostate neck, the urinary
channel is opened, which allows a less constricted

urinary flow. -Blockers have a quick onset of
action, within 35 days; however, once the medica-
tion is stopped, symptoms usually return to pre-
treatment, baseline levels. There are five main
-blockers: two second-generation drugs, terazosin
(Hytrin, Abbott Laboratories, Toronto, Ontario,
Canada) and doxazosin (Cardura, Pfizer Inc, Saint-
Laurent, Quebec, Canada) [MacDonald et al.
2004]; and three third-generation drugs, tamsulo-
sin (Flomax, Boehringer Ingelheim Ltd, Burling-
ton, Ontario, Canada), alfuzosin (Xatral, Sanofi-
Aventis, Laval, Quebec, Canada), and silodosin
(Rapaflo, Actavis Inc, Mississauga, Ontario, Can-
ada) [MacDonald and Wilt, 2005]. Both terazosin
and doxazosin require dose titration because of
their antihypertensive properties. Tamsulosin, alfu-
zosin, and silodosin usually do not require dose
titration and have fewer cardiovascular side effects
[Milani and Djavan, 2005]. All five agents are gen-
erally equally effective [Djavan and Marberger,
1999] and their side effects include light headed-
ness from orthostatic hypotension (510% of
patients), dizziness (510%), weakness (5%), head-
ache (5%), asthenia (510%), nasal congestion
(5%), and retrograde ejaculation (310%) [Mac-
Donald etal. 2004]. Although -blockers improve
urine flow quickly, they do not reduce prostate size,
and as a result they do not reduce the risk of future
urinary retention or the need for BPH-related sur-
gery [Kaplan et al. 2006]. In patients with severe
allergies to sulfa, an allergic reaction to tamsulosin
has been reported, and therefore this drug should
be avoided in such patients.
Silodosin (Rapaflo, Actavis Inc, Mississauga,
Ontario, Canada) is a super-selective -blocker
that has recently become available in Canada. This
drug blocks 1a-adrenergic receptors and, to a
much lesser degree, 1b and 1d receptors. The
heightened selectivity of silodosin may result in
fewer cardiovascular side effects, which are mainly
regulated by 1b receptors [Kawabe etal. 2006]. A
number of studies have confirmed the safety of
silodosin, especially in terms of cardiovascular
safety. There are negligible effects on heart rate or
electrocardiogram, including PR segment and
QRS complex [Montorsi, 2010]. Side effects
include upper respiratory tract infection (219% of
patients), diarrhea (27%), dizziness (35%), and
orthostatic hypotension (3%). Alterations in ejacu-
latory function range from 5% to 28%, with a
median of 20% of patients experiencing retrograde
ejaculation. However, only about 2% of patients
discontinued silodosin therapy based on ejacula-
tory dysfunction alone [Morganroth etal. 2010].
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C Olesovsky and A Kapoor
A major study comparing silodosin with tamsulo-
sin was published in Europe [Chapple etal. 2011]
and involved 1228 patients randomized to tamsu-
losin versus silodosin versus placebo for 12 weeks.
This study found no significant differences
between tamsulosin and silodosin in terms of IPSS
for storage or voiding symptoms, which suggests
that both drugs are equally efficacious in the treat-
ment of BPH. Two other studies [Miyakita etal.
2010] have suggested that silodosin may be more
effective than tamsulosin, but in both these stud-
ies suboptimal dosing of tamsulosin (0.2 mg daily)
was used as the comparator. Ejaculatory dysfunc-
tion was higher in the silodosin group (14.2%)
versus the tamsulosin group (2.1%). Interestingly,
patients with ejaculatory dysfunction had the
highest efficacy with silodosin, suggesting that the
presence of ejaculatory dysfunction can be used as
a surrogate for efficacy [Homma et al. 2010].
Cardiovascular side effects were comparable for
both groups, and although silodosin demonstrated
a more favorable cardiovascular profile than tam-
sulosin, this difference was not statistically signifi-
cant. Recent studies have suggested that silodosin
may have a quicker onset of action than tamsulo-
sin [Homma etal. 2010].
5-Reductase inhibitors.There are two main iso-
forms of 5-AR: the type 1 isoform is mainly found
in the peripheral skin as well as the liver, whereas
the type 2 isoform is the major enzyme in the gen-
ital tissues and hair follicles [Russell and Wilson,
1994]. Both isoforms are found in all zones of
normal prostatic tissue; however, in BPH the type
2 isoform was found to be in significantly higher
concentrations in the transition zone of the pros-
tate [Iehl etal. 1999]. It was also found that there
was a significantly higher concentration of the
type 1 isoform in prostate cancer specimens
[Thomas et al. 2003], with under expression of
type 2 in prostate cancer versus BPH or normal
prostates [Luo et al. 2003]. Furthermore, con-
genital type 2 5-AR deficiency results in patients
with prostates that remain small and entirely
composed of stromal tissue [Imperato-McGinley
etal. 1992; Sinnecker etal. 1996], leading the fur-
ther investigation into the role of 5-AR inhibition
in the treatment of androgen-dependent aberrant
prostatic hyperplasia seen in BPH.
The 5-ARIs inhibit the conversion of testosterone
to DHT, the main mediator of BPH progression.
This causes the prostate to decrease in size and
slow the progress of prostate growth [Roehrborn
et al. 2002]. The onset of action with 5-ARIs is
Therapeutic Advances in Urology 8(4)
slower than with -blockers, usually taking 46
months. The two main 5-ARIs are finasteride
(Proscar, Merck & Co, Kirkland, Quebec, Canada)
and dutasteride (Avodart, GlaxoSmithKline Inc,
Mississauga, Ontario, Canada) [Bartsch et al.
2000; Clark etal. 2004]. Finasteride inhibits the
type 2 5-AR isoform, whereas dutasteride inhibits
both type 1 and type 2 isoforms. With this dual
blockade, dutasteride lowers DHT production in
the prostate by over 90%, whereas finasteride low-
ers DHT by 70% [McConnell et al. 1998]. As a
result, dutasteride may have a faster onset of action
than finasteride, but it is believed there are no
long-term benefits to the increased DHT suppres-
sion achieved with dutasteride [Nickel etal. 2011].
The 5-ARI side effects include ED (in 58% of
patients), ejaculatory dysfunction (15%),
decreased libido (5%), and, rarely, gynecomastia
(1%). By shrinking the prostate, the 5-ARIs have
been shown to improve BPH-related symptoms
and to reduce the risk of future urinary retention
and BPH-related surgery [Roehrborn etal. 2002].
To date, no long-term comparison studies have
been conducted between the commercially avail-
able 5-ARIs, dutasteride and finasteride. There
have only been limited data from a single 1-year
study comparing the two. The Enlarged Prostate
International Comparator study is the only pro-
spective, multicenter, randomized, double-blind,
double-dummy, 12-month parallel-group study of
orally administered daily finasteride versus dutas-
teride for BPH [Nickel etal. 2011]. It involved a
total of 1630 men, randomized 1:1 to either 5 mg
oral finasteride or 0.5 mg oral dutasteride admin-
istered daily. After the 12-month double-blinded
phase, patients had an option to enroll in a
24-month open-label phase where patients all
received dutasteride 0.5 mg once daily. This study
demonstrated that over a 1-year period, dutas-
teride and finasteride show no statistically signifi-
cant difference and are equally effective in
reducing prostate size, improving maximum uri-
nary flow rate (Qmax), as well as improving voiding
symptoms associated with BPH, with similar rates
of adverse events (AEs) [Nickel etal. 2011].
While, -blockers do not affect PSA and have no
effect on prostate cancer risk, the 5-ARIs lower
PSA by 50% after 6 months on therapy [Debruyne
et al. 2004]. Therefore, if a patients PSA is
8 ng/ml prior to the initiation of a 5-ARI, then
after 46 months of therapy, the PSA should be in
the 4 ng/ml range. While continuing on 5-ARI the
PSA value should stay around this level. If the
PSA rises on 5-ARI then a referral to a urologist
260 http://tau.sagepub.com
is mandatory to exclude the development of new
prostate cancer. While the patient is receiving a
5-ARI, the prostate should be checked with an
annual digital rectal exam (DRE).
Controversy still exists about the increased risk of
developing high-grade prostate cancer in patients
taking a 5-ARI such as finasteride or dutasteride.
Health Canada and the US Food and Drug
Administration issued a label change for finas-
teride and dutasteride to include new safety infor-
mation about the possible increased risk of being
diagnosed with high-grade prostate cancer while
on these agents, based on analysis of data from the
Prostate Cancer Prevention Trial (PCPT) [Health
Canada, 2012] and the Reduction by Dutasteride
of Prostate Cancer Events (REDUCE) trial
[Roehrborn etal. 2011]. Some experts have pro-
posed that the increased risk of high-grade pros-
tate cancer may be an artifact resulting from the
interpretation of prostate biopsies in these studies.
Current recommendations are to exclude prostate
cancer in patients with BPH (based on PSA and
DRE) prior to initiating 5-ARI for BPH.
Phosphodiesterase 5 inhibitors.As previously
stated, ED and LUTS related to BPH often coex-
ist in aging men [McVary and McKenna, 2004].
BPH not only causes prostatic obstruction and
bladder neck contraction, but it may also alter
smooth muscle relaxation, reduce blood flow, and
reduce the function of nerves and the endothe-
lium [McVary etal. 2007a]. A number of patho-
physiological mechanisms support the relationship
between LUTS and ED. For example, a reduc-
tion in nitric oxide synthase (NOS) containing
nerves and increased Rho-kinase activity are both
observed in men with LUTS and can lead to ED
[McVary, 2006]. Fewer NOS-containing nerves
make it more difficult to produce nitric oxide
(NO), which is involved in activating guanylate
cyclase, an enzyme that generates cGMP. Typi-
cally, cGMP will go on to stimulate smooth mus-
cle relaxation and arterial dilation in order to
cause erections [McVary, 2006]. Under normal
conditions, PDE-5 promotes smooth muscle con-
traction by degrading cGMP; therefore, PDE-5
inhibitors can facilitate smooth muscle relaxation
in men with BPH by inhibiting its degradation
[Corbin, 2004]. Recent studies of oral PDE-5
inhibitors, including tadalafil, vardenafil (Levitra,
Bayer HealthCare Pharmaceuticals Inc, Missis-
sauga, Ontario, Canada), and sildenafil (Viagra,
Pfizer Inc, Saint-Laurent, Quebec, Canada), have
demonstrated significant improvements of LUTS
in patients with BPH [McVary etal. 2007a; Stief

etal. 2008; Tamimi etal. 2010]. A dosage of 5 mg
tadalafil/day significantly improved IPSS com-
pared with placebo [Egerdie et al. 2012], with
improvement onset occurring within 2 weeks.
Although urodynamic profiles were not signifi-
cantly improved with daily tadalafil, patients
symptom scores improved and side effects were
minimal, including headache, back pain, facial
flushing, dyspepsia, and nasopharyngitis.
Combination therapy.Studies have shown the
benefit of combination therapy with 5-ARIs and
-blockers [Gormley etal. 1992). The benefit is
greatest in patients with large prostates, where the
5-ARI shrinks the prostate and the -blocker
relaxes the smooth muscle of the prostate provid-
ing combination benefits. For patients with
smaller prostates, -blockers alone may be suffi-
cient to alleviate urinary symptoms. Two land-
mark studies examined combination therapy for
BPH: the Medical Therapy of Prostate Symptoms
(mTOPS) study and the Combination of Avodart
and Tamsulosin (CombAT) study.
The mTOPS study was a landmark trial compar-
ing monotherapy with an -blocker (doxazosin)
or a 5-ARI (finasteride) versus combination ther-
apy (doxazosin and finasteride) for BPH
[McConnell etal. 2003]. This study randomized
patients into four treatment groups: an -blocker
(doxazosin) alone, a 5-ARI (finasteride) alone,
combination therapy, and placebo [McConnell
et al. 2003]. Combination therapy provided the
most effective increase in flow rate, improvement
in symptom scores, reduction in risk of acute uri-
nary retention (AUR), and reduction in the need
for surgery. Prostate volume decreased in patients
who received finasteride alone, and in patients
who were treated with finasteride plus an -blocker.
Patients who were treated with an -blocker alone
or with placebo had an increased prostate volume
over time, and they did not have a reduced need
for future BPH-related surgery or a reduced risk
of developing AUR.
The CombAT study was designed to examine
whether the combination of a 5-ARI (dutas-
teride) and an -blocker (tamsulosin) was more
effective than monotherapy alone for improving
symptoms for men who had BPH, or to prevent
the progression of BPH [Roehrborn etal. 2009].
A total of 4844 patients were randomized 1:1:1
to combination 0.5 mg dutasteride once daily
and 0.4 mg tamsulosin once daily (n = 1610),
0.5 mg dutasteride once daily with tamsulosin
http://tau.sagepub.com 261
C Olesovsky and A Kapoor
matched placebo once daily (n = 1623), or
0.4 mg tamsulosin with dutasteride matched pla-
cebo once daily (n = 1611). There was no double
placebo group as both monotherapies had estab-
lished efficacy, so it was considered unethical to
treat this patient group with placebo for 4 years.
The study was powered at 94% at year 4 for the
primary comparison of combination therapy ver-
sus tamsulosin. The 4-year results and the 2-year
results showed that there was an improvement in
the quality of life and an improvement in symp-
tom scores in men with proven, enlarged pros-
tates that were larger than 30 ml [Roehrborn
etal. 2009]. With improvement on combination
therapy, in most cases men were able to stop tak-
ing the -blocker after 69 months [Roehrborn
etal. 2009]. After stopping the -blocker most of
the men were still able to maintain a fairly good,
symptom-free response. Jalyn, a single-capsule
combination of dutasteride 0.5 mg and tamsulo-
sin 0.4 mg, was approved for use in men with
symptomatic BPH based on the study results
from the CombAT trial.
The standard therapy for managing a patient with
BPH is initiating an -blocker with a quick onset
of action, between 3 and 5 days. Selective
-blockers include tamsulosin, alfuzosin, and
more recently, silodosin. For patients with larger
prostates, the addition of a 5-ARI such as finas-
teride or dutasteride may be considered to reduce
prostate volume, reduce the risk of AUR, and
decrease the risk of future prostate-related sur-
gery. After 69 months of combination therapy
with an -blocker and a 5-ARI, physicians may
consider stopping the -blocker. In addition to
treating patients with BPH with drugs from the
5-ARI class and the -blocker class, drugs from
the PDE-5 inhibitor class may now be considered
for treating BPH. Once daily tadalafil 5 mg has
been shown to improve BPH-related symptoms
and is a current treatment option for patients.
In the mTOPS and CombAT studies the thera-
peutic potential of combining certain 5-ARIs with
-blockers was evaluated. The positive results
achieved in both of these landmark studies have
opened the door to more research into combinato-
rial pharmacotherapies. This review will investi-
gate whether there is a similar therapeutic benefit
in treating men with BPH using the combined
treatment of 5-ARIs and PDE-5 inhibitors.
Specifically, this review will focus on evaluating the
efficacy and safety of tadalafil and finasteride in the
treatment of LUTS and ED in men with BPH.
Therapeutic Advances in Urology 8(4)
Tadalafil and finasteride combinatorial
treatment
Tadalafil
Tadalafil is an orally administered synthetic car-
boline-based compound with vasodilatory activity
and the chemical name of (6R-trans)-6-(1,3-
benzodioxol-5-yl)- 2,3,6,7,12,12a-hexahydro-
2-methyl-pyrazino [1, 2:1,6] pyrido[3,4-b]
indole-1,4-dione [National Center for
Biotechnology, 2015a]. Tadalafil selectively
inhibits the PDE-5-mediated cGMP degradation
in the corpus cavernosum. In turn, the increased
levels of cGMP promote prolonged muscle relax-
ation, vasodilation, and blood engorgement of the
corpus cavernosa leading to prolonged penile
erection and potential improvement of LUTS
caused by BPH [National Center for
Biotechnology, 2015a]. The NO cascade is the
major physiological process that is targeted by
tadalafil. Typically this cascade leads to the acti-
vation of guanylate cyclase, which in turn pro-
duces an increase cGMP. This molecule has a
variety of roles in the body, but most importantly
it stimulates vasodilation. Under normal condi-
tions cGMP is degraded by PDE-5, but by inhib-
iting this enzyme, tadalafil allows cGMP to exist
in higher levels and exert beneficial vasodilatory
activity [Curran and Keating, 2003]. In Canada,
5 mg daily tadalafil was approved for the treat-
ment of BPH and ED, as of June 2012.
Pharmacodynamics.Clinical trials have shown
that through the inhibition of PDE-5, tadalafil
can greatly improve clinically relevant measures
of LUTS secondary to BPH along with erectile
function (EF) in those who are sexually active
and suffering from ED [McVary et al. 2007b;
Roehrborn etal. 2008; Oelke etal. 2012]. Several
double-blind, placebo-controlled, randomized
controlled trials (RCTs) have already been con-
ducted and their results are remarkably consis-
tent. Tadalafil seems to significantly improve the
mean change from baseline in IPSS as early as
12 weeks after beginning treatment [Oelke etal.
2012; Egerdie etal. 2012]. In one study looking at
four clinically relevant doses of tadalafil, the IPSS
least squares mean change from baseline to end
point was significantly improved for 2.5 mg
(3.9), 5 mg (4.9), 10 mg (5.2), and 20 mg
(5.2) of daily tadalafil compared with placebo
(2.3) [Roehrborn etal. 2008]. In another RCT
it was found that tadalafil significantly improved
the mean change from baseline in IPSS at 6 weeks
for 5 mg tadalafil (2.8 versus placebo 1.2) and
262 http://tau.sagepub.com
at 12 weeks for 5/20 mg tadalafil (3.8 versus pla-
cebo 1.7) [McVary et al. 2007b]. Studies sug-
gests that a three-point change in the IPSS
represents the minimum clinically meaningful
change [Barry et al. 1995] and we see changes
approaching this threshold in many of the partici-
pant groups in these two studies.
Besides changes in IPSS, other secondary meas-
ures are also significantly improved by treatment
with tadalafil. These include IPSS irritative and
obstructive domains, IPSS quality of life index
(IPSS QOL), BPH Impact Index (BII) and also
the International Index of Erectile Function
within the erectile function domain (IIEF-EF)
[McVary etal. 2007b; Roehrborn etal. 2008]. In
one study 56% of men with BPH LUTS who
were sexually active and suffering from ED saw
significant improvements in their IIEF-EF scores
[McVary etal. 2007b]. Similar results were also
found in the four-dose tadalafil RCT among this
subset of men in the study [Roehrborn et al.
2008]. There is still some debate as to whether
tadalafil can improve uroflowmetry parameters
such as Qmax. Several studies have shown a
numerical improvement in this parameter in
groups of subjects taking tadalafil; however, the
improvement was not statistically significant
[McVary et al. 2007b; Roehrborn et al. 2008].
Recently, in an international RCT the mean
change in Qmax among men taking 5 mg of tada-
lafil for 12 weeks was 2.4 ml/s, which was statisti-
cally significant higher than the placebo control
group [Oelke et al. 2012]. Researchers in this
study were conservative in stating that these find-
ings could have been random or due to their
study population starting with lower baseline
Qmax values. In addition, BPH guidelines state
that there is a poor correlation between symp-
toms and Qmax [Oelke etal. 2012]. Nonetheless,
in vitro studies have shown that PDE inhibitors
can induce smooth muscle relaxation in the
human bladder neck and prostate, which may
promote the increase observed in Qmax values in
these studies [Uckert etal. 2008].
Pharmacokinetics and metabolism.As with other
PDE-5 inhibitors, tadalafil is rapidly absorbed
after oral administration; it has a tmax of approxi-
mately 2 h and an onset time of 30120 min post
dose [Mehrotra etal. 2007; Eardley and Cartledge,
2002]. Studies have found that the peak plasma
concentration of tadalafil (Cmax) was 378 g/liter
following a therapeutic 20 mg dose administration
[Rosen and Kostis, 2003; Sussman, 2004].

Although tadalafils absolute bioavailability has
not been reported, it is known that at least 36% of
the dose is absorbed from an oral solution [Meh-
rotra etal. 2007]. The absorption and other phar-
macodynamic properties of tadalafil are unaffected
by food intake prior to administration [Brock,
2003]. Furthermore, it is highly plasma protein
bound (94%) and the two principle plasma pro-
teins to which it binds are albumin and 1 acid
glycoprotein [Mehrotra etal. 2007]. There is high
distribution observed as well for tadalafil, with an
apparent volume of distribution of 6070 liters
[Curran and Keating, 2003]. Metabolism of
tadalafil mainly occurs through the cytochrome
P450 3A (CYP3A4) oxidative process. Unlike
other PDE-5 inhibitors such as vardnafil and
sildenafil, which are metabolized into more than
10 different metabolites, tadalafil is primarily
metabolized by CYP3A4 to a single catechol
metabolite. This catechol metabolite then under-
goes methylation and glucuronidation to form
methylcatechol and methylcatechol glucuronide
metabolites [Mehrotra et al. 2007]. The major
tadalafil metabolite in the plasma is inactive; in
fact its affinity towards PDE-5 is 10,000 fold less
[Curran and Keating, 2003]. In contrast, many of
the metabolites of vardnafil and sildenafil have
major activity and contribute to the overall effi-
cacy and safety profile of these drugs [Cheitlin
etal. 1999]. When it comes to the elimination of
tadalafil, the primary route is through hepatic
metabolism and renal excretion of the unchanged
drug. For the most part, oral tadalafil is excreted
through feces (61%) as inactive metabolites, but
some is also excreted through the urine (36%)
[Curran and Keating, 2003]. Additionally, tadalafil
has a low hepatic extraction ratio with a mean oral
clearance of 2.5 liter/h in healthy subjects. Due to
its low systemic clearance rate relative to other
PDE-5 inhibitors, tadalafil has a much higher half
life at approximately 17.5 h [Mehrotra etal. 2007;
Meibohm and Derendorf, 1997].
Finasteride
Finasteride is an orally administered synthetic
4-azasteroid compound and its chemical name is
N-(1,1-dimethylethyl)-3-oxo-(5,17)-4-
azaandrost-1-ene-17-carboxamide [National
Center for Biotechnology, 2015b]. It is a com-
petitive and selective inhibitor of the type 2, 5-AR
isoenzyme, which is an intracellular enzyme that
converts testosterone to DHT [Bartsch et al.
2000]. The reduction in serum DHT levels
results in diminished stimulation of ARs in the
http://tau.sagepub.com 263
C Olesovsky and A Kapoor
nuclei of prostate cells and consequently dimin-
ished prostate cell proliferation [National Center
for Biotechnology, 2015b]. Approval by the US
Food and Drug Administration was obtained in
1992 as monotherapy for the treatment of symp-
tomatic BPH.
Pharmacodynamics.Many clinical trials have
sought to analyze the effects of finasteride in vivo.
Through its ability to selectively and competi-
tively inhibit the type 2 5-AR isoenzyme, finaste-
ride can have a significant impact on levels of
DHT within the body. Type 2 5-AR is the pre-
dominant isoenzyme found in prostatic tissue
[Wilde and Goa, 1999], which helps to explain
why the greatest reduction in DHT is observed in
prostatic tissue. It has been found that finasteride
can reduce prostatic DHT levels over 90%, but
only circulating DHT levels by 6080% [Wilde
and Goa, 1999]. These results are congruent to
those found in a double-blind, placebo-controlled
RCT that measured levels of prostatic DHT fol-
lowing a 7-day daily treatment of finasteride at
either 1, 5, 10, 50, or 100 mg/day. Regardless of
the dose given, prostatic DHT levels declined to
15% or less of the control levels within 1 week of
treatment [McConnell etal. 1992]. Interestingly,
in both of these studies prostatic testosterone lev-
els seem to increase in a reciprocal manner yet
have no significant ability to affect prostatic
growth or morphology [Wilde and Goa, 1999;
McConnell etal. 1992]. Meanwhile, the decrease
in DHT had a multitude of effects, including an
apparent reduction in prostate size through finas-
teride-induced atrophy and apoptosis after 6
months of treatment [Wilde and Goa, 1999].
Besides lowering DHT levels in the prostate and
to a lesser extent in the serum, a double-blind,
placebo-controlled, randomized trial in which
5 mg finasteride was administered daily to a group
of men with BPH showed that it could also sig-
nificantly reduce total BPH symptom score and
increase Qmax [Andersen etal. 1995]. The maxi-
mum urinary flow rate decreased in the placebo
group by 19%, but improved in the finasteride
group by 12%, leading to a between-group differ-
ence that was statistically significant (1.8 ml/s)
[Andersen et al. 1995]. Furthermore, a pooled
analysis of RCTs with 2-year follow-up data com-
paring finasteride with placebo was performed to
analyze differences in AUR and BPH-related sur-
gical interventions. Results from the pooled anal-
ysis show that treatment with finasteride for 2
years reduced the frequency of AUR by 57% and
also significantly decreased the frequency of
Therapeutic Advances in Urology 8(4)
surgical interventions (4.2% in the finasteride
group versus 6.5% in the placebo group) [Ander-
sen etal. 1997]. This study is particularly impor-
tant as it supports the idea that finasteride can
improve the long-term management of BPH.
Pharmacokinetics and metabolism. Finasteride is
rapidly absorbed after oral administration and it
has a tmax of 2 h when mean peak plasma concen-
trations are achieved [Carlin et al. 1992]. Food
was shown to slow the rate of absorption, but not
the overall extent, and this has not been shown to
be clinically significant [Wilde and Goa, 1999].
Finasteride has been shown to have a bioavailabil-
ity of 80% after oral administration and demon-
strates dose proportionality in plasma
concentrations [Carlin etal. 1992]. In addition, it
is highly plasma protein bound (90%), mainly to
albumin and 1 acid glycoprotein [Carlin et al.
1992]. There is extensive distribution of drug
observed, with a steady-state volume of distribu-
tion of 76 liters [Wilde and Goa, 1999]. In vitro
studies have shown that finasteride is metabolized
through an oxidative process by CYP450, specifi-
cally by the 3A4 and 2C19 isoenzymes [Chen
et al. 2009]. Finasteride is extensively metabo-
lized in the liver to essentially inactive metabo-
lites, including -hydroxyfinasteride and
fineasteride--oic acid [Lundahl etal. 2009]. The
majority of an oral dose is excreted through feces
and bile (75%) compared with the urine (25%)
and its half life is reported to be approximately
9 h [Wilde and Goa, 1999; Carlin etal. 1992].
Therapeutic trials
To date, several clinical trials have been done
using a combinatorial treatment of tadalafil and
finasteride [Casab etal. 2014; Roehrborn etal.
2015; Elkelany et al. 2015]. The first placebo-
controlled study was an international randomized,
controlled, double-blind study in men who were
over 45 years old with a baseline IPSS of 13 or
greater and prostate volume of 30 ml or greater
[Casab et al. 2014]. The study was conducted
from November 2010 to September 2012 and
randomized participants to two different groups:
once daily placebo/5 mg finasteride (n = 350)
(PBO/FIN) and once daily 5 mg tadalafil/5 mg
finasteride (n = 346) (TAD/FIN) for 26 weeks.
IPSS and IIEF-EF were used to assess changes in
LUTS and EF, respectively, in order to evaluate
whether the combinatorial therapy was superior
to finasteride alone. Of the 696 participants rand-
omized, 659 completed 12 weeks of therapy and
264 http://tau.sagepub.com
592 completed all 26 weeks [TAD/FIN 306
(88.4%) and PBO/FIN 286 (81.7%)]. TAD/FIN
combinatorial therapy led to significant improve-
ments in IPSS total scores compared with those
on the finasteride monotherapy after 4, 12, and
26 weeks. The least squares (LS) mean change
from baseline with TAD/FIN at 12 weeks was
5.2 versus 3.8 for PBO/FIN, which represents a
least squares total difference (LSTD) of 1.4
(p < 0.001). Significant LSTD were observed in
the 4- and 26-week time points as well, specifi-
cally they were 1.7 and 1.0, respectively.
Another primary outcome evaluated by this study
was EF among sexually active patients who had
ED at baseline (n = 201 PBO/FIN and n = 203
TAD/FIN). Results show that men receiving the
TAD/FIN therapy had significantly improved
IIEF-EF scores at all three times as well. The LS
mean changes in IEFF-EF scores were 3.7, 4.7,
and 4.7 after 4, 12, and 26 weeks of TAD/FIN,
respectively. Overall, the LSTDs between TAD/
FIN and PBO/FIN at the three respective time
points from baseline were 4.9, 4.1, and 4.7
(p < 0.001). The difference in EF remained essen-
tially the same throughout the duration of the
trial, indicating the significant benefit of tadalafil
[Elkelany etal. 2015]. Another interesting finding
from this study was observed in a subgroup of
men who had no prior ED. Despite not having
any pervious dysfunction the TAD/FIN therapy
improved sexual desire, EF, orgasmic function,
and overall satisfaction with intercourse. It is
believed that these effects are a result of tadalafil
stimulating the NO cascade through the upregula-
tion of cGMP, leading to increased blood flow
and the neural response to male genitalia
[Elkelany et al. 2015]. Several other secondary
outcomes were measured as well, including IPSS
(storage and voiding subscore), IPSS QOL, erec-
tile function domain of IIEF-EF, Patient Global
Impression of Improvement (PGII) and clinician
Global Impression of Improvement (CGII).
Interestingly, all five key secondary efficacy out-
comes were statistically significantly improved in
the TAD/FIN group as well. Overall, this study
made conclusive findings that daily 5 mg tadalafil
coadministered with 5 mg finasteride in men with
LUTS and ED secondary to BPH resulted in sig-
nificant and early LUTS improvement compared
with monotherapy alone [Casab etal. 2014].
A subsequent study looking at the same study
participants was designed to evaluate treatment
satisfaction and clinically meaningful symptom

improvement [Roehrborn et al. 2015]. As
described above, the RCT had a 6-month treat-
ment period and men were randomized into
either the TAD/FIN combinatorial therapy group
or PBO/FIN monotherapy group. In this study,
post hoc analysis was performed of the minimal
clinically important differences (MCID) in IPSS
and prespecified van Elteren analysis was done
for treatment satisfaction based on the Treatment
Satisfaction Scale-Benign Prostatic Hyperplasia
(TSS-BPH). According to past literature and the
American Urological Association, there are two
ways to define the MCID: a decrease of at least
three points in total IPSS or at least a 25%
decrease in total IPSS [Barry etal. 1995; McVary
etal. 2010]. Both of these definitions were con-
sidered when performing the post hoc analysis of
the MCID in IPSS. At weeks4, 12, and 26, the
proportion of TAD/FIN responders was 57.0%,
68.8%, and 71.4%, respectively, and the propor-
tion of PBO/FIN responders was 47.9%, 60.7%,
and 70.2% when defining responders as those
who displayed at least a three-point decrease in
total IPSS. Alternatively, when responders were
defined as those who displayed at least a 25%
decrease in total IPSS, the proportion of TAD/
FIN responders was 44.8%, 55.5%, and 62.0%
for the three time points and 32.9%, 51.9%, and
58.3% for the PBO/FIN group. Odds ratio of
IPSS decrease of at least three points was statisti-
cally significant in favor of TAD/FIN at week4
and week12 [OR 1.45, 95% confidence interval
(CI) 1.071.97 and OR 1.48, 95% CI 1.072.05,
respectively], but were not significantly different
at week 26 (OR 1.14, 95% CI 0.811.61)
[Roehrborn etal. 2015].
In this study treatment satisfaction was another
primary outcome and was measured through the
TSS-BPH, which is a 13-item questionnaire split
into three sections: satisfaction with efficacy, dos-
ing and side effects, with low scores representing
a higher overall patient satisfaction [Black et al.
2009; Hareendran and Abraham, 2005]. TSS-
BPH data are only available from the final time
point in this study, which presents a significant
limitation for this study. Nonetheless, data from
the 6-month end point demonstrate that patient
satisfaction is significantly higher in the TAD/
FIN group compared with the PBO/FIN group.
This higher satisfaction is apparent in the total
TSS-BPH scores (mean 2.0 TAD/FIN versus 2.1
PBO/FIN, p = 0.031) and also the efficacy sub-
score (mean 33.7 TAD/FIN versus 36.6 PBO/
FIN, p = 0.025), but not in the dosing or side
http://tau.sagepub.com 265
C Olesovsky and A Kapoor
effects subscores. Combined, data from the post
hoc analysis and prespecified van Elteren analysis
support the superiority of TAD/FIN combinato-
rial therapy over finasteride monotherapy. Men
taking daily 5 mg tadalafil coadministered with
5 mg finasteride were more likely to achieve a
MCID in IPSS and to have higher patient per-
ceived satisfaction compared with men taking just
finasteride. These data further support the utility
of coadministration of tadalafil for early symptom
improvement in men starting treatment with a
5-ARI [Roehrborn etal. 2015].
Past evidence supports a benefit of the -blocker
and a 5-ARI combinatorial therapy in treating
and improving BPH LUTS. More recent studies
suggest that combining PDE-5 inhibitors with
5-ARIs offers a novel therapy capable of produc-
ing positive treatment results comparable in effi-
cacy [Casab etal. 2014; Roehrborn etal. 2015;
Elkelany etal. 2015]. From past clinical evidence
it seems like men with prostatic volumes greater
than 30 ml along with those who have moderate
to severe urinary symptoms will benefit most
from this new therapy [Elkelany et al. 2015].
Furthermore, this therapy is ideal in men who
want to avoid surgical intervention and the nega-
tive sexual side effects such as retrograde ejacula-
tion commonly observed in those on -blocker
therapy. Unlike the -blocker and a 5-ARI com-
binatorial therapy, it seems like tadalafil coadmin-
istered with finasteride offers a novel secondary
benefit in its ability to improve EF without caus-
ing sexual side effects [Elkelany et al. 2015].
Thus, this therapy is attractive for men who have
existing ED prior to treatment course. Lastly,
although 5-ARI therapy does prevent the progres-
sion of BPH and reduce the need for surgical
intervention, often it takes between 6 and 12
months before these positive changes are
observed. Combining tadalafil in this treatment
regime has been shown to speed up the onset of
action and thus offers another benefit to this novel
combinatorial therapy [Elkelany etal. 2015].
Safety and tolerability
The safety and tolerability profile of tadalafil and
finasteride have previously been evaluated in mul-
tiple studies investigating these drugs as mono-
therapeutic agents. In a 12-week single-blind
RCT in which men were randomly assigned to
either 5 mg of tadalafil or placebo, AEs were com-
pared between the two groups [McVary et al.
2007b]. Among the 280 men in the study, the
Therapeutic Advances in Urology 8(4)
most common treatment-emergent adverse events
(TEAEs) were increased erection (5.1% tadalafil
versus 1.4% placebo), dyspepsia (4.3% tadalafil
versus 0% placebo), back pain (3.6% tadalafil ver-
sus 0% placebo) and headache (2.9% tadalafil ver-
sus 0.7% placebo). Despite these AEs there were
no reports of priapism and between the two groups
there were no significant changes in PSA or other
relevant laboratory values. Furthermore, the only
serious adverse event (SAE) occurred in the pla-
cebo control group and there were no clinically
relevant changes in vital signs or reports of AUR.
Overall, the proportion of patients who discontin-
ued based on TEAEs was similar between the two
groups: 3.6% in the tadalafil group compared with
1.4% in the placebo group [McVary etal. 2007b].
Similar results were also replicated in a larger
RCT investigating multiple dosing levels of tada-
lafil [Roehrborn et al. 2008]. In this study the
major TEAEs were also back pain (3.4% tadalafil
versus 2.8% placebo), headache (3.4% tadalafil
versus 2.8% placebo), dyspepsia (3.3% tadalafil
versus 0% placebo), and myalgia (2.1% tadalafil
versus 0% placebo). All TEAEs were infrequent in
participants and rarely did they lead to discontinu-
ation in either group. Among the pooled tadalafil
groups, 4.8% discontinued based on TEAEs,
while in the placebo group the proportion was
2.4%. Although discontinuation was more likely
in the treatment branches of this trial, from a
safety perspective all doses of tadalafil were well
tolerated. Furthermore, although the incidence of
patients with one or more TEAEs increased with
increasing tadalafil doses, no clear relationship
was observed between the tadalafil dose and indi-
vidual AEs. In addition, no clinically relevant
changes in laboratory parameters, vital signs,
mean PSA or mean post void residual (PVR) urine
were observed. Interestingly, the proportion of
SAEs was higher in the placebo group, suggesting
that they are not attributed to the tadalafil treat-
ment [Roehrborn et al. 2008]. Furthermore,
according to manufacture guidelines, individuals
with angina, renal or hepatic impairment and
those who are taking -blockers, antihypertensives
or potent CYP3A4 inhibitors should not take
tadalafil as it could worsen or potentiate symp-
toms and effects [Elkelany etal. 2015]. It is also
suggested that tadalafil is contraindicated in men
taking nitrates for cardiac disease and in men who
have a history of serious hypersensitivity reactions
to tadalafil [Elkelany etal. 2015]
Similar studies investigating the efficacy of finas-
teride monotherapy provide insight into its safety
266 http://tau.sagepub.com
and tolerability profile as well. The most common
TEAEs with finasteride therapy are all sexually
related and included impotence (2.1%), decreased
libido (1%), and gynecomastia (0.4%) [Wilde
and Goa, 1999]. In a large RCT with over 7000
participants comparing finasteride with placebo
over 2 years, AEs related to sexual dysfunction
were significantly greater in the finasteride group
(2.119%) compared with the placebo group
(0.610%). Fortunately, most AEs were mild and
the proportion of discontinuations due to AEs
was similar in both groups in this study.
Interestingly, neither the dose of finasteride nor
the length of therapy were contributing factors in
the incidence of these sexually related AEs [Wilde
and Goa, 1999]. Other large multicenter, rand-
omized, placebo-controlled trials comparing dif-
ferent doses of finasteride have also been
completed to evaluate the drugs safety in men
with BPH. Patients in one study were randomized
to either 1 mg of finasteride, 5 mg of finasteride,
or placebo for 12 months. Following the 12
months patients were enrolled in a 2-year open
extension study and received 5 mg of finasteride
regardless of their original therapy [Stoner, 1994].
The group receiving 5 mg of finasteride from
baseline was the major focus given that this is the
approved therapeutic dosage for men with BPH.
Among the 543 men who started in the 5 mg fin-
asteride group, after 3 years, 297 (55%) had com-
pleted the necessary data collection to be
considered in the analysis. Out of the remaining
246 participants, 68 (12%) lacked sufficient data
and 178 patients (33%) dropped out of the study
prior to reaching the 3-year time mark. Most of
these dropouts were attributed to loss of follow-
up or withdrawn consent as opposed to a result of
clinical or sexual TEAEs [Stoner, 1994]. Among
those who could be analyzed, results show that
finasteride has a strong safety and tolerability pro-
file. Across the 36-month time period of this
study there was no increase in the rate at which
AEs occurred. In fact, as the duration of the treat-
ment continued, new drug-related sexual AEs
actually decreased and 60% of men who had a
sexual AE found that it was resolved with contin-
ued treatment. The most common drug-related
AE was impotence, which occurred in 3.7%,
3.2%, and 2.1% of finasteride-treated partici-
pants after 13 years, respectively (1.1% pla-
cebo). Other drug-related AEs include decreased
libido (3.3% 1 year versus 1.6% placebo) and
decreased ejaculate volume (2.6% 1 year versus
0.9% placebo). Although some sexual drug-
related AEs were more likely in participants

taking 5 mg of finasteride compared with placebo,
there were no significant differences in the occur-
rence of most clinical AEs over the 36 months.
Furthermore, there were no significant differ-
ences in the percentage of patients who reported
SAEs over the course of the study when compar-
ing placebo (9.4%) with 5 mg finasteride (6.8%).
For the vast majority of these SAEs they were
considered nondrug related, further highlighting
the safety of therapeutic doses of finasteride
[Stoner, 1994]. As stated previously there is still
some uncertainty as to whether finasteride
increases an individuals risk of developing high-
grade prostatic cancer. Men aged 55 and over
with a normal DRE and PSA up to 3.0 ng/ml at
baseline taking finasteride 5 mg/day in the 7-year
PCPT had an increased risk of Gleason score
810 prostate cancer (finasteride 1.8% versus pla-
cebo 1.1%). The impact of these results has not
yet been established and it is unclear whether the
reduction in prostate volume caused by finas-
teride or study-related factors played a role in
them. One follow-up study suggests that the
effects of finasteride on prostate volume and
selective inhibition of low-grade cancer may have
contributed to the increase in high-grade cancers
with finasteride in the PCPT [Lucia etal. 2007].
In the latest RCTs exploring finasteride and tada-
lafil as combinatorial agents, a high safety profile
has been observed [Casab etal. 2014; Roehrborn
etal. 2015]. In these trials participants were rand-
omized to two different groups: once daily pla-
cebo/5 mg finasteride (n = 350) (PBO/FIN) and
once daily 5 mg tadalafil/5 mg finasteride
(n = 346) (TAD/FIN) for 26 weeks. Due to the
similarities in the metabolism of finasteride and
tadalafil through CYP3A4 isoenzymes researchers
did not anticipate there would be any major inter-
action between these two drugs. Past evidence
suggests that neither agent can inhibit or induce
CYP3A4 activity, allowing for these two drugs to
be combined in a therapy without much concern.
Results from the study reinforce these findings
and show that the incidence and severity of AEs
was not increased or worsened in the TAD/FIN
group. Overall the safety profile of TAD/FIN
therapy did not deviate from the safety profile
established in monotherapeutic trials described
previously. Interestingly, the incidence of sexually
related AEs such as impotence, decreased libido,
and ejaculatory abnormalities were less common
in the TAD/FIN group compared with the PBO/
FIN group [Casab et al. 2014]. These AEs are
commonly reported among men prescribed
http://tau.sagepub.com 267
C Olesovsky and A Kapoor
finasteride and were shown to be higher in the
PBO/FIN group. Interestingly, although the inci-
dence of these AEs were elevated in the PBO/FIN
group, the proportion in the PBO/FIN group was
lower than that typically reported for 5-ARI mon-
otherapy. Researchers attributed these finding to
patient bias, speculating that the fact participants
knew they had a 50% chance of receiving a drug
known to improve sexual function reduced the
overall reporting of these types of AEs [Casab
etal. 2014]. During the 26-week study there were
a total of two deaths. One man passed away from
metastatic pancreatic carcinoma 65 days after ran-
domization to the TAD/FIN group, while the
other man was in the PBO/FIN group and died
from a cerebrovascular incident 148 days after
randomization. Neither of these deaths were
believed to have any relation to the drug therapy
or the study procedure. As expected, classical AEs
of tadalafil such as back pain, headache, dyspep-
sia, and flu-like symptoms were reported in 1.7%,
3.4%, 0.6%, and 2.3% of men on PBO/FIN versus
4.6%, 3.5%, 2.3%, and 2.3% of men on combina-
tion therapy. Although the incidence of TEAEs
was higher in the TAD/FIN group (31.3%) com-
pared with the PBO/FIN group (27.1%), this dif-
ference was not statistically significant.
Furthermore, only a small proportion of these
TEAEs were characterized as being related to the
treatment itself (PBO/FIN 5.4% versus TAD/FIN
8.7%). The number of SAEs and discontinuations
due to AEs was also low in both groups and not
significantly different between either of the treat-
ment groups. Fortunately, there was significant
difference in the occurrence of treatment-related
sexual AEs in favor of the TAD/FIN group, sug-
gestive of an additional benefit of this combinato-
rial therapy [Casab etal. 2014].
Conclusion
A variety of treatment options exist for those with
BPH; however, pharmacotherapies are desirable
due to their minimal invasiveness. With three
classes of drugs available for the treatment of
BPH, much of the most recent research has been
towards finding new combinatorial therapies that
improve symptom relief. 5-ARI/-blocker coad-
ministration has long since been accepted as one
such combinatorial therapy for those with BPH.
Although this therapy does offer additional LUTS
relief compared with monotherapies, it also
increases the incidence of sexually related AEs.
Due to this limitation, the search for other combi-
natorial therapies effective in treating BPH has
Therapeutic Advances in Urology 8(4)
continued. Initial studies investigating 5-ARI/
PDE-5 inhibitor coadministration show that the
combination of finasteride and tadalafil is a safe
and effective alternative therapy. Tadalafil and
finasteride together can relieve LUTS in men
with BPH while also help protect individuals from
the negative sexually related AEs reported by
those on 5-ARI/-blocker therapy.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of
interest.
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