Prostate-specific antigen (PSA) concentrations in hypogonadal men during 6 years of

Prostate-specific antigen (PSA) concentrations
in hypogonadal men during 6 years of
transdermal testosterone treatment
Jean-Pierre Raynaud, Jean Gardette*, Jacques Rollet† and Jean-Jacques Legros‡
Université Pierre et Marie Curie, 4 place Jussieu, 75252 Paris, *40 rue de Chezy 92200, Neuilly/seine, †Institut
Rhône alpin, Médicentre Val Ouest 69130 Ecully, France, and ‡CHR Citadelle, Université de Liège, Belgium
What’s known on the subject? and What does the study add?
• Hypogonadism affects an estimated 2–4 million men in the USA, but only 5% receive treatment. Testosterone
replacement therapy reduces the effects of testosterone deficiency on sexual function, mood and energy in hypogonadal
patients. Long-term hypogonadism management requires testosterone treatment to restore serum concentrations of
testosterone and its active metabolites, within physiological ranges; a testosterone preparation that achieves physiological
plasma concentrations without supra-physiological escape is a preferred option. A previous 1-year study European
clinical study showed the efficacy and safety of a transdermal testosterone patch (Testopatch®).
• The present study shows the long-term (6-year) safety and efficacy of Testopatch in patients with primary or secondary
hypogonadism. We show that, over the long-term, Testopatch was associated with no relevant changes in PSA
concentration and PSA velocity, or any significant prostate risks (there were no cases of prostate cancer).
Objective
• To assess the change in prostate-specific antigen (PSA)
concentrations in patients with primary or secondary
hypogonadism, receiving transdermal testosterone.
Patients and Methods
• This was an interventional, 6-year study, conducted in
Urology and Endocrinology centres in Belgium, France,
Germany, the Netherlands and Spain.
• Participants were primary (48%) or secondary (52%)
hypogonadal patients who received two 60 cm2
testosterone patches (Testopatch®), delivering 4.8 mg of
testosterone per day, applied every 2 days.
• During treatment, total testosterone (TT),
dihydrotestosterone, oestradiol and, PSA concentrations
were measured in a centralised laboratory every 3
months during the first year, and every 6 months
thereafter.
Results
• In all, 200 patients [mean (sd) age 41.0 (12.5) years, body
weight 82.5 (13.7) kg, height 177.2 (9.3) cm, body mass
index 26.2 (3.4) kg/m2] were treated with transdermal
testosterone patches.
• In all, 161 patients completed the 1-year study and 115
entered into a 5-year study extension; 51 patients
completed the sixth year of the study.
• The mean baseline concentrations of TT and PSA were
1.4 ng/mL and 0.47 ng/mL, respectively; TT serum
concentrations >3 ng/mL were achieved in 85% of
patients and fluctuated between 4.4 and 6.0 ng/mL.
• At each successive 6-month time point, mean the PSA
values were 0.60, 0.67, 0.76, 0.70, 0.61, 0.68, 0.64, 0.71,
0.75, 0.74, 1.01, 0.78, 0.80 ng/mL, respectively. The mean
PSA velocity was negligible (0.00–0.03 ng/mL/year) from
30 months to the end of the trial, except for a value of
0.08 at 60 months. Seven patients had a PSA
concentration of >4 ng/mL due to a sharp PSA increase.
Six of these patients had prostatitis and PSA
concentrations returned to previous levels with
appropriate treatment. No prostate cancer was reported
during the trial.
Conclusion
• These data support a strong safety profile for Testopatch,
even at the highest registered dosage.
Keywords
testosterone, hypogonadism, treatment, transdermal
© 2013 BJU International | doi:10.1111/j.1464-410X.2012.11514.x
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Raynaud et al.
Introduction
Testosterone replacement therapy (TRT) is a key issue for
the management of hypogonadism, attenuating the effects
of testosterone deficiency on sexual function, energy and
mood [1–5]. The aim of TRT in hypogonadal patients is to
restore hormone concentrations (testosterone and its
metabolites) to the normal range of healthy young men,
and to select the lowest dose that gives positive effects on
desired endpoints. Although the decline of testosterone
concentrations with age is often very slow, a significant
number of men aged >50 years have biological testosterone
concentrations below the normal range. Hypogonadism
affects an estimated 2–4 million men in the USA, but only
5% receive treatment [1].
Management guidelines have been issued by various
associations and societies [6], with the consensus that
‘testosterone therapy for symptomatic men with androgen
deficiency, who have low testosterone concentrations,
induce and maintain secondary characteristics and improve
their sexual function, sense of well-being, muscle mass and
strength, and bone mineral density’. In clinical trials, TRT
has been shown to have very little effect on the prostate
gland [7]; indeed, a statistically non-significant increase
in prostate androgen concentrations was observed with
TRT [8].
Long-term management of hypogonadism requires
testosterone treatment to restore serum concentrations of
total testosterone (TT) and its active metabolites,
dihydrotestosterone (DHT) and oestradiol (E2), within
physiological ranges [1,9]. A testosterone preparation that
achieves physiological plasma concentrations without
supra-physiological escape is a preferred option.
Transdermally administered testosterone, by avoiding the
first pass effect in the liver, may be the best way of
administration, if local tolerability is managed properly.
The Institut de Recherche Pierre Fabre (IRPF) has
developed a ‘drug in adhesive’ transdermal patch
(Testopatch®). Initially, a 1-year European clinical study was
conducted to treat men with primary or secondary
hypogonadism and results have been published elsewhere
[10]. During the course of that study, an additional
extension was proposed to all patients who wanted to
continue on Testopatch, renewable every year according to
the willingness of the patient. The objective of the
extension study was to obtain information on the
long-term safety and efficacy of the highest Testopatch
dosage. No dose adaptation was planned in this extension
study.
study. Patients were recruited from January 2002 to
December 2008. Screening for prostate cancer using
PSA monitoring and Digital Rectal Examination were
performed before initiating therapy and throughout
treatment, every 3 months for the first year and every
6 months thereafter, according to accepted
recommendations [11].
At baseline and every 6 months over 6 years, TT,
bioavailable testosterone (BT), DHT and E2 were assayed
using time-resolved-fluoroimmunoassay in a centralized
hormonal laboratory (reference central laboratory normal
ranges are 2.69–7.77 ng/mL for TT and 0.75–2.75 ng/mL
for BT [12–14]; routine biological analyses and PSA
(Immulite 2000 PSA ref L2KPS6) were conducted by MDS
Central Laboratory (95560 Baillet, France); vital signs and
clinical symptoms, were assessed by the investigator
according to the Aging Male’s Symptoms (AMS) rating
scale [15] and adhesiveness and local tolerability according
to the USA Food and Drug Administration (FDA)
guidelines [16]; notification of any skin reaction was
reported by the patient. Patients with treatment-emergent
adverse events (TEAEs) were tabulated by group according
to the MeDRA V6.1 coding system.
Inclusion Criteria
• Age >18 years.
• Body mass index (BMI) !32 kg/m2
• Signed an informed consent at inclusion and every year
thereafter
• TT concentration of !2.5 ng/mL.
Exclusion Criteria
• PSA concentration of "2 ng/mL, haematocrit "52%,
blood pressure >160/90 mmHg, glucose level of
>7.1 mmol/L.
• Diabetes, epilepsy, migraine, asthma, liver or renal failure,
oedema, hirsutism, psoriasis, eczema.
• History of allergy to patch, alcohol or drug abuse, history
of cancer.
• Treatment with barbiturates, anticoagulants, insulin,
ketoconazole, spironolactone, finasteride, anti-androgens,
LHRH analogues, sildenafil.
At the end of each year, a 1-year extension was proposed to
the patient and, for consenting patients, preventive
measures were taken. The scientific committee agreed that
the threshold concentration for study continuation was a
PSA concentration of >3 ng/mL.
Patients and Methods
Treatment
This was a European multicentre (Belgium, France,
Germany, the Netherlands and Spain), open label, 6-year
Testopatch is a matricial, ‘drug-in-adhesive’ transdermal
delivery system, consisting of a transparent backing film, a
2 © 2013 BJU International
PSA change during 6 years of transdermal testosterone
release liner and, in-between, an adhesive matrix contains
0.5 mg/cm2 testosterone and each 60 cm2 Testopatch
delivers 2.4 mg/24 h [17,18]. Two patches were applied for 2
days to the upper arm, lower back, upper buttock or thigh.
Results
Patient Demographics
In all, 200 patients with primary (48%) or secondary (52%)
hypogonadism [mean (sd) age 41.0 (12.5) years; median
(range) 40 (18–68) years, mean (sd) bodyweight
82.5(13.7) kg, height 177.2 (9.3) cm, BMI 26.2 (3.4) kg/m2].
were treated with Testopatch; 161 patients completed the
first year and 115 patients entered into the study extension:
97, 73, 59, 57 and 51 patients (26%) completed 2, 3, 4, 5 and
6 years, respectively. Over time, the ratio between primary
and secondary hypogonadism did not change. At study end,
26 patients had primary and 25 secondary hypogonadism.
The high non-completer rate seen at the end of the first
year is due to administrative reasons; when the extension
was administratively accepted, the study was already closed
for a large number of patients and they could not enter
into the extension (accounting for 11.5% of the overall
discontinuation rate). Furthermore, one investigating centre
in the Netherlands was closed due to a restructure of the
hospital facilities (patients lost to follow-up) and, in a
Belgian centre, the investigator decided to switch patients
to a phase I study. Discontinuation due to a lack of effect
was low (insufficient response 7.5%).
Apart from the administrative reasons, described above,
that account for the high non-completer rate, the main
treatment-related reasons for study discontinuation
included local tolerability (15.0%), patch adhesiveness
(9.5%) and inconvenience (5.5%) [together accounting for
60.5% of non-completers and discontinuations]. Other
reasons were serious AEs (1.5%), AEs (3.5%), laboratory
eligibility criteria (2.5%), compliance (1%), sponsor
decision (1.5%) and other (3.5%).
Population Data Sets
The intention-to-treat (ITT) safety data set comprised 200
patients who signed the informed consent and applied two
patches at least once. The ‘ITT efficacy’ data set included
patients with at least one available on-treatment
testosterone assessment (the first assessment was after 3
months of treatment). The ‘completers’ data set consisted of
patients who completed the 6-year study.
Hormone Concentrations
For each time point, TT concentrations are shown in
Table 1 using Hodges-Lehmann estimates (95% CI) and
Table 1 Testosterone concentrations (ng/mL) at baseline and at each
time point.
Time, months
Patients, n
Hodges-Lehmann
estimate (95%
CI), ng/mL
183
145
133
104
98
81
75
62
59
57
57
53
51
1.33 (1.18–1.47)
5.50 (5.26–6.65)
4.92 (4.38–5.48)
4.93 (4.38–5.48)
4.22 (3.77–4.74)
4.52 (3.96–5.07)
4.37 (3.93–4.86)
4.78 (4.26–5.23)
4.53 (4.03–4.95)
4.21 (3.82–4.66)
5.26 (4.50–5.91)
5.53 (4.86–6.25)
5.18 (4.48–6.02)
Baseline
6
12
18
24
30
36
42
48
54
60
66
72
For each time point, testosterone concentrations are given using Hodges-Lehmann
estimates (95% CI) and using mean values (minimum, median, maximum, 95%
CI), depicted in Figure 1 with box plots. It should be noted that the usual mean,
which relies on the assumption of symmetric distribution, was not adequate to
assess hormone concentrations. It is the same for the median, which does not reflect
the impact of skew on the distribution. Consequently, the Hodges-Lehmann
estimator, which is less sensitive to outliers than the mean, was regarded as a more
robust estimate of the central position of the distribution (i.e. the location
parameter).
using mean values (minimum, median, maximum, 95% CI),
depicted in Fig. 1 with box plots. It should be noted that the
usual mean, which relies on the assumption of symmetric
distribution, was not adequate to assess hormone
concentrations. The median also does not reflect the
impact of skew on the distribution. Consequently, the
Hodges-Lehman estimator, which is less sensitive to
outliers than the mean, was regarded as a more robust
estimate of the central position of the distribution (i.e. the
location parameter).
In the ‘ITT efficacy’ data set, TT concentrations were
restored in the low–middle range, fluctuating around
4.5–5.5 ng/mL during the study. BT, DHT and E2 were also
restored within the normal range and remained stable
over time. At the end of the 6-year study, there were 51
‘completers’. These ‘completers’ showed an identical
response to the ITT group for all evaluated parameters (see
Fig. 2 for testosterone).
Biological Response
In the ‘ITT efficacy’ data set, the total AMS score decreased
from 37.83 (14.17) at baseline to 28.85 (10.76), and the
psychological, somatic and sexual sub-scores from 9.81
(4.35) to 7.81 (2.82), from 15.92 (6.29) to 12.38 (4.94) and
from 12.09 (5.48) to 8.29 (3.15), respectively, over the 6
years of the study. The somatic and sexual sub-scores
appeared to be the most sensitive to testosterone treatment:
both decreased rapidly during the first 6 months and
© 2013 BJU International
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Raynaud et al.
Fig. 1 Total testosterone (TT) levels by visits in
4 Clipped Boxes
the intention-to-treat (ITT) efficacy “All
15
available” samples.
14
13
Total Testosterone, ng/mL
12
11
10
9
8
7
6
5
4
3
2
1
0
M0
M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 M66 M72
Visits, Months
Max at M6 = 27.5, at M12 = 47.9, at M24 = 15.4, at M72 = 18.3
(Patients with TT levels > 15 ng/mL: At M6: Patient # 1301, TT = 18.68; Patient # 2438:
TT = 18.19; Patient # 4107: TT = 27.54; Patient # 5014: TT = 24.55; At M12: Patient # 1208:
TT = 47.94; Patient 4211: TT = 23.01; At M24: Patient # 1301, TT = 15.43; At M72: Patient
# 2447: TT = 18.3)
remained stable thereafter. At study end, the total AMS
score was at the same level as that seen in a normal
population of healthy volunteers, as described by Raynaud
et al. [19]. The low impact on the psychological sub-score
suggests that the response was not associated with a
placebo effect.
Biochemical Analysis
Over the 6 years of the study, erythrocyte levels increased
<2%, haemoglobin <5% and the mean haematocrit
increased from 44% to 46%.
Triglyceride levels remained stable. Cholesterol levels
decreased by 10% during the first 2 years and remained
stable thereafter. Low-density lipoprotein decreased during
the first 3 years, and then increased slightly. High-density
lipoprotein levels fluctuated at ª1.35 mmol/L. None of
these changes were of clinical significance.
There were no changes in creatinine, sodium, potassium,
chloride, calcium and glucose levels. There were no
clinically relevant mean changes in blood pressure and
heart rate. The mean change in patient weight remained
<3 kg.
4 © 2013 BJU International
Prostate Safety
Mean PSA concentration and mean changes
In the ‘ITT safety’ data set (n = 200), the mean PSA
concentration increased from 0.47 ng/mL at baseline to
0.60 ng/mL at 3 months and then steadily increased at
each time point, up to 0.80 ng/mL after 6 years (Table 2,
Fig. 3).
In the ‘completers’ data set (n = 51), mean PSA
concentrations and the change in mean PSA over the 6
years of the study had the same profile of distribution as
those observed in the ‘ITT safety’ data set (Table 2).
In the ‘ITT safety’ data set, >90.0% of patients had PSA
concentrations of <2 ng/mL over the 6 years of the study.
Less than 5% of patients had a PSA concentration of
2–4 ng/mL between 3 and 42 months and, 3–10% between
48 and 72 months.
One patient (number 1103) who had a PSA concentration
of 3.1 ng/mL at 12 months was withdrawn by the sponsor
because this value did not meet the inclusion criteria (PSA
threshold concentration >3 ng/mL) for entry into the first
year of the extension. One month after being withdrawn,
PSA change during 6 years of transdermal testosterone
Fig. 2 Total testosterone (TT) levels by visits in
4 Clipped Boxes
the Completers “All available samples”.
15
14
13
Total Testosterone, ng/mL
12
11
10
9
8
7
6
5
4
3
2
1
0
M0
M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 M66 M72
Visits , Months
Max at M6 = 18.7, at M12 = 47.9, at M24 = 15.4, at M72 = 18.3
(At M6: patient #1301, TT = 18.7; patient #2438, TT = 18.19; At M12: patient # 1208, TT =
47.9; At M72: patient # 2447, TT = 18.3)
the patient had prostatitis with a PSA concentration of
43.75 ng/mL. PSA concentrations decreased to 6.4 ng/mL
and to 2.0 ng/mL, 3 and 6 months later, respectively. The
patient received oral testosterone undecanoate
(Pantestone®) and PSA concentrations were 3.3 and
3.5 ng/mL, at 3 and 6 years, respectively.
During a short period, seven patients had a PSA
concentration of >4 ng/mL. Among these patients, five had
an episode of prostatitis and PSA concentrations returned
to <4 ng/mL within 3–6 months following adequate
treatment (Table 3). The sixth patient (number 2102), aged
49 years, had a PSA concentration of 6.8 ng/mL at 60
months that remained >4 ng/mL (5.88 ng/mL) 1 month
later, at which point the patient discontinued. A DRE and
an echography revealed no prostatic hypertrophy but a
hypoechogenic mass. A suspect biopsy led to a
tomodensitometry analysis. Results were negative and
antibiotic treatment induced a PSA decrease to 2.39 ng/mL
1 month later.
The seventh patient (number 4213), aged 59 years, with a
history of TURP 6 years before entering the study, showed
the following PSA evolution: a concentration of 1.60 ng/mL
at baseline, 3.80 ng/mL at 12 months, with a re-test
indicating a concentration of 4.70 ng/mL. Subsequently, the
PSA concentration increased to 5.4 ng/mL at 18 months
and the patient was withdrawn from the study. No biopsy
was taken.
Among the 200 patients, 193 patients (96.5%) had no PSA
concentrations >4 ng/mL and 188 patients (94.0%) had no
increase >1.4 ng/mL within any 12-month period of
treatment. DRE was normal at each examination. No
prostate cancer was reported during the study.
The change in mean PSA increased by 0.14 ng/mL at 3
months and then progressively increased up to 0.30 ng/mL
until the end of the trial. As shown in Table 2, the lower
95% CI indicates that the increase was already statistically
significant at 3 months and significance was maintained at
all future time points, until the end of the study, in both the
ITT safety population and the ‘completers’. Considering that
this initial increase in mean PSA concentration could be
due to replenishment of the androgen binding sites after
androgen depletion during the wash-out period, the
increase between PSA concentrations at 3 months and all
subsequent time points was analysed. Increases in PSA
concentrations between 3 months and 6, 12, 18, 24, 30, 36,
42, 48 and 54 months were not statistically significant.
However, the slow but constant increase became significant
at the fifth and sixth year. Similar results were seen when
the value of reference for PSA concentration was taken at 6
and 12 months.
© 2013 BJU International
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Raynaud et al.
Table 2 Mean and change in PSA concentrations (ng/mL) in the ITT safety and completers population.
ITT safety
3 months
Baseline
Value
Change
6 months
Baseline
Value
Change
12 months
Baseline
Value
Change
18 months
Baseline
Value
Change
24 months
Baseline
Value
Change
30 months
Baseline
Value
Change
36 months
Baseline
Value
Change
42 months
Baseline
Value
Change
48 months
Baseline
Value
Change
54 months
Baseline
Value
Change
60 months
Baseline
Value
Change
66 months
Baseline
Value
Change
72 months
Baseline
Value
Change
Completers
Mean (sd)
Min/median/max
95% CI
Mean (sd)
Min/median/max
95% CI
N = 185
0.46 (0.42)
0.60 (0.50)
0.14 (0.35)
N = 157
0.45 (0.41)
0.67 (0.86)
0.22 (0.72)
N = 145
0.47 (0.41)
0.76 (1.38)
0.29 (1.31)
N = 105
0.49 (0.41)
0.70 (0.65)
0.21 (0.48)
N = 98
0.48 (0.39)
0.61 (0.48)
0.13 (0.35)
N = 80
0.47 (0.37)
0.68 (0.62)
0.21 (0.56)
N = 75
0.48 (0.38)
0.64 (0.47)
0.16 (0.35)
N = 62
0.49 (0.40)
0.71 (0.59)
0.22 (0.38)
N = 59
0.50 (0.41)
0.75 (0.65)
0.25 (0.52)
N = 57
0.50 (0.41)
0.74 (0.53)
0.24 (0.41)
N = 57
0.50 (0.41)
1.01 (1.35)
0.51 (1.21)
N = 54
0.50 (0.42)
0.78 (0.63)
0.28 (0.42)
N = 51
0.50 (0.43)
0.80 (0.59)
0.30 (0.38)
N = 185
0.05/0.4/2.5
0.05/0.5/4.2
-1.0/0.1/2.6
N = 157
0.05/0.4/1.9
0.05/0.5/9.3
-1.2/0.1/8.1
N = 145
0.05/0.4/1.9
0.05/0.5/15.7
-1.1/0.1/15.2
N = 105
0.05/0.4/1.9
0.05/0.5/5.4
-1.1/0.1/3.8
N = 98
0.05/0.4/1.9
0.05/0.5/3.0
-1.1/0.1/1.5
N = 80
0.05/0.4/1.9
0.1/0.5/4.5
-1.0/0.1/4.5
N = 75
0.05/0.4/1.9
0.1/0.5/2.2
-1.2/0.15/1.5
N = 62
0.05/0.4/1.9
0.05/0.5/3.0
-1.0/0.2/1.7
N = 59
0.05/0.4/1.9
0.1/0.6/3.1
-1.0/0.1/2.4
N = 57
0.05/0.4/1.9
0.1/0.6/2.6
-0.8/0.2/1.5
N = 57
0.05/0.4/1.9
0.05/0.7/6.8
-1.2/0.2/6.0
N = 54
0.05/0.4/1.9
0.1/0.6/3.0
-0.9/0.2/1.5
N = 51
0.05/0.4/1.9
0.1/0.7/2.5
-0.80/0.3/1.5
N = 185
N = 52
0.50 (0.43)
0.64 (0.44)
0.14 (0.36)
N = 52
0.50 (0.43)
0.67 (0.48)
0.17 (0.32)
N = 52
0.50 (0.43)
0.66 (0.46)
0.16 (0.33)
N = 52
0.50 (0.43)
0.67 (0.45)
0.17 (0.34)
N = 52
0.50 (0.42)
0.66 (0.48)
0.16 (0.35)
N = 52
0.50 (0.42)
0.76 (0.73
0.26 (0.68)
N = 52
0.50 (0.43)
0.68 (0.52)
0.18 (0.39)
N = 52
0.50 (0.43)
0.75 (0.57)
0.25 (0.41)
N = 52
0.50 (0.43)
0.74 (0.59)
0.23 (0.48)
N = 52
0.50 (0.43)
0.75 (0.54)
0.25 (0.42)
N = 52
0.50 (0.43)
0.95 (1.15)
0.45 (0.99)
N = 52
0.50 (0.43)
0.79 (0.64)
0.29 (0.42)
N = 51
0.50 (0.43)
0.80 (0.59)
0.30 (0.38)
N = 52
0.05/0.4/1.9
0.10/0.5/1.9
-1.0/0.1/1.6
N = 52
0.05/0.4/1.9
0.1/0.6/2.2
-1.2/0.2/0.9
N = 52
0.05/0.4/1.9
0.1/0.5/2.5
-1.1/0.1/1.2
N = 52
0.05/0.4/1.9
0.1/0.6/2.3
-1.1/0.15/1.2
N = 52
0.05/0.4/1.9
0.1/0.6/2.4
-1.1/0.2/1.2
N = 52
0.05/0.4/1.9
0.1/0.6/4.5
-1.0/0.2/4.5
N = 52
0.05/0.4/1.9
0.1/0.5/2.2
-1.2/0.2/1.5
N = 52
0.05/0.4/1.9
0.05/0.6/3.0
-1.0/0.2/1.7
N = 52
0.05/0.4/1.9
0.1/0.6/2.7
-1.0/0.15/2.4
N = 52
0.05/0.4/1.9
0.1/0.65/2.6
-0.8/0.2/1.5
N = 52
0.05/0.4/1.9
0.05/0.7/6.3
-1.2/0.2/5.7
N = 52
0.05/0.4/1.9
0.1/0.6/3.0
-0.9/0.2/1.5
N = 51
0.05/0.4/1.9
0.1/0.7/2.5
-0.80/0.3/1.5
N = 52
0.53–0.68
0.09–0.19
N = 157
0.54–0.81
0.10–0.33
N = 145
0.53–0.98
0.07–0.50
N = 105
0.58–0.83
0.11–0.30
N = 98
0.51–0.70
0.06–0.20
N = 80
0.54–0.82
0.08–0.33
N = 75
0.53–0.75
0.08–0.24
N = 62
0.57–0.85
0.13–0.32
N = 59
0.58–0.92
0.12–0.39
N = 57
0.60–0.88
0.13–0.35
N = 57
0.65–1.37
0.19–0.83
N = 54
0.61–0.95
0.17–0.40
N = 51
0.64–0.97
0.19–0.41
PSA velocity
PSA velocity (ng/mL/year) remained stable over the 6 years
of the study, ranging from 0.00 to 0.02 ng/mL/year, except
at 60 months, when PSA velocity increased up to
0.08 ng/mL/year due to an outlier value corresponding to a
patient with prostatitis. In all, 10 patients had at least one
PSA velocity value >0.4 ng/mL/year.
6 © 2013 BJU International
0.51–0.76
0.04–0.24
N = 52
0.53–0.80
0.08–0.26
N = 52
0.53–0.79
0.07–0.25
N = 52
0.55–0.80
0.08–0.27
N = 52
0.53–0.80
0.07–0.26
N = 52
0.56–0.97
0.07–0.45
N = 52
0.54–0.83
0.07–0.29
N = 52
0.59–0.91
0.14–0.36
N = 52
0.57–0.90
0.10–0.37
N = 52
0.60–0.90
0.13–0.37
N = 52
0.63–1.26
0.17–0.72
N = 52
0.61–0.97
0.18–0.41
N = 51
0.64–0.97
0.19–0.41
Considering all 200 patients, only four had PSA
concentrations >4 ng/mL, a PSA increase >1.4 ng/mL and a
PSA velocity >0.4 ng/mL/year
AEs
For the 36 serious AEs reported by 25 patients, a causal
relationship with the study drug was excluded, except for
PSA change during 6 years of transdermal testosterone
Fig. 3 Prostate Specific Antigen (PSA)
5 Clipped Boxes
concentrations by visits [Intention-to-treat
4.0
(ITT) – Safety].
3.5
3.0
PSA, ng/mL
2.5
2.0
1.5
1.0
0.5
0
M0
M6 M12 M18 M24 M30 M36 M42 M48 M54 M60 M66 M72
Visits, Months
Max at M6 = 9.3, at M12 = 15.7, at M18 = 5.4, at M30 = 4.5, at M60 = 6.8
Table 3 Patients with a PSA concentration increase of >4 ng/mL.
Patient
number.
2408*
2001*
2423*
2528*
2418*
2102
4213
Age,
years
PSA, ng/mL
baseline
PSA, ng/mL
(month)
PSA, ng/mL
(month)
Follow-up
26
30
46
36
61
49
59
0.2
0.6
1.4
0.5
1.2
0.8
1.6
4.5 (30)
6.3 (66)
4.5 (60)
15.7 (12)
9.3 (6)
6.8 (60)
4.2 (3)
0.8 (36)
1.2 (66)
2.5 (62)
0.5 (18)
2.9 (12)
5.9 (61)
5.4 (18)
Remained in the trial until study end; PSA 0.35 ng/mL
Remained in the trial until study end; PSA 1.0 ng/mL
Remained in the trial until study end; PSA 0.35 ng/mL
Discontinued (month 24) due to inconvenience; PSA 0.5 ng/mL
Discontinued (month 12) due to local tolerability; PSA 2.9 ng/mL
Withdrawn (month 61); antibiotics (month 64): PSA 2.4 ng/mL
Patient was withdrawn (month 18); PSA 5.4 ng/mL
*All five patients had prostatitis, which was resolved !6 months by antibiotic treatment.
two patients. One patient presented an exacerbation of
chronic fatigue syndrome and low back pain, and the
second patient presented a transient ischaemic attack at
46 months (causal relationship was deemed to be
doubtful).
One patient (aged 39 years) died after the first 6 months of
treatment: he had McCune-Albright syndrome and used a
wheelchair due to hip dysplasia for a period of 5 years. The
patient, hospitalised due to a fall leading to a non-displaced
fracture of the right humerus, slipped 1 week later,
suffering from quadriplegia (C1–C2 dislocation with
compression) and died from a pulmonary embolism. These
events were considered as not related to the study drug by
the investigators and by the sponsor.
In all, 155 patients reported a total of 1136 TEAEs; a
relationship with treatment was not excluded for 380
TEAEs. Administration site reactions were one of the most
frequent TEAEs. According to the investigators, during the
study, 44.3–62.6% of patients had no evidence of skin
irritation, 32.2–50.7% of patients had minimal erythema,
barely perceptible; definite erythema, readily visible
appeared in <6.3% of patients and erythema and papules in
two patients only. Local corrective treatment (topical
corticosteroids), which is frequently needed during
© 2013 BJU International
7
Raynaud et al.
Androderm® application [20,21], was only required for two
patients.
Discussion
The present interventional study was conducted to assess
the long-term safety of a treatment, Testopatch, which
restores testosterone concentrations within the
physiological range. In the present study, every year each
patient had the choice to continue and the sponsor or
investigator had the opportunity to exclude a patient if the
PSA concentration was >3 ng/mL and/or if the testosterone
concentration was <2.5 ng/mL. Based on these laboratory
eligibility criteria, only five of 200 patients withdrew from
the study. There were no significant safety events at the
highest dosage of Testopatch. Unfortunately, it was very
difficult to follow patients once they stopped treatment,
either after discontinuation or at study closure. However, it
was of interest to verify whether, with ageing during the
study, patients were exposed to a potential prostate safety
problem. This appears not to be the case and, furthermore,
strongly indicates that any sharp increase in PSA
concentration is due to prostatitis and not due to an
exacerbation of a latent cancer.
In the seven patients with an increase of PSA concentration
of >4 ng/mL, for six of them the increase in PSA was
retested to eliminate laboratory errors, and antibiotics were
administered, resulting in an immediate decrease in PSA
concentrations and a return to initial values within 6
months. Thus, when a sharp increase in PSA concentration
is seen in a hypogonadal treated patient, it is essential to
verify the presence of prostatitis and initiate antibiotic
treatment, if necessary, before stopping TRT and
embarking on an invasive search for prostate cancer.
The small PSA concentration increase in the present study
is indicative of the physiological stimulation of the prostate
by testosterone and its metabolites [22]. It has been
postulated in the Saturation Model [23] that ‘physiologic
concentrations of testosterone provide an excess of
testosterone and DHT for optimal prostatic growth
requirements. However, reducing testosterone
concentration below a critical concentration threshold (the
saturation point) creates an intracellular milieu in which
the availability of androgen becomes the rate-limiting step
governing prostate growth’. This model is based on
evidence that binding of androgen to the androgen
receptor follows a similar saturation curve [24].
That the hypogonadal patients had been deprived of
treatment by a wash-out period could explain that the
secretion of PSA became sensitive to the re-introduction of
exogenous testosterone and increased until reaching a
plateau within 3 months. This has been reported previously
by Arver et al. [4] who showed that PSA concentrations
8 © 2013 BJU International
decreased from 1.0 ng/mL during i.m. testosterone
enanthate treatment to 0.5 ng/mL after a 3–4 week
wash-out period and increased to 0.66 ng/mL during
permeation-enhanced transdermal testosterone treatment.
In a small group of 25 consecutive men who received
testosterone gel for 1 year, Rhoden and Morgentaler [25]
reported a mean increase in baseline PSA concentrations
after 1 year of treatment (0.18 ng/mL) that was similar to
concentrations seen in the present study (0.21 ng/mL),
despite the fact that baseline PSA concentrations [mean
(sd) 1.8 (1.9) ng/mL) were higher than those in the present
study [0.46 (0.42) ng/mL]. Furthermore, in the study by
Rhoden and Morgentaler, although a proportion (21%) of
all patients had decreased PSA concentrations after 1 year
of treatment with i.m. testosterone (n = 33) or testosterone
gel (n = 25), PSA concentrations in almost 80% of patients
were either unchanged or increased [25]; the authors
concluded that TRT caused only a mild increase in PSA
concentrations in most hypogonadal men and did not
appear to be influenced by the mode of TRT, age, or
baseline PSA or testosterone concentrations [25].
In a multicentre, randomised, cross-over study [26], 44 men
aged >18 years and with a TT concentration of !2.5 ng/mL
after a wash-out period, received either two patches
(Testopatch) every other day in the morning or two
capsules (Pantestone; 40 mg twice daily), each treatment for
a 22-day period. PSA concentrations were slightly
increased, by 0.18 and 0.15 ng/mL, at the end of the first
treatment period [from a mean (sd) 0.78 (0.66) to
0.96 (0.76) ng/mL, and from 0.81 (0.75) to
0.96 (0.86) ng/mL for Testopatch and Pantestone,
respectively). Thus, the small increase in PSA concentration
after testosterone administration is very rapid. Only three
patients in each group had a PSA concentration of
>2 ng/mL after the first treatment period. Of these six
patients, three already had elevated PSA concentrations at
screening. The maximum PSA concentration recorded was
3.23 ng/mL, after Pantestone treatment.
In a 6-month cross-sectional study, in which hypogonadal
patients were treated with testosterone preparations, the
prostate volume increased to a level that can be expected in
normal men of comparable age [7]. It has been reported
that there was little change in the PSA concentrations in
patients continuing on TRT >2 years, despite increases in
mean TT or BT concentrations [27].
Patient numbers were very different between the start and
the end of the present study and, at study end, the
population was 6 years older. Furthermore, all patients had
been hypogonadal for many years and were undergoing
TRT. Depending on the formulation, patients had to stop
treatment from 1 to 3 weeks before entering into the trial.
We do not know the PSA concentration when the patient
PSA change during 6 years of transdermal testosterone
was on TRT, thus baseline values were somewhat
underestimated and we cannot appreciate how worrisome
the rise in PSA concentration is over time with TRT.
In the present study, 15% of patients treated with
Testopatch withdrew due to local tolerability concerns. As
expected for a transdermal product, skin irritation was the
most commonly reported AE. However, this must be placed
in perspective by comparison with other marketed patches
[4,20,21]. For example, Arver et al. [4] reported that,
in a 1-year long-term efficacy and safety study of a
permeation-enhanced testosterone transdermal system in
hypogonadal men, while 56% of patients had transient
erythema or itching at some time during the study, only 9%
discontinued transdermal TRT due to skin irritation and
that mild skin irritation was ameliorated by applying
topical hydrotestosterone or diphenhydramine.
Furthermore, the present study was of 1-year duration in
only 36 patients, compared with the overall study duration
(6 years) including 200 patients, thus amplifying the
reasons for discontinuation due to local tolerability.
No prostate cancer was reported during the present study
and there was no correlation between testosterone
concentrations and an increase in PSA concentration. The
mean age of patients (41 years) and the limited number of
patients (200) included in the present study population,
preclude the ability to draw definite conclusions relating
to an increased risk of prostate cancer. This study
population, with a median age lower than the common
age for prostate cancer, is representative of men with
primary or secondary hypogonadism already receiving
conventional TRT. Results cannot be extrapolated to the
ageing male testosterone-deficient population, but they
add evidence with regard to the safety of TRT in ageing
males.
In a very elegant study, Morgentaler et al. [28] have shown
that TRT in men with untreated prostate cancer (Gleason
score 6) and elected to active surveillance, the PSA
concentration did not increase after a median of 2.5 years
and patients had an improvement in quality of life (libido,
sexual performance, mood and energy).
The reluctance to treat patients is essentially based upon a
risk assessment. Should we treat symptomatic patients
when we do not know to what extent TRT increases
prostate cancer risk and promotes prostate cancer growth?
Suppression of testicular androgen secretion by castration
(surgical or medical) causes prostate cancer regression but
it has never been either observed or demonstrated that
raising testosterone concentrations in hypogonadal intact
men leads to enhanced prostate cancer growth. Currently,
the absolute contraindication for TRT is prostate cancer,
even if there is no solid evidence that exogenous androgens
promote the development of prostate cancer [29,30].
According to Morgentaler [31], ‘the withholding of
TRT in men because of the fear of prostate cancer risk
or progression is no longer tenable in an age of
evidence-based medicine, because neither evidence nor
theory supports this position. It is time for a more
sophisticated rethinking of the relation between
testosterone and prostate cancer, one that is still internally
consistent, scientifically based, and accounts for all the risk
and various set of clinical and research data regarding
prostate cancer and hormones’.
The results of the present study support the concept that
TRT is not associated with significant prostate risks. Only a
minor change in PSA concentration was noted over 5 years
of study, and no cancers were detected.
In conclusion, for prostate safety, as evidenced by no
relevant changes in PSA concentrations and PSA velocity,
Testopatch (2 ¥ 60 cm2) applied every 2 days is safe.
Acknowledgements
The authors gratefully acknowledge the other members of
the Testopatch Study Group:
L. Bassas, Fundación Puigvert, Barcelona, Spain; A. Beckers,
CHU Liège, Liège, Belgium; M. Berse, Urologische Praxis,
Duisburg, Germany; P. Bondil, Centre Hospitalier de
Chambéry, Chambéry, France; A. Charro, Hospital Clínico
San Carlos, Madrid, Spain; D. Chevallier, Hôpital Pasteur,
Nice, France; F. Comhaire, UZ Gent, Gent, Belgium; P.
Coremans, UZA, Dienst Fertiliteit, Edegem, Belgium; B.
Cuzin, Hôpital Edouard Herriot, Lyon, France; B. Delemer,
Hôpital de Maison Blanche, Reims, France; J. Duarte,
Hop.12 de Octubre, Madrid, Spain; E. Hellmis, Urologische
Gemeinschaftspraxis, Duisburg, Germany; J. Hermabessière,
Centre République, Clermont-Ferrand, France; A. Hermus,
Universitair Medisch Centrum St Radboud, Nijmegen, the
Netherlands; H. Koppeschaar, Universitair Medisch
Centrum Utrecht, Utrecht, the Netherlands; J-M. Kuhn,
CHU de Rouen, Bois Guillaume, France; A. Leriche, Hôpital
Henry Gabrielle, St Genis Laval, France; J-P. Louvet, CHU
Rangueil-Larrey, Toulouse, France; J.M. Miralles, Hospital
Clínico Universitario de Salamanca, Salamanca, Spain; M.
Pugeat, Hôpital Neuro Unité 34, Bron, France; W. Ricart,
Hospital Universitari Josep Trueta; Girona, Spain; A.
Sanmarti, Hospital Germans Trias i Pujol, Badalona, Spain;
J. Soler, Ciutat Sanitaria i Universitaria de Bellvitge, L’
Hospitalet de Llobregat, Spain; W. Spiegelhalder,
Urologische Praxis, Mettman, Germany; C. Stief,
Ludwigs-Maximilians-Universität, München, Germany; A.
Tabarin, Hôpital de Haut l’Evêque, Pessac, France; A.
Joannes. Van der Lelij, Academisch Ziekenhuis Dijkzigt,
Rotterdam, the Netherlands; D. Vanderschueren, UZ
Leuven, Leuven, Belgium; J.A. Vasquez, MD, Hospital de
Cruces, Barakaldo, Spain.
© 2013 BJU International
9
Raynaud et al.
The authors also thank David P. Figgitt PhD, Content Ed
Net, for providing editorial assistance in the preparation of
this manuscript.
13
Conflict of Interest
None declared. Source of funding: Pierre Fabre
Medicament.
14
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Correspondence: Jean-Pierre Raynaud, 51 bvd Suchet, Paris
75016, France.
e-mail: [email protected]
Abbreviations: AE, adverse event; AMS, Aging Male’s
Symptoms (rating scale); BMI, body mass index; BT,
bioavailable testosterone; DHT, dihydrotestosterone; E2,
oestradiol; ITT, intention to treat; (TE)AE,
(treatment-emergent) adverse event; TRT, testosterone
replacement therapy; TT, total testosterone.
© 2013 BJU International
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