An overview of the principles of ADT for prostate cancer and the various drug types used.

1. Part of the “Enhancing Prostate Cancer Care” MOOC
Catherine Holborn
Senior Lecturer in Radiotherapy & Oncology
Sheffield Hallam University

2. Introduction
This presentation aims to provide an overview of
Androgen Deprivation Therapy (ADT), also referred to as
Hormone therapy, for prostate cancer.
It covers the basic principles and methods and provides
an insight into the side effects
It does not cover the use of these methods (when and
how they are used) in the management of the different
stages of prostate cancer

3. Principles of ADT
Prostate cells (normal and malignant) are physiologically dependent
on androgens to grow, function and proliferate
Testosterone is the primary male androgen. The testes are the major
source of testosterone
 The adrenal glands also produce 'weak' androgens. These can be converted into more potent
testosterone. Overall though, their effect is negligible in comparison to testosterone production in the
testes.
Dihydrotestosterone (DHT) is a metabolite of testosterone and is a
more potent androgen
Testosterone doesn’t ‘cause’ prostate cancer but promotes and
encourages growth.
Androgen deprivation can help to induce apoptosis (cell death) or at
the very least prevent further growth. It can be achieved in two
main ways:
 Surgical or medical ‘castration’; stops the production of testosterone
 Anti-androgen therapy; inhibits the action of testosterone preventing its
interaction with the receptors on the prostate cancer cells

4. Main testosterone production
Very broadly, the hypothalamus and pituitary will send
signals to the testes which cause them to produce
testosterone.
The hypothalamus, releases a hormone called either
'gonadotropin releasing hormone ' (GnRH) or 'luteinizing
hormone releasing hormone' (LHRH).
This is passed to the pituitary which responds to produce
two gonadotropins. These are called Luteinizing Hormone
(LH) and Follicle Stimulating Hormone (FSH).
In males, LH binds with the Leydig cells in the testes and
promotes the synthesis of testosterone.
FSH binds with Sertoli cells in the seminiferous tubules and
promotes spermatogenesis.

5. Stopping the production of testosterone
As a general rule, this is the most common first line
approach to hormone therapy for prostate cancer
Surgically, this would involve a bilateral orchidectomy
(removal of the testes)
Medically, there are a number of ways in which the
production of testosterone can be stopped/reduced;
Oestrogens e.g. Diethylstilboestrol (DES)
LHRH agonists e.g. busereline, gosereline, leuproreline,
triptoreline
LHRH antagonists e.g. abarelix, degarelix

6. Bilateral orchidectomy
In terms of testosterone reduction, this method of
surgical castration is considered the gold standard of
androgen deprivation therapy (ADT) against which the
effectiveness of other therapies are measured
Current definition of castration is <20ng/dl ¹
This is less favoured though given the psychological
impact. It is also permanent.
Nevertheless, men should be offered this as an option if
appropriate.
1. Schulman CC, Irani J, Morote J, Schalken JA, Montorsi F, Chlosta PL, Heidenreich A. Androgen-Deprivation
Therapy in Prostate Cancer: A European Expert Panel Review. European Urology Supplements. 2010; 9:675-
691

7. Oestrogens
Mechanisms of action:
Down regulate LHRH secretion (and ultimately testosterone
production)
Androgen inactivation
Direct suppression of leydig cell function
Direct cytotoxicity (tested in-vitro)
DES is the most commonly used oestrogen (doses of 1mg, possibly
3mg)
However, it has fallen out of favour due to the associated risks of
cardiac toxicity and adverse cardiovascular events
Hence it is not recommended as a first line option
Oestrogen skin patches ( as an alternative administration method)
are being researched to see if these reduce this cardiovascular risk

8. LHRH agonists (LHRHa)
The preferred method of first line ADT for prostate
cancer.
Note the term ‘agonist’ not ‘antagonist’.
LHRH agonists stimulate the pituitary to produce
more Leutenising Hormone (LH) which causes an
initial elevation in testosterone production within the
testes.
However, prolonged exposure eventually causes the
pituitary receptors to ‘down regulate’ and
testosterone is ultimately reduced/stopped

9. PSA flare
The initial rise in testosterone can cause the PSA levels to rise
slightly (as prostate growth is encouraged). This is called the
‘flare’ phenomenon. It is important that patients are aware.
It begins 2-3 days after the first injection and lasts
approximately 1 week
It can have detrimental effects in those with advanced disease
e.g. bone pain, bladder outlet obstruction, obstructive renal
failure and cord compression. If the latter is a risk then the use
of LHRH agonists should be avoided
Anti-androgens e.g. Cyproterone, started on the same day and
lasting for two weeks, can be used to counteract this flare

10. LHRH antagonists
These drugs compete for and bind to the LHRH pituitary
receptors preventing the normal signals for testosterone
production, reaching the testes
This causes a rapid decrease in testosterone production and
there is no prostate flare with these drugs
HOWEVER, they are associated with histamine-mediated side
effects (allergic reactions), which in many cases have been
serious e.g. anaphylactic shock (particularly so with abarelix,
degarelix lessens the risk)
Their benefits over the more traditional LHRH agonists are yet
to be proven in light of these side effects

11. Recent promising evidence
A met-analysis by Klotz et al (2014)² pooled individual patient data from 5
comparative randomised clinical trials of degarelix vs. LHRHa. Efficacy and
safety were assessed.
Key results
Degarelix was found to increase PSA progression free survival;
especially for those with an initial PSA <20ng/ml. Those with >20ng/ml
correlated with a increased risk of progression.
Degarelix was also associated with increased overall survival;
interestingly, due to a decreased risk of cardiovascular disease – a
promising benefit!
Decreased joint, musculoskeletal and urinary tract events were also
observed with degarelix
2. Klotz L, et al. Disease Control Outcomes from Analysis of Pooled Individual Patient Data from Five
Comparative Randomised Clinical Trials of Degarelix Versus Luteinising Hormone-releasing Hormone
Agonists. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2013.12.063

12. Anti-androgens
These have a similar structure to testosterone and bind
with the testosterone receptors on the prostate cells,
blocking the effects of testosterone.
There are two main groups of anti-androgens:
Steroidal
E.g. cyproterone
Non-steroidal
E.g. flutamide, bicalutamide

13. Non-steroidal anti-androgens
Don’t lower testosterone levels therefore libido,
overall physical performance and bone mineral
density, are more likely to be preserved
They are not without side effects though e.g.
gynaecomastia, breast pain and hot flashes. Liver
toxicity is also a problem and liver function must be
checked regularly
Bicalutamide shows a more favourable safety and
tolerability profile

14. Steroidal anti-androgens
Cyproterone acetate is the most common. The most
effective dose is still under investigation
In contrast to non-steroidal anti-androgens they also
have progestational properties which help to ‘lower’
testosterone levels; so loss of libido may still be an
issue

15. Key effects of testosterone
Reviewing the key roles of testosterone within the body,
helps to explain the side effects that are observed when
this is removed:
Growth of muscle mass
Bone growth, increased bone density and strength
Maturation of sex organs and secondary sexual
characteristics e.g. body hair
Sexual arousal / libido
Positive effect on cognitive functions such as attention,
memory and spatial ability

16. An overview of key side effects
Hot flashes (flushes); can be significant, very bothersome
and distressful. Can disrupt daily activities and plans.
Fatigue; a common symptom and multi-faceted. Can be
related to a reduction in testosterone but may also be
related to other treatments, physical and psycho-social
factors
Cognitive decline; forgetfulness, lack of concentration and
mood changes
Sexual dysfunction and loss of libido; drugs that block
testosterone action rather than decrease its levels may be
used if a man is concerned about this, but they may not be
as effective in terms of disease control

17. Effects more likely with longer term use
Osteoporosis; bone mineral density is reduced
Increasing risk of weight gain and obesity; lean muscle
mass reduces and fat mass increases, especially around
the tummy area
Increases the risk of sarcopenia; a term used to describe
the erosion of skeletal muscle and general frailty/feeling
weak; can increase the risk of falls and further increase
the risk of fractures
Hormone therapy also increase serum cholesterol and
triglyceride levels and so can increase the risk of
cardiovascular complications

18. The impact of ADT on general wellbeing and quality of life will
be explored more ion week 4 of the MOOC.