An overview of the treatment for advanced metastatic prostate cancer.

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

2. Definition
Disease that has spread distant to the prostate
This can include clinical evidence of spread to the pelvic
lymph nodes (N1)
It can also include distant metastases that have spread
via the circulatory system (M1)
The most common site of distant metastases is the bone

3. Aim of presentation
To provide an overview of the treatment of advanced/
metastatic prostate cancer
Detail on the different methods of Androgen
Deprivation Therapy (ADT) has been provided in a
previous presentation
Symptom management/treatment will also be
covered in a separate presentation

4. First line treatment with ADT
Androgen Deprivation Therapy (ADT) is the first line treatment
for advanced/metastatic prostate cancer
 For N1,M0 patients, this may be combined with radical radiotherapy to treat the local
disease and pelvic lymph nodes (benefits investigated as part of the ‘Stampede’ trial)
ADT using either medical or surgical castration methods i.e.
stopping the production of testosterone in the testes, is the
preferred approach
Can be achieved with either a bilateral orchidectomy (removal
of testes) or more commonly the use of LHRH agonists
Anti-androgen therapy (a different method that blocks the
testosterone from reaching the growth receptors on the cell
surface) is used to counteract any tumour flare that is possible
in the first 1-2 weeks of LHRHa use.

5. Alternatives
For men who are symptomatic and/or at risk of complications
e.g. spinal cord compression, LHRHa’s may not be appropriate
(risk of tumour flare).
The use of an LHRH antagonist e.g. Degarelix, or anti-androgen
therapy may be considered as an alternative
Anti-androgens as an alternative monotherapy to castration
(high dose Bicalutamide 150mg), may also be considered for
men who wish to retain their sexual function. However, anti-androgen
therapy is less effective than LHRHa therapy and can
compromise survival.
The man must be aware of its potential impact on survival and
be prepared to revert to LHRHa if sexual function is not
preserved.

6. Timing of first line treatment
There is no question that ADT should be started immediately
for men with symptomatic metastatic disease.
For asymptomatic men, immediate ADT will delay progression
to the symptomatic stage and avoid/decrease the risk of
cancer related complications such as a spinal cord
compression or pathological fracture.
No clear differences in survival have been observed between
immediate vs. deferred ADT for asymptomatic men.
Some men may wish to avoid the side effects of ADT and a
watchful waiting approach may be considered, delaying
treatment until symptoms occur. However, they must be well
informed about the risks of early symptomatic progression.

7. Intermittent ADT
Side effects associated with long terms use of ADT can be
extensive and have a significant impact on a mans quality of
life.
It is also thought that a resistance to lowered levels of
testosterone, or an androgen independent clone, may develop
over time.
Cycles of alternating ‘off’ and ‘on’ periods may be used to limit
side effects and may also delay the onset of resistance
(keeping the cells ‘sensitised’ and ‘reliant’ on testosterone).
It is mostly recommended for men who achieve an adequate
PSA response with initial therapy.
This is less likely in men with high pre-treat PSA, a more
advanced clinical stage and a higher metastatic burden.
Men on an intermittent regime must be monitored closely.

8. Castrate Resistant Prostate Cancer
Men are defined as having Castrate Resistant Prostate
Cancer (CRPC) once their cancer has shown signs of
progression, despite first line attempts to deprive the
cells of testosterone through either medical or surgical
castration
Several consecutive rises in the PSA level from the initial
PSA nadir (lowest level reached), is a common indication.
There may also be clinical signs e.g. symptoms or
radiographic evidence of progression

9. Hormone Refractory?
The term hormone refractory prostate cancer (HRPC) was, until
recently, a more commonly used term
It was thought that the cancer cells began to grow despite a
lack of testosterone i.e. they were androgen ‘independent’.
This isn’t necessarily the case.
It is now thought that the cancer cells still require testosterone
to activate the growth receptor sites
Testosterone produced by the testes has been stopped but an
intra-prostatic androgen synthesis still occurs, which converts
testosterone that has been secreted by the adrenal glands, into
the more potent Dihydrotestosterone (DHT).

10. Secondary ADT options
For those patients who are hormone ‘naive’ i.e. not had
previous ADT, they can expect some quite spectacular results.
However;
When first line treatment does not achieve an adequate
suppression of testosterone (typically levels of <20ng/ml) or if
CRPC develops, additional methods of hormone manipulation
may then be tried:
Addition of an anti-androgen (Combined Androgen
Blockade – CAB)
Use of dexamethasone (0.5mg daily) and possibly
ketoconazole (drugs that can help to stop adrenal glands
producing testosterone)
Use of oestrogens

11. More recent agents
Abiraterone Acetate
An inhibitor of an enzyme responsible for the
intra-prostatic androgen synthesis previously
described
Enzalutamide (MDV3100)
Blocks the androgen growth receptors and has
been found to be 8-10 times more effective than
bicalutamide (conventional anti-androgen)

12. Use in chemo naive patients
Second line ADT with Abiraterone Acetate has been shown to
improve overall survival and radiographic progression free
survival*, and also delay the need for chemotherapy
However, the use of Abiraterone Acetate and Enzalutamide
prior to the use of any chemotherapy is not always
available/recommended in certain countries e.g. NHS/NICE in
the UK**
* Arguably a more reliable measure of treatment response at this stage, than PSA response alone
** At time of writing – Sept 2014

13. Other agents
Sipuleucel-T is another promising agent and is a form
of immunotherapy which initiates an immune
response against cells expressing the enzyme Prostatic
Acid Phosphatase (PAP).
May be an option for men who are asymptomatic or
with minimal symptoms.

14. CRPC and chemotherapy
If disease progression occurs despite the second and
third line attempts mentioned previously then ADT
should continue as the androgen receptor is know to
remain active.
However, chemotherapy should also now be considered.
In particular for those men with:
Detectable metastases
Symptoms of metastases and progression
Rapidly rising PSA (may be asymptomatic)
It is not used for men who do not have CRPC outside of a
clinical trial.

15. History of Chemotherapy
A number of studies have been conducted in this area.
Research continues and is essential!
Mitoxantrone plus prednisone vs. prednisone only
Mitoxantrone regime improved pain control and QOL but no
improvement in survival
Doxetaxel based therapy then researched
Superior in PSA reduction and small survival benefit
Docetaxel plus prednisone now the first line standard
(delivered every 3 weeks for up to 10 cycles)
But side effects can be substantial. A good performance status
is needed e.g. >60% Karnofsky Performance Status (KPS)

16. Progression after docetaxel
If the disease should progress following treatment
with docetaxel then Abiraterone Acetate and
Enzalutamide may then be tried.
Second line chemotherapy options may also be
considered.
Much more research and innovation is needed and is
ongoing in this area

17. Second line chemotherapy
Mitoxantrone may be used but with minimal effect
Re-treatment with docetaxel may be considered if a good
response was found the first time around, but some may not
recommend this
Another promising drug is Cabazitaxel which has shown
survival advantages but has significant side effects and may be
contraindicated in men with liver problems
Cabozanitab is a drug type known as a tyrosine kinase
inhibitor. It works to stop the action of tyrosine kinase which is
a protein on the cells surface that signals the cell to grow,
divide and form new blood vessels. Research is underway
regarding its effectiveness.

18. Treatment of symptoms
Treatment may be needed if the disease becomes
symptomatic and begins to affect the patients quality
of life.
A range of treatments and therapies, underpinned by
a holistic approach to care, is required.

19. The principles of symptom management and an overview of the possible
symptoms associated with advanced prostate cancer and how these
might be managed, is covered in a separate learning resource.