Part of the “Enhancing Prostate Cancer Care” MOOC

Catherine HolbornSenior Lecturer in Radiotherapy & Oncology

Sheffield Hallam University

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

Aim of presentationTo 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

First line treatment with ADTAndrogen 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.

AlternativesFor 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.

Timing of first line treatmentThere 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.

Intermittent ADTSide 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.

Castrate Resistant Prostate CancerMen 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

Hormone Refractory?The term hormone refractory prostate cancer (HRPC) was, until

recently, a more commonly used termIt 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 sitesTestosterone 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).

Secondary ADT optionsFor 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

More recent agentsAbiraterone 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)

Use in chemo naive patientsSecond 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

Other agentsSipuleucel-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.

CRPC and chemotherapyIf 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 metastasesSymptoms of metastases and progressionRapidly rising PSA (may be asymptomatic)

It is not used for men who do not have CRPC outside of a clinical trial.

History of ChemotherapyA 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 researchedSuperior 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)

Progression after docetaxelIf 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

Second line chemotherapyMitoxantrone may be used but with minimal effectRe-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.

Treatment of symptomsTreatment 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.

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.