What is secondary hormone therapy?

[JimJimJimJim]

Men who:

• have been on primary hormone therapy,
  
• had their cancer controlled for some time,
  
• then have rising PSA,
  

may be candidates for secondary hormone therapy.

First your doctor will test your testosterone level. This is because for a small number of men their PSA may be rising because of primary hormone treatment is not strong enough for them. Changing the dose may bring their testosterone down, and with it their PSA.

Of course, many factors will come into your doctor's judgement whether you are suited to any secondary hormone treatment.

Your doctor will consider many aspects of your general health, how well you responded to primary hormone treatment, and especially - how fast your PSA is rising.

For some men, very fast rising PSA may indicate chemotherapy without any secondary hormone treatment.

Secondary hormone therapy includes the anti-androgens and estrogens.

For men who respond to one secondary hormone treatment, it it sometimes possible to use several in sequence. Sometimes an estrogen (especially estradiol patches or creams) is added to an anti-androgen. Sometimes an estrogen is used alone.

Though some men get a very prolonged response, in general each response is shorter than the last.

Most often doctors choose to continue the primary hormone therapy, adding the secondary hormone therapy to it.

The anti-androgens are:

• Cosudex/Casodex (bicalutamide)
  
• Anandron (Nilutamide), Nilandron(Nilutamide)
  
• Eulexin (Flutamide), all nonsteroidal, and
  
• Androcur (Cyproterone, a steroid)
  

Stronger anti-androgens are:

• Nizoral (Ketoconazole),
  
• and sometimes Zytiga (abiraterone acetate) and Xtandi (enzalutamide) are regarded as anti-androgens.
  
  • (In the USA Zytiga (abiraterone) is covered by insurance after chemotherapy with Taxotere (docetaxel). In late 2012, the USA FDA approved its use pre-chemotherapy. In Australia, as of 17 December 2012, Zytiga (abiraterone) may be prescribed, but is not covered by PBS. Xtandi (enzalutamide) was given USA FDA approval in August 2012 for use after chemotherapy. It is not available in Australia.)
    

The estrogens are:

• DES (diethyl diphosphate) (not often because of side effects) and
  
• Estradiol (also spelled oestradiol), commonly as patches or creams. This is sometimes used alone for older men because it is gentler (though reported to be less effective).
  

Estradiol is sometimes in combination with an anti-androgen. Dr Snuffy Myers, an American medical oncologist, reports good results with a combination of Ketoconazole, estradiol patches, and Leukine (an immune stimulator). This is not a proven treatment because no studies have been published. Leukine is not available in Australia, but some men import it from the USA (upon recommendation of their doctors).

This summary has been prepared by someone who is not a doctor, and it is probably wrong or misleading in some ways.

If you think this information might be relevant to you, ask your doctor.

Edited December 17, 2012 by Admin
Added Xtandi (enzalutamide) information from Alan (below)

[Admin]

Posted on behalf of Alan Barlee:

Hi Jim,

A few additional points to add to the excellent summary that you posted:-

The advantage of estradiol patches like Estraderm is that transdermal (through the skin) administration means that, unlike orally administered hormones like DES (diethyl stilbestrol), the hormone by-passes the liver, thereby avoiding the metabolites that can cause deep-vein blood clots in some people. Unlike primary hormone therapeutics that switch off testicular production of testosterone, estrogen therapy does not increase bone turnover and long-term osteoporosis, but it can give problems with breast enlargement (gynecomastia).

Ketoconazole is a bit hard on the liver and can cause uncomfortable side effects, especially at the higher dose rate that seems to be needed to arrest PCa.

Anti-androgens' preferentially block androgen (testosterone) receptors at the PCa cell surface - some better than others. The new drug abiratirone (Zytiga) is more like beefed-up ketoconazole in its mode of action (i.e. it inhibits a key enzyme needed in the body's synthesis of testosterone, especially that occurring in the adrenals and inside the nucleus of PCa cells). It needs to be used in conjunction with a corticosteroid like prednisone, and it also involves some fasting before and after the tablets.

The other new drug enzalutamide (Xtandi) is a true anti-androgen, and is many times more effective than bicalutamide (Cosudex). It is approved for use in the USA but but not yet in Australia. There are no food or steroidal complications with enzalutamide.

Research is continuing into optimising the sequencing and combination of this arsenal of drugs.

Regards,

Alan

[Zak]

Any updates since 2012 please?

 

[alanbarlee]

G'day Zac,

 

Things have certainly moved along since 2012. Let's try to summarise.

 

An important treatment criterion is whether PSA is recurring after primary treatment, i.e. surgery (RP) or radiation (RT). Another is whether recurrent PSA is increasing in the context of low testosterone induced by primary androgen deprivation or ADT medications (i.e. castrate resistant). A third is whether there is positive evidence of metastasis (e.g. from a CT scan, a bone scan, an MRI scan or a PET/CT scan - including the new one based on 68-gallium). These three progressively higher risk criteria confirm unsuccessful primary treatment, i.e. locally recurring disease or distant metastasis (to bone, lymph nodes or organs) , although only the last of these strictly defines 'Stage 4' disease.

 

A number of clinical trials are leading to chemotherapy (docetaxel/Taxotere) accompanying initial ADT when primary treatment is unsuccessful, i.e. when PSA rises rapidly after treatment or when a patient initially presents with metastatic disease. This treatment is usually well tolerated, and often leads to long periods of PSA-indicated  cancer control. This adds to the case for combination therapies rather than strictly sequential treatments. which seems to be strengthening with newer treatments of more aggressive disease. 

 

Second generation ADT drugs (as distinct from the 'secondary ADT' options that Jim mentioned) are important breakthroughs since 2012.  These are abiraterone (Zytiga), which has effectively replaced ketoconizole, and enzalutamide (Zytiga), a potent anti-androgen: either (but not both) of these are available on the PBS  after unsuccessful chemotherapy, or when docetaxel therapy cannot be tolerated: both give extended control of metastatic PCa. An upcoming possibility in this category is apalutamide (Erleada) for earlier use, but this has not yet received a PBS  listing.

 

Cabazitaxel (Jevtana) is a newer chemotherapy treatment available on the PBS when docetaxel fails. It has a different side effect profile to docetaxel, and is often well tolerated. 

 

In a different category is 223-radium (Xofigo), a radiopharmaceutical that effectively targets bone-only metastases. This drug is finally in the process of being made available under Medicare.

 

To protect bone strength (sometimes declining bone density is a problem side effect with ADT), we now have denosumab sitting alongside Zometa.

 

Trials with 177-lutetium-PSMA are progressing here and overseas, and are showing considerable promise.

 

There are indications that immunotherapy may eventually be useful for prostate cancer, with trials with pembrolizumab (Keytruda) helping in 10-15% of cases. This is a 'watch this space' treatment.     

 

Finally, there is exciting progress being made in the area of genomics, with particular genes (e.g. BRCA2) being linked to aggressive disease that so-called PARP inhibitors like olaparib can be used to target.

 

We are fortunate that the explosion of new and emerging treatments during this decade is offering new hope to so many men with advanced prostate cancer. May it continue!

 

Cheers,

Alan   

[Zak]

Definitely! Thank you for the update Alan