Australian study validates a biomarker to predict the success of chemotherapy

[Wendy_Winnall]

Chemotherapy can be a good treatment for metastatic prostate cancer. But it doesn’t work for everyone. Unfortunately it takes months of treatment before the success of chemotherapy can be determined. Researchers are trying to find a good blood test biomarker as an early indicator of chemotherapy success. Major progress in this search has recently been made by Australian researchers.

Treatment of advanced prostate cancer

Hormone therapy (androgen deprivation therapy: ADT) is usually an effective initial treatment for men with advanced prostate cancer. ADT stops tumour growth and keeps PSA levels low for men whose cancer has spread out of the prostate. But as time goes by, many men find their cancer has become resistant to ADT. PSA levels start to rise again and eventually new tumours are seen on scans. This stage of prostate cancer is known as metastatic castration resistant prostate cancer (mCRPC).

Treatments for men with mCRPC included chemotherapy with docetaxel, chemotherapy with cabazitaxel, drugs such as Zytiga (Abiraterone) or Xtandi (Enzalutamide), or treatment with Xofigo (Radium 223). Chemotherapy with docetaxel is a common first choice. It usually brings significant benefits such as increased survival times, decreased symptoms and pain. But chemotherapy has side effects that can be difficult to tolerate. These include extreme tiredness, nausea, weight-loss, reduced immune responses and neuropathy (pain in the hands and feet). Not all men experience each of these side effects.

Unfortunately, chemotherapy with docetaxel does not help all men with mCRPC. Some men experience the toxic side effects, but the drugs do nothing to slow tumour growth. It would be very useful to know if chemotherapy is failing early on. The patient could then choose another treatment rather than suffer the side effects of chemotherapy with no benefit.

Biomarkers to predict chemotherapy success

How do we know whether chemotherapy is working? Ultimately, we want to see less tumours present on scans. But it takes a long time for this to happen. It’s very useful to know early on whether the cancer is responding to the chemotherapy. PSA levels can be used. But in the first few weeks after chemotherapy they are not accurate enough. It usually takes 3 cycles of treatment before PSA levels can be used to gauge success. This takes about 9 weeks.  

A new biomarker to predict the success of chemotherapy soon after starting the treatment is urgently needed. A biomarker is a biological molecule that can give information about a disease or treatment. In this case, a biomarker is something that we can test for, that will predict whether the docetaxel will shrink the prostate tumours and improve survival times.

Despite a large amount of research, very few biomarkers have been found that are useful for prostate cancer. Although many potential biomarkers have been discovered in preliminary studies, they don’t work well enough in real situations with patients. It’s very important to validate a biomarker by testing its ability to predict outcomes using a large group of clinical samples.

Biomarker research in Sydney

A new publication in the top journal European Urology has reported important progress developing a prostate cancer biomarker. The first author of the study is Dr Kate Mahon, a medical oncologist at the Chris O’Brien Lifehouse in Sydney. As a medical researcher she also holds appointments at the Garvan Institute of Medical Research, University of NSW and University of Sydney. Dr Mahon is the recipient of a Clinician Scientist Award from PCFA, funded by The Movember Foundation. Her research focusses on treatment for men with advanced prostate cancer.

Dr Mahon’s research group have developed a biomarker to predict the success of chemotherapy with docetaxel for men with mCRPC. This biomarker is DNA for the gene glutathione-S-transferase 1 (mGSTP1). Previous research has shown that mGSTP1 DNA in the blood is associated with tumour aggressiveness. It might also be associated with the total amount of prostate cancer in the body.

The new publication from Dr Mahon validates mGSTP1 DNA as a biomarker. To perform this study, the researchers used samples from a previous clinical trial. The SYNERGY trial was a large international randomised controlled trial. It tested whether adding custirsen to docetaxel chemotherapy would improve survival for men with mCRPC. Unfortunately, there was no benefit to adding custirsen. During the SYNERGY trial, blood samples were stored that could be used in other studies. Dr Mahon has used blood samples from 600 men in the SYNERGY trial to validate the mGSTP1 biomarker.

Dr Mahon’s results showed that:

• mGSTP1 DNA was detected in 81% of patients at the start of the trial (men with mCRPC who had not yet been treated with chemotherapy)
• Of the men with detectable mGSTP1 DNA before chemotherapy, 53% saw this disappear from their blood after 2 cycles (6 weeks) of chemotherapy
• mGSTP1 DNA disappearing was strongly associated with men surviving for longer
• mCSTP1 DNA disappearing was also a good indicator of PSA levels taking longer to rise after treatment

The most important finding from this study is that mGSTP1 DNA was a better biomarker than PSA for chemotherapy success. The results indicated that the decision to continue or stop chemotherapy after 6 weeks was better if it was made using mGSTP1 DNA. In their paper, the researchers predicted that “many of these patients may be spared unnecessary toxicity and have the opportunity to be treated sooner by potentially effective alternative agents”.

The final step necessary to bring the mGSTP1 DNA biomarker into clinical practice is a randomised trial to ask whether patients have improved outcomes if the new biomarker is used to direct their treatment choices. The researchers hope to start this trial soon.

PCFA is proud to have supported Dr Mahon with a Clinician Scientist Awarded, funded through The Movember Foundation. This study is an excellent example of donations to prostate cancer research leading to major progress by Australian researchers.