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Promising results from the ENZAMET clinical trial

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Enzalutamide (Xtandi) is a medicine that helps men with metastatic prostate cancer live longer. In Australia it’s used by men with late-stage disease, called metastatic castration resistant prostate cancer. A large Australian and New Zealand clinical trial has now shown that Enzalutamide improves survival times if taken at an earlier stage, with hormone therapy. But unfortunately adding Enzalutamide to hormone therapy brings a higher risk of side effects.

Current use of Enzalutamide in Australia

Enzalutamide is an anti-androgen drug that slows prostate tumour growth at later stages of disease. Enzalutamide acts by inhibiting androgen receptor proteins. These receptors are present inside prostate cancer cells. Testosterone and other hormones bind to these receptors, promoting cell growth. By stopping male hormones from binding to the androgen receptor, Enzalutamide slows prostate cancer growth.

Enzalutamide was approved and subsidised for use in Australia in 2014. It can be prescribed to men with metastatic castration resistant prostate cancer. These are men whose cancer has spread and continues to grow, despite hormone therapy (androgen deprivation therapy, ADT). Men can be prescribed Enzalutamide if their cancer has progressed despite chemotherapy with docetaxel, or if they can’t have docetaxel.

As a drug that blocks the effects of male hormones, Enzalutamide has the potential to slow prostate tumour growth if used at earlier stages of the disease. This potential has now been tested in a clinical trial run by ANZUP.

ANZUP clinical trials

ANZUP are the Australia and New Zealand Urogenital and Prostate cancer trials group. Their mission is to conduct clinical trial research to improve treatment of bladder, kidney, testicular and prostate cancers. Their organisation consists of dedicated health professionals involved in the research and treatment of these cancers. They have over 10 clinical trials currently underway.

The ENZAMET trial

First results from the ENZAMET clinical trial were recently reported. This ANZUP trial is an international projedt that was designed and coordinated in Australia. Patients were recruited from Australia, New Zealand and four other countries.

The researchers conducting this trial are a large group of collaborating clinicians and scientists from Australia and New Zealand. They were led by Prof Ian Davis, a medical oncologist and Chair of the ANZUP board.

The ENZAMET trial tested a new treatment regime for men with metastatic hormone-sensitive prostate cancer. These men have prostate cancer that has already spread before receiving ADT. Currently, they usually start their treatment with ADT plus an added anti-androgen drug. Once the ADT no longer controls tumour growth, they go on to have chemotherapy, or Enzalutamide or Abiraterone.

The aim of the ENZAMET trial is to ask whether Enzalutamide added to ADT improved survival times for men with metastatic hormone-sensitive prostate cancer.

1,125 men volunteered for this trial. They were randomly assigned to receive either Enzalutamide, or an anti-androgen drug. Men took either drug in addition to their ADT treatment to slow the growth of their metastatic prostate cancer. 563 men took Enzalutamide with their ADT, compared to 562 who took a standard anti-androgen with their ADT.

These men were followed-up with regular tests every 12 weeks for an average of 34 months, so far. Many needed further treatment, such as chemotherapy, as their tumours had stared growing again.

First results from the ENZAMET trial were released after almost 3 years of follow-up. They were presented recently at the ASCO conference in Cicago and published in the top journal, the New England Journal of Medicine. The ENZAMET trial results showed that:

  • Men taking Enzalutamide were more likely to be alive after an average 34 months of follow-up. There were 102 deaths in the Enzalutamide group, compared to 143 deaths in the standard care group.
  • Men taking Enzalutamide were less likely to see their PSA levels rise compared to men who had the standard treatment.
  • Men taking Enzalutamide were also less likely to have new tumours seen on scans.

Side effects from adding Enzalutamide to ADT

Unfortunately, men who took Enzalutamide had a higher chance of side effects. These included:

  • fatigue (25% of men taking Enzalutamide versus 14% with standard therapy)
  • seizures (6 men who took Enzalutamide versus 1 man who took standard therapy),
  • febrile neutropenia (fever/infection with low blood counts)
  • neuropathy (pain in hands and feet).

So the increase in survival time came at a cost of an increased chances of side effects from Enzalutamide.

Enzalutamide with ADT and chemotherapy

Many of the men in this trial needed chemotherapy. They took a chemotherapy drug called docetaxel. Currently, Enzalutamide is not taken at the same time as chemotherapy. The researchers asked whether Enzalutamide was beneficial for men who had docetaxel chemotherapy as well as ADT. They compared results for men who had all three treatments, to men who had ADT and docetaxel chemotherapy, but did not take Enzalutamide.

This analysis showed that the beneficial effects of Enzalutamide were not as strong if the men needed chemotherapy as well. Furthermore, men taking all three treatments were more likely to suffer side effects such as pain in their hands and feet. So adding Enzalutamide to ADT was not as beneficial for men needing chemotherapy as well, and they suffered worse side effects having the three treatments.

Conclusions from the ENZAMET study

The researchers concluded that Enzalutamide treatment with ADT increased survival time and time until cancer progression compared to the anti-androgen drug control. This conclusion is valid for men with metastatic hormone-sensitive prostate cancer. But adding Enzalutamide to ADT led to a higher rate of side effects.

The effects of Enzalutamide on survival were not as strong for men taking chemotherapy, and these men experienced more side effects. More research is necessary to determine whether Enzalutamide is worthwhile for these men.

What does this mean for Australians with prostate cancer?

Enzalutamide cannot yet be prescribed to men with metastatic hormone-sensitive prostate cancer. This needs a new application and approval from the TGA. Listing by the PBS will also be needed to ensure that this drug is subsidised for these men, making it affordable. Unfortunately, these wheels turn slowly; we will need to wait for all these applications to be made and approved before Australian men can be prescribed affordable Enzalutamide with ADT for this stage of prostate cancer.

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