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Apalutamide improves survival times in men with metastatic prostate cancer when used with hormone therapy.

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Apalutamide (Erlyand) is a new drug that delays disease progression in men with advanced prostate cancer whose PSA is rising despite hormone therapy. Apalutamide has now been tested as a treatment at an earlier stage of advanced prostate cancer. This week’s blog describes exciting new results from the TITAN clinical trial.

New uses for existing prostate cancer drugs

A common “first-line” therapy for men with metastatic prostate cancer is androgen deprivation therapy (hormone therapy, ADT). These drugs are given to men who already have metastatic prostate cancer when diagnosed, or whose localised prostate cancer has spread despite treatment. ADT successfully slows prostate tumour growth, often for a year or two. But unfortunately, most men taking ADT see their cancer become resistant to this treatment. For these men, doctors often prescribe chemotherapy, or drugs such as Enzalutamide (Xtandi) or Abiraterone (Zytiga).

New drugs are usually developed for very specific stages of prostate cancer. But the same drug might be useful at earlier stages of the cancer, or in combination with other treatments. But we can’t just assume that this is the case. Clinical trials are needed to test whether a drug that works at one stage will work at another stage, or can be combined with other drugs. Otherwise there is a risk that people will be suffering the side effects from drugs that are doing no good, or even doing harm.

Past clinical trials have shown that men with metastatic prostate cancer taking ADT will survival longer if they also take Abiraterone and the anti-inflammatory drug predisone. The Australian ENZAMET trial has also shown that Enzalutamide (Xtandi) improves survival for these men. But these longer survival times come with an increase in the risk for side effects from the additional drugs.

Apalutamide

Apalutamide (Erlyand) is designed to stop the action of testosterone. It does this by binding to androgen receptor proteins. Androgen receptors inside prostate cancer cells bind to testosterone and similar male sex hormones. Binding of testosterone to this receptor tells the cancer cells to grow and multiply. Apalutamide sticks to the androgen receptor, stopping testosterone’s access. This stops testosterone from stimulating tumour growth. The way Apalutamide works is very similar to Enzalutamide.

Last year, the SPARTAN trial demonstrated that Apalutamide could delay the time until progression of advanced prostate cancer. The men taking Apalutamide in this trial had found that ADT no longer kept their PSA levels low, but they didn’t have metastatic tumours seen in CT or bone scans. These men are said to have non-metastatic castration-resistant prostate cancer. Unfortunately, it’s too early to tell whether Apalutamide is improving survival times for these men.

Apalutamide is registered with the TGA, so it can be prescribed in Australia. But unfortunately it’s not yet listed by the PBS, so it’s extremely expensive.

A new trial, called TITAN, has tested whether Apalutamide benefits men at a different stage of prostate cancer.

The TITAN clinical trial

TITAN stands for Targeted Investigational Treatment Analysis of Novel anti-androgen. The TITAN clinical trial tested whether Apalutamide improves survival times when used with ADT for their metastatic prostate cancer. These men are said to have hormone-sensitive metastatic prostate cancer.

The TITAN trial was led by Prof Kim Chi of BC Cancer and Vancouver Prostate Centre in Canada. It’s an international trial that recruited volunteers from 260 clinics in 23 different countries.

TITAN is an international, double-blind, phase 3 randomised controlled trial. This makes it the top level of evidence available; the type of evidence needed to change the way prostate cancer is treated. The first results from this trial were recently published in a top journal, The New England Journal of Medicine.

The men joining the TITAN trial had prostate cancer with tumours spread by metastasis. They had at least one tumour detected in their bones. There were men who had metastatic disease at the time they were diagnosed, as well as men whose localised prostate cancer had spread. This trial included a wide variety of men: some had a lot of tumours and some had only a few, some had been treated with radiotherapy or surgery, some had ADT previously and some had chemotherapy with docetaxel before. But none of the men had prostate cancer that had stopped responding to ADT.

Participants in the trial were randomly assigned into groups. 525 men took Apalutamide with their ADT. They were compared to 527 who took a placebo with their ADT (control group). Neither these men nor the scientists and doctors performing the trial knew which drugs they were taking until the first results were all in.

The first results came from data taken after almost 2 years of follow-up. These results showed that:

  • Men taking Apalutamide were less likely to die within the 2-year period than men taking ADT alone. 82.4% of men in the Apalutamide group survived compared to 73.5% of men in the control group.
  • Men taking Apalutamide were less likely to see their cancer progress. 68.2% of these men remained free of new tumours on scans, compared to 47.5% of men taking the placebo.
  • Men taking Apalutamide also had a longer average time until their PSA rose and fewer symptoms from disease progression.

Adverse effects

Adding a new drug to ADT may increase the risk of side effects. So the researchers carefully noted any adverse effects for men taking Apalutamide compared to men taking ADT only. Their results showed that:

  • Adverse events experienced on the trial (in both groups) included hot flushes, fatigue, high blood pressure, pain, rash, constipation and numerous others. Not all men experienced these problems.
  • Serious adverse events were experienced by 19.8% of the men taking Apalutamide, compared to 20.3% of the men in the control group.
  • The chances of adverse effects were very similar in both groups, with the exception of rash. 27.1% of men taking Apalutamide experienced a rash compared to 8.5% of men in the control group.

These results show that men taking ADT for metastatic prostate cancer have a risk of experiencing numerous difficult side effects. But the good news is that adding Apalutamide did not add too much to this burden.

This successful clinical trial has demonstrated that Apalutamide increased survival times and delayed disease progression for men taking ADT for metastatic prostate cancer. Adding Apalutamide to ADT did not lead to a substantial increase in side effects for these men. The wide variety of men in this international trial is similar to the real-life setting in which the drug should be used. This strengthens the evidence that Apalutamide should be effective for men with this stage of prostate cancer.

What does this mean for Australian men?

This trial is considered to have reached the top level of evidence needed to change clinical practice. So these results should mean that Apalutamide eventually becomes available in Australia for men to take along with their ADT, if suitable.

Apalutamide is currently approved by the TGA for use in Australia. But it’s only approved for use by men whose ADT has failed to keep their PSA levels low, without new tumour appearing on scans. These men are said to have non-metastatic castration resistant prostate cancer. For this purpose, Apalutamide can be prescribed, but it’s not yet subsidised by the PBS. So it is extremely expensive.

The TITAN trial has shown that Apalutamide is also a good treatment at a different stage –called hormone-sensitive metastatic prostate cancer. For its prescription in Australia, a new application needs to be made to the TGA for this purpose. Unfortunately the regulatory wheels turn slowly, and we need to wait for some time until Australian men are allowed access to this drug at affordable prices.

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