Darolutamide, a new drug in development for men with non-metastatic castration resistant prostate cancer

[Wendy_Winnall]

Men with prostate cancer, who have a rising PSA despite hormone therapy, know their cancer is on the move. New treatments are needed to slow cancer growth at this stage. The successful ARAMIS clinical trial has demonstrated that Darolutamide can slow tumour progression, giving these men more time before their cancer spreads. But the path to this drug becoming available in Australia is unclear.

Androgen deprivation therapy and anti-androgen drugs

Most prostate tumours rely on testosterone for their growth. Testosterone is one of numerous similar male hormones that can promote tumour growth. These male hormones are collectively known as androgens. Androgen deprivation therapy (hormone therapy; ADT) consists of drugs that stop these hormones acting on tumours. A common type of ADT is a group of medicines called gonadotrophin-releasing hormone (GnRH) inhibitors. These drugs stop the pituitary gland from making GnRH hormones, which tell the testicles to make testosterone. Surgery to remove the testicles, called orchiectomy, has a similar effect on testosterone.

Unfortunately, prostate cancers have a nasty habit of becoming resistant to ADT or orchiectomy. One way they do this is the tumours themselves start to make their own testosterone. So blocking testosterone from the testicles no longer works.

New types of anti-androgen drugs are also used to slow tumour growth at later stages of prostate cancer. Enzalutamide (Xtandi) acts on the androgen receptor. This receptor is present inside prostate cancer cells. Testosterone and other hormones bind to this receptor, promoting cell growth. By stopping male hormones from binding to the androgen receptor, Enzalutamide slows prostate cancer growth. Abiraterone (Zytiga) is also an anti-androgen drug. Abiraterone mimics testosterone. It binds to receptors and enzymes where testosterone would normally be. This inhibits both the production of testosterone and the ability of testosterone to promote tumour growth. These drugs can block the actions of testosterone, no matter where it is produced.

Anti-androgen drugs for non-metastatic castration resistant prostate cancer

Men with advanced prostate cancer, whose PSA is rising despite ADT, don’t have easy access to drugs that can slow their tumour growth at this stage. Once metastatic tumours are detected, they go on to have chemotherapy or other options such as Enzalutamide or Abiraterone. But there are men with what’s termed “non-metastatic castration resistant prostate cancer”. These are men whose PSA is rising despite ADT, but there are no tumours visible on scans. They know their tumours are growing again and want them treated. There is one drug, Apalutamide (Erlyand), that is approved in Australia for these men to take. In clinical trials, Apalutamide increases the time these men have before their cancer spreads. But Apalutamide is not yet subsidised by the PBS, making affordable access challenging.

There is good evidence that Enzalutamide can also benefit men at this stage of prostate cancer. Like Apalutamide, Enzalutamide was used alongside ADT during the successful PROSPER trial. But its use for this stage of prostate cancer is not yet approved by the TGA or subsidised by the PBS in Australia.

Like Enzalutamide, Apalutamide stops the androgen receptors from binding to male hormones. This works well to slow tumour growth, but unfortunately there is a risk of difficult side effects from both drugs.

Darolutamide

Darolutamide is new drug that is being developed to treat men with non-metastatic castration-resistant prostate cancer. It’s an anti-androgen drug that also stops the androgen receptor from binding male hormones. But this drug a very different type of molecule to Enzalutamide and Apalutamide. Preclinical studies (using the drug on animals) have shown that Darolutamide does not easily cross the blood-brain barrier. Darolutamide also has a lower interaction with normal cellular processes. It’s therefore hoped that Darolutamide can slow prostate cancer growth with fewer side effects compared to the current drugs.

Early clinical trials with humans incitate that Darolutamide can slow tumour growth in men with metastatic castration resistant prostate cancer who had no previous chemotherapy. The ARAMIS trial then asked whether Darolutamide could benefit men the castration resistant prostate cancer that was not yet metastatic.

The ARAMIS trial

Exciting results from the ARAMIS trial have been presented at this year’s ASCO conference and published in a top journal. The ARAMIS trial is a gold-standard clinical trial; evidence from this trial should be strong enough to change clinical practice. It's a randomised controlled trial – people entering the trial were randomly allocated to placebo or drug treatment. It’s also a double-blinded trial, meaning that the participants did not know whether they had drug or placebo, and neither did the scientists gathering the results, at the time. Aramis is also an international trial, recruiting patients at 409 centres in 36 countries.

Men joining the ARAMIS trial had high-risk, non-metastatic castration resistant prostate cancer. This means they were on ADT with rising PSA. PSA levels were at least 2 ng/ml and had a doubling time of 10 months or less. These men did not have metastatic tumours visible on scans.

Two thirds of the men joining the ARAMIS trial were allocated to the Darolutamide group. They took the drug as a tablet, twice a day with food. One third joining the trial took placebos instead (identical pills with no drug). 1509 men volunteered for the trial (955 in the Darolutamide group and 554 in the placebo group).

The main outcome measured in this trial is called metastasis-free survival. It’s defined as the time to evidence of tumours spreading on scans, or death from any cause, whichever occurs first. Metastasis-free survival is an important indicator of the ability of a drug to improve survival times. ARAMIS results showed that Darolutamide increased metastasis-free survival. The average metastasis-free survival was 40.4 months in the Darolutamide group, compared with 18.4 months for men taking the placebo.

The Darolutamide treatment also:

- increased the average amount of time before significant pain was experienced (40.3 months for the Darolutamide group compared to 25.4 months for placebo)

- prolonged the time before chemotherapy was needed

- was associated with a lower risk of death, within the trial time period

- increased time before PSA levels rapidly rose (33.2 months for the Darolutamide group compared to 7.3 months for placebo)

In terms of safety and side effects, Darolutamide was similar to placebo. Serious adverse events occurred in 24.8% of patients in the Darolutamide group and 20.0% in the placebo group. These events included fractures, falls, seizures, and weight loss.

How did the men taking placebos experience adverse effects? Adverse effects can result from the disease or from treatments. These men taking placebos were still taking ADT. ADT has numerous side effects and the risk of some serious side effects. These results show that taking Darolutamide only slightly increased the risk of adverse effects, compared to what is expected for these men on ADT.

The ARAMIS trial has provided evidence that Darolutamide can slow prostate cancer progression in men with non-metastatic castration resistant prostate cancer, with reasonable safety in terms of side effects.

There is now evidence that Enzalutamide, Darolutamide and Apalutamide can benefit men with “non-metastatic castration resistant prostate cancer”. This evidence comes from trials that recruited men at a specific stage of prostate cancer. Joining the trial were men whose PSA was rising but they had no metastatic tumours visible on scans. For Apalutamide, during the SPARTAN trial, and Enzalutamide, during the PROSPER trial, the scans used to look for metastatic tumours were CT scans. They didn’t use PSMA-PET, a more sensitive procedure that can see small tumours at an earlier stage. The ARAMIS trial for Darolutamide probably used CT scans as well, but it’s not clear from their publication.

Treatment of men with non-metastatic castration resistant prostate cancer in Australia

What exactly is non-metastatic castration resistant prostate cancer? This is a really interesting question, as some clinicians claim it doesn’t really exist. If a prostate and its tumour are successfully removed, and the cancer comes back, then these new tumours cannot be in the prostate gland. For a small proportion of these men, the returning tumours are only in the region where the prostate used to be (the “prostate bed”). But for most, the rising PSA has come from tumours that have spread. These metastatic tumours start very small – too small to be seen on scans. They can only be detected once large enough. So most men on ADT, with a rising PSA, probably have metastatic castration resistant prostate cancer. But they are not diagnosed as such, since the metastatic tumours do not show up on their scans.

It’s these very men who have joined the trial for Apalutamide and Darolutamide. This has interesting consequences for Australia.

The situation in Australia is different to the US and many European countries. In Australia, it’s very common for men with a rising PSA while on ADT, to have PSMA-PET scans. These scans are less popular elsewhere. PSMA-PET scans are very sensitive for small prostate tumours that have spread to other regions. They can pick up the early metastatic stage of prostate cancer. Once metastatic tumours have been detected, these men can access subsidised treatments such as chemotherapy, Enzalutamide or Abiraterone.

In Australia, Apalutamide is approved by the TGA (but not yet subsidised by the PBS) for treating men with a rising PSA, but not tumours seen on CT scans. It’s unclear how many of these men have had PSMA-PET scans showing tumours. So it’s unclear exactly how many of these men will likely use Apalutamide (as well as Darolutamide if it’s also approved), and how many will go on to the other treatments instead.

In the US, the need for these new drugs is clear. These same men, with the same stage of prostate cancer, also exist in Australia. But due to differences in the scans conducted in Australia, the same men may have different diagnoses, and will be offered different treatments. The way forward for both Darolutamide and Apalutamide in the Australian market is currently unclear. However, these new drugs will doubtless benefit many men world-wide, which is always good news.