Selective oestrogen receptor degraders as treatment for ER positive/HER2 negative advanced/metastatic breast cancer

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Published: 19 Dec 2019
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Dr Philippe Aftimos - Institut Jules Bordet, Brussels, Belgium

Dr Philippe Aftimos speaks to ecancer at the 2019 San Antonio Breast Cancer Symposium about selective oestrogen receptor degraders as treatment for ER positive/HER2 negative advanced/metastatic breast cancer.

He explains that now there is a new more potent class of agents being developed: The selective oestrogen receptor degraders.

These agents are more potent than the therapies that we have because they can overcome the mechanisms of resistance.

Dr Aftimos discusses the background, methods and results of two studies which evaluated the use of oral selective oestrogen receptor degrader elacestrant.

 

I would like to discuss today a new class of therapies in breast cancer, specifically the ER positive HER2 negative subtype, so the hormone receptor positive. Endocrine therapy has been the mainstay of treatment for years but we have now a new class of agents, more potent, more efficient, being developed. This class is called the selective oestrogen receptor degraders. At this meeting there were three posters, two posters and one poster discussion, that were discussing the specific agent called elacestrant. These agents are very important because we already had a selective oestrogen receptor degrader called fulvestrant which was an injection, intramuscular, and the new classes now are oral. So this is better for patients to have a pill instead of an injection. These agents are also more potent.

The first abstract that was authored by Bardia et al presented the final results of the phase I study. The phase I study was the first time they tested this agent against breast cancer. That was part a that served to determine the dose that was tolerable and there were two other parts, part b and part c, that were expansions where more patients were treated to get more information. Finally, a part d where there were ten patients that were heavily pre-treated meaning they had many treatments including the CDK4/6 inhibitors. Now these patients had received at least three lines of endocrine therapy as a median, they had received a chemotherapy, so the response rate is usually low with endocrine therapy after this pre-treatment. However, in the study the response rate was very promising, it was 19%, so 19% of patients had some shrinkage in their breast cancers which is very promising for the future. From the tolerability point of view the main adverse event was gastrointestinal toxicity, some nausea, but most of this was low grade, it was manageable. So this is quite promising for the future.

These agents are probably more potent than the endocrine therapies that we have because they can overcome the mechanisms of resistance. So endocrine therapy is used also in the early setting when patients after surgery receive these agents to prevent relapse but the cancer cells can adapt and develop acquired mechanisms of resistance. One of them is the ESR1 mutations. So the ESR mutations are mutations in the oestrogen receptor, the target of the therapy. Since our endocrine therapies serve to reduce and even annihilate the level of oestrogen in the body with these ESR1 mutations the oestrogen receptor can be activated in the absence of oestrogen. This is a mechanism of resistance and the tumour grows.

So it was hypothesised that these agents can overcome this mechanism of resistance and destroy the cancer cells. So the second abstract was actually work we did on liquid biopsies. Liquid biopsies are not invasive so it’s a blood draw from the patient, we don’t need to do a biopsy. We know that cancer cells shed DNA in the bloodstream and with liquid biopsies we isolate this DNA from the plasma and then we apply the next generation sequencing technologies to identify the mutations. We had in the combination of two phase I studies with elacestrant about 57 patients that had baseline liquid biopsies, meaning before starting the treatment, during and at the end of treatment at progression. We identified in the large majority some molecular alterations in about more than 90% of the patients and less than 50%, it was 41% and 47% of patients respectively, had ESR1 mutations and PIK3CA mutations. So these mutations are important for the treatment of breast cancer. For PIK3CA mutations now we have specific targeted drugs.

We saw that in the presence of these two mutations the patients still responded and this response was correlated with a decrease in the variant allele frequency, meaning in the presence of these mutations in the bloodstream. So this proved also the concept that this drug can be active when we have mechanisms of resistance.

Finally, these results have led to a phase III pivotal study that is called EMERALD and this was a poster in the trials in progress category. A phase III study is the study that precedes regulatory approval if we prove that it is better than standard of care. So this study will enrol about 466 patients with ER positive HER2 negative metastatic breast cancer. This is a study in the second and third line setting after CDK4/6 inhibitors. Patients are randomised open label either to elacestrant or to endocrine therapy of physician’s choice. So the physician can choose based on the pre-treatment either fulvestrant or an aromatase inhibitor. The study started enrolment a few months ago and we hope good results for the patients. If these agents come to clinical practice and they reverse resistance they can be promising in the early setting when we can still cure patients. If we can use them in the early setting we might be able to improve cure rates.

Are the mutations being identified potential biomarkers to select which patients would receive the most benefit?

It’s a very good question. Isolating these ESR1 mutations actually is a mechanism of resistance to this. So if we detect an ESR1 mutation in our patient we will not use the approved endocrine therapies because we know that they don’t work. So we would be able to select the patients that need a better therapy and actually in the EMERALD phase III study there are two co-primary endpoints – one is for the full patient population and one is specific for the patients with ESR1 mutations because it’s a stratifying factor in the study. So we determine this as soon as the patient is enrolled in the study.

Is there anything you would like to add?

Elacestrant is not the only novel SERD that is being developed so I’m aware of at least four or five other agents by different pharma companies and I think this is very good news for the patients.