FAKTION And The Breast Cancer Drug Paving A Future For Hormonal Therapies

– by Margherita Carucci and Angela Casbard on behalf of the FAKTION CTR Team

When a patient is diagnosed with cancer, their doctor will prescribe a drug or a combination of drugs for destroying or keeping the cancer cells under control. But how do doctors know which drugs are the best treatment for their patient with cancer? Behind the doctor’s prescription of a specific treatment and the patient’s use of those drugs are years of research, testing, successes and failures that comprise the journey of a drug from the laboratory to the pharmacy shelf.

Today, we’d like to focus on a specific drug for certain types of breast cancer called capivasertib (also known by the trade name Truqap) that the Centre for Trials Research (CTR) helped along its journey to the pharmacy shelf through the FAKTION trial.

Breast cancer cells which have the oestrogen receptor (ER positive or ER+) are more likely to grow when the hormone oestrogen is present in the bloodstream. This can be treated with drugs that interfere with the action of oestrogen or the oestrogen receptor. Although these drugs are often effective for a while, the cancer can frequently become resistant and the drugs stop working. A new treatment strategy is then needed to control the disease. Capivasertib (tablet) is a drug that blocks the activity of a protein called AKT, responsible for the growth of the cancer cells. It is combined with fulvestrant (an injection), which is a hormonal therapy drug used in breast cancer to stop the oestrogen from reaching the cancer cells, thereby preventing them from growing.

Some preliminary work showed that the combination of capivasertib and fulvestrant may increase the effectiveness of both drugs in stopping the cancer cells from growing. However, further research was necessary for confirming this hypothesis through the essential stages of lab work, clinical trials, and regulatory checks.

After preliminary laboratory research, capivasertib (or AZD5363, as it was known at the time) was introduced to human beings in clinical trials, an aspect of clinical research that is vital in assessing how safe and effective a treatment is to cure or prevent particular symptoms.

The FAKTION trial tested the combination of the two drugs on 149 postmenopausal women with advanced oestrogen receptor positive breast cancer that no longer responded to hormone therapy. These patients were under the care of a consultant oncologist in an NHS hospital in the UK, and consented to be treated with capivasertib (or placebo) and fulvestrant.

The FAKTION trial was coordinated by the Centre For Trials Research (CTR) Cancer Division. The team at CTR prepared the necessary paperwork for approvals by UK regulatory bodies, collected and analysed data from the trial participants, and made sure that policies and regulations were followed by all the parties involved so that the participants’ rights, safety, and wellbeing were protected and the trial information was recorded, handled, and stored appropriately.

The FAKTION trial included two phases.

In Phase 1b, the combination of capivasertib + fulvestrant was tested on 9 participants with the aim of assessing the maximum dose of capivasertib that patients could tolerate. This was followed by Phase 2, where 140 participants were randomly divided into two groups to receive either (a) capivasertib + fulvestrant (69 participants) or (b) the placebo (dummy drug) + fulvestrant (71 participants). Both groups of participants were treated until their tumour grew or until their body could no longer tolerate the side effects of the drugs or they sadly died. In both phases, the FAKTION participants received the drugs provided for free by AstraZeneca, who manufactured capivasertib and funded the trial with the support and endorsement of Cancer Research UK.

The data collected during FAKTION Phase 2 was analysed and the results were very promising:  in participants who received capivasertib + fulvestrant, the tumour started growing on average 10.3 months after the start of treatment while the time to disease progression for those allocated to placebo + fulvestrant was 4.8 months.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(20)30237-0/fulltext

The FAKTION Team followed these participants up to assess whether capivarsertib helps patients to live longer and showed that the participants’ overall survival (i.e. from time of diagnosis to death) was on average 29.3 months in the capivasertib + fulvestrant  group and 23.4 months in the placebo + fulvestrant group. The FAKTION Team also did some more work on the blood and tumour tissues samples donated by the participants which showed that the capivasertib appeared to be particularly effective in patients  with a mutation in the tumour called the PIK3/AKT/PTEN pathway alteration. In this group, the drug extended the time before the cancer returns to an average of 12.8 months (versus 4.6 months in the placebo group) and before death to an average of 38.9 months (versus 20 months in the placebo group).

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00284-4/fulltext

The FAKTION data and design contributed to the subsequent Phase 3 trial called CAPItello-291, which was run by AstraZeneca, in a larger group that included international patients. This clinical trial’s data confirmed FAKTION’s results on the benefits of capivasertib + fulvestrant and on the safe and effective use of capivasertib in  women with advanced or metastatic breast cancer.

Capivasertib’s journey continued toward the granting of a licence that is the necessary step for confirming that the drug is safe and effective and that we can trust it for its widespread use. On 16^th November 2023, the Food and Drug Administration (FDA) in the USA approved capivasertib (or Truqap, its trade name) for the treatment of the type of breast cancer researched in the FAKTION trial.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer

With this approval, doctors can prescribe capivasertib to their patients in the USA. Because each country has its own processes for granting a licence, capivasertib is not yet available to patients in the UK or EU. Further regulatory checks are required by the national Medicine and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) before this drug is available on the pharmacy’s shelf in the UK and EU. We hope that these checks will be completed soon and that breast cancer patients will soon benefit from this treatment, which was first shown to be effective thanks to the hard work of the FAKTION trial team and CTR.

Related blog: https://blogs.cardiff.ac.uk/centre-for-trials-research/my-asco-centre-for-trials-research-at-the-american-society-of-clinical-oncology-2019/

-Margherita Carucci and Angela Casbard on behalf of the FAKTION CTR Team