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A new type of targeted medicine has shown ‘remarkable’ benefits for patients with advanced breast cancer in a major phase III clinical trial. The drug capivasertib combined with hormone therapy doubled the time it took for cancer to progress in people with advanced forms of the most common type of breast cancer. The findings, presented at the San Antonio Breast Cancer Symposium, establish capivasertib as a potential new treatment for people with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER-2) negative breast cancer. Capivasertib is a potential first-in-class drug that blocks activity of the cancer-driving protein molecule AKT. It was discovered by pharmaceutical company AstraZeneca following a program of drug discovery research at The Institute of Cancer Research, London in collaboration with Astex Pharmaceuticals. Capivasertib trial details The drug was found to be effective across all patients treated in the trial, including a group who had tumors with mutations in the AKT signaling pathway. The international CAPItello-291 study is the first phase III trial of capivasertib to report findings and was led by researchers at The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust. It was sponsored and funded by AstraZeneca. The CAPItello-291 trial enrolled 708 women and men with an advanced form of ER-positive, HER-2 low or negative locally advanced or metastatic breast cancer. Participants on the trial had seen their cancer recur or progress on standard hormone treatments, and the majority had also previously been treated with CDK4/6 inhibitors – drugs that block cancer cells from multiplying. In current clinical practice, patients continue to receive fulvestrant hormone therapy, but this is often not effective, and many are left only with the option of chemotherapy, a treatment which can lead to debilitating side effects. In the trial, adding capivasertib to fulvestrant hormone therapy doubled the median time to disease progression, from 3.6 months to 7.2 months. The treatment shrank tumors in 23% of patients, compared with 12% of patients who received fulvestrant hormone treatment plus a placebo. The targeted drug was more effective for patients whose cancers had alterations to the AKT signaling pathway. Genetic alterations to the AKT pathway can drive both cancer’s development and treatment resistance. Tumor profiling Genetic alterations of the AKT pathway – revealed by tumor profiling – were present for 41% of patients on the trial. In this group treated with capivasertib and hormone therapy, it took an average of 7.3 months for the cancer to worsen compared with 3.1 months for those who received hormone therapy alone. Some 29% of patients with AKT pathway alterations who received capivasertib with hormone therapy saw their tumors shrink following treatment, compared with only 9.7% who received a placebo and hormone therapy. Side effects from capivasertib with hormone therapy were manageable and consistent with previous studies. More than two thirds of people with advanced breast cancer have ER-positive, HER-2 negative disease. ER-positive, HER-2 negative breast cancers have higher levels of the estrogen receptor – allowing them to grow in the presence of estrogen – but do not over-produce copies of the human epidermal growth factor. The development of capivasertib followed years of fundamental research at the ICR, aimed at understanding how the AKT protein is regulated. In 2002 ICR scientists published the 3D structure of AKT and showed how the protein is activated. Targeting AKT Researchers in the ICR’s Centre for Cancer Drug Discovery, with funding from Cancer Research UK, then worked in collaboration with Astex Pharmaceuticals to design small-inhibitors which would target AKT, based on its 3D structure. In 2005, a series of prototype drug compounds discovered by the ICR and Astex was shown to have very promising activity against a range of human tumors grown in mice and was licensed to AstraZeneca. Then, in 2010, AstraZeneca announced its discovery of capivasertib, and began to develop the drug as a potential treatment for various forms of cancer. The initial clinical development of capivasertib was centered on an early-stage trial, which was led by the ICR and its partner hospital The Royal Marsden. Subsequently, phase II studies were completed in the UK in collaboration with the UK Cancer Research Network. The trials used biomarkers that were developed at ICR to show proof of concept that the AKT protein was inhibited by capivasertib. Researchers in the Breast Cancer Now Toby Robins Research Centre at the ICR continue to research AKT biology to open up new ways of using treatments targeting the pathway. 'A huge shock' Linda Kelly, 65, from Milton Keynes, U.K., joined the CAPItello-291 trial at The Royal Marsden in August 2021. She was diagnosed with ER-positive HER-2 negative breast cancer in July 2000 and following a mastectomy, chemotherapy and radiotherapy, she received hormone therapy for five years. Three years ago, she received the news that not only had her cancer returned but it had spread to her bones and chest wall. She said: “To be diagnosed with breast cancer again almost 20 years after my first diagnosis was a huge shock, but I was reassured to be in the safe hands of The Royal Marsden. My cancer was initially treated successfully with targeted drug therapy but after 18 months the disease had progressed to my liver and I joined the CAPItello-291 trial. The results have been amazing. There has been a substantial reduction in my disease, my cancer has not progressed, and I haven’t had any new tumors. “The treatment is far less debilitating than chemotherapy and I’ve been given the gift of a longer life. My future is still uncertain, but I now have the confidence to live my life to the full. I recently married my partner of 20 years, and I have felt fit and healthy enough to travel within the UK and abroad, spend time with family and friends, and keep up my fitness through cycling and walking.” Capivasertib combined with hormone therapy can shrink tumors Trial leader Nicholas Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said: “This is a fantastic finding for patients with breast cancer. Even with the best current treatments, people with this type of advanced breast cancer will eventually see their cancer stop responding to treatment, and it will progress. We’re delighted that this potential first-in-class drug combined with hormone therapy can slow the progression of these advanced cancers, and in almost a third of cases can shrink tumors. “We are hopeful that capivasertib combined with hormone therapy will now become a new treatment option for patients whose cancer has progressed on hormone therapy plus a CDK4/6 inhibitor. We believe this new treatment could allow more women and men to live well and live longer with breast cancer.” Landmark moment Kristian Helin, chief executive at The Institute of Cancer Research, London, said: “This is a landmark moment for the treatment of advanced forms of the most common type of breast cancer. It’s incredibly exciting to see a drug that was discovered following research conducted at the ICR now show remarkable benefits for patients in a phase III trial. Capivasertib could offer a completely new treatment option for these patients. “This is a major success story for UK science – the discovery and development of capivasertib showcases the benefits of collaboration between academia, charities and industry to bring game-changing new treatments to people with cancer as quickly as possible. “I look forward to seeing further results from the CAPitello-291 trial, and I am hopeful that longer follow-up will show that capivasertib also extends the length of time that people survive with advanced breast cancer. But the existing findings are already strong enough for capivasertib to be submitted to regulators to be considered for approval as a new breast cancer treatment.”

Astex Pharmaceuticals

New targeted drug shows benefit against breast cancer in first phase III trial

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