Last week, the U.K. Medicine and Healthcare products Regulatory Agency (MHRA) granted approval to first-in-class AstraZeneca’s AKT inhibitor, capivasertib. The drug designed to fight hormone receptor (HR)-positive, HER2-negative (HR+/HER2-) breast cancer had already received U.S. Food and Drug Administration (FDA) approval last November.
Capivasertib, marketed as Truquap, is the result of the collaboration between AstraZeneca and U.K.-based Astex Pharmaceuticals. This AKT inhibitor targets the PI3K/AKT/mTOR signaling pathway, which is often dysregulated in various cancers, including breast cancer. This approval might not only be a win for AstraZeneca and Astex but also the first step for AKT inhibitors in oncology.
In this article, we take a closer look at capivasertib and what it could mean in the broader AKT inhibitor landscape in oncology.
Table of contents
Capivasertib for breast cancer: what is its mechanism of action?
The AKT kinases are proteins involved in the PI3K/AKT/mTOR signaling pathway, which is involved in cell proliferation and survival. In many cancers, including breast cancer, this pathway is overactive due to gene mutations such as PIK3CA, AKT1, and PTEN. Capivasertib blocks AKT, disrupting these signals and preventing cancer cells from growing and spreading.
HR+/HER2- breast cancer is characterized by the presence of HR for estrogen or progesterone but lacks overexpression or amplification of the HER2 protein. Biomarkers such as PIK3CA, AKT1, and PTEN play a critical role in the development and progression of HR+/HER2- breast cancer. Mutations or alterations in these genes can activate the PI3K/AKT/mTOR pathway, driving cancer cell growth and survival.
Current treatment options for HR+/HER2- breast cancer primarily include endocrine therapies such as aromatase inhibitors, selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs). While these treatments can be effective, many patients eventually develop resistance. Chemotherapy and targeted therapies like CDK4/6 inhibitors are also used, but they can have significant side effects and may not be effective in all patients.
In phase 3 clinical trials, capivasertib demonstrated convincing results, eventually leading to its approvals by the FDA and more recently the MHRA. Participants were randomized to receive either capivasertib with fulvestrant (an estrogen receptor antagonist) or a placebo with fulvestrant. Patients receiving capivasertib had a median progression-free survival (PFS) of 7.3 months compared to 3.1 months for the placebo group. The overall response rate (ORR) was significantly higher in the capivasertib group, especially among patients with PIK3CA, AKT1, or PTEN mutations. Also, the safety profile of the drug was found manageable as the most common side effects were diarrhea, rashes, and hyperglycemia.
AKT inhibitors: The broader picture
AKT inhibitors could offer several potential advantages in oncology. By specifically targeting the PI3K/AKT/mTOR pathway, these drugs can effectively inhibit tumor growth in cancers with pathway aberrations, providing a more tailored treatment approach.
AKT inhibitors are often used in combination with other therapies, such as endocrine therapies or chemotherapy, to enhance overall treatment efficacy and overcome resistance mechanisms. So, as AKT inhibitors progress through the pipelines it also enhances the potential of other treatments that are currently standard of care for HR+/HER2- cancers. Given the prevalence of PI3K/AKT/mTOR pathway alterations in many cancers, AKT inhibitors have broad applicability across multiple cancer types.
AstraZeneca may be at the forefront of the field with capivasertiv but several other AKT inhibitors are currently in development or clinical use, although Roche decided to drop Ipatasertib in early 2023 after it showed mixed results. The same goes for Merck’s MK-2206.
Which other promising AKT inhibitor drugs are in clinical trials?
Here are a couple of promising candidates in the AKT inhibitor space:
Taiho Pharmaceuticals’ TAS-117
Currently in phase 1 clinical trials and tested in patients with advanced solid tumors, TAS-117 is an allosteric AKT inhibitor, meaning it works by preventing the localization of AKT to prevent its activation. In phase 1 the drug was well tolerated with the most common side effect being gastrointestinal disturbances. The effective inhibition of AKT was confirmed and partial responses in patients were observed potentially indicating anti-tumor activity though it is still early to compare its efficacy to more advanced candidates such as capivasertib.
Laekna’s afuresertib
Initially developed by GSK, afuresrtib was then acquired by Novartis and later licensed out to Chinese biotech Laekna. Since 2018 Laekna has progressed afuresertib through the pipeline as it completed a phase 2 trial at the end of 2023 and is now advancing the candidate into phase 3.
Phase 2 evaluated its efficacy and safety in combination with fulvestrant for treating patients with locally advanced or metastatic HR+/HER2- breast cancer who had failed standard therapies. The combination therapy was found to be safe with no serious adverse events during the trial. With an ORR of 30% and a disease control rate (DCR) of 80%, the treatment is showing mixed results, not improving significantly the outcome for participants. The PFS was however comparable to capivasertib’s with 7.3 months.
While not alone in the AKT space, the fruit of the collaboration between Astex and AstraZeneca is the clear frontrunner. Indeed Astex Pharmaceuticals is a strong partner in oncology as several of its collaborations have reached the market.
A closer look into Astex’s pipeline
AstraZenaca isn’t the only biotech giant that worked with the U.K.-based company, as Jansen and Novartis also brought a collaboration with Astex to market.
Kisqali (ribociclib), the collaborative asset of Novartis and Astex is a selective cyclin-dependent kinase (CDK) inhibitor that specifically targets CDK4 and CDK6. In cancer cells, overactivation of CDK4 and 6 can lead to uncontrolled cell division and tumor growth. By inhibiting these kinases, ribociclib helps slow down the proliferation of cancer cells. Kisqali received approval in 99 countries for use including the FDA approval for HR+/HER2- metastatic breast cancer.
The collaboration with Janssen led to the market approval of balversa (erdafitinib), a targeted therapy designed to treat urothelial carcinoma. It specifically targets fibroblast growth factor receptors (FGFRs), particularly FGFR2 and FGFR3, which are often altered in cancer. These alterations can lead to uncontrolled cell growth and cancer progression.
Balversa is approved for use in adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible FGFR3 genetic alterations. The drug was first granted accelerated approval by the FDA in April 2019 and received full FDA approval in January 2024.
Astex also collaborates with GSK on an early-stage asset and has a proprietary pipeline with candidates targeting solid tumors in the range of phase 1 to phase 2 clinical trials.
About the recent MHRA approval of capivasertib, Astex’s chief executive officer (CEO) Harren Jhoti highlighted the collaborative effort it has been to bring this asset to market. “The early discovery research was a great collaborative effort, and I would like to acknowledge the impressive pioneering research carried out by our colleagues at the ICR (Institute of Cancer Research), including solving the 3D crystal structure of AKT, which was vital in enabling our initial drug discovery approach.”
To say capivasertib is the first of many AKT inhibitors to reach the market would be a bold statement. However, AstraZeneca and Astex demonstrated the technology certainly had potential despite a few similar candidates being dropped in development after showing mixed results. Let’s keep an eye on the AKT targeting drug market as it is possible capivasertib has opened the way for others to reach approval.
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