Prexasertib is a targeted therapeutic drug under investigation for cancer treatment. It is designed to selectively interfere with specific processes within cancer cells, aiming to halt their uncontrolled growth and division. This represents an evolving strategy in cancer therapy, moving towards more precise interventions.
How Prexasertib Works
Prexasertib functions by inhibiting checkpoint kinase 1 (CHK1) and, to a lesser extent, checkpoint kinase 2 (CHK2). These proteins are integral components of the cell’s DNA damage response (DDR) pathway. Their primary role involves pausing the cell cycle to allow for DNA repair when damage is detected, a natural cellular mechanism that prevents the replication of faulty DNA.
Cancer cells often have increased DNA damage and rapid division, making them reliant on these checkpoint proteins to survive. Prexasertib disrupts this repair mechanism by inhibiting CHK1 and CHK2. This forces cancer cells to continue dividing despite damaged DNA. The accumulation of unrepaired DNA damage eventually leads to “mitotic catastrophe” and cell death in these cells.
Prexasertib in Clinical Research
Prexasertib is being investigated across various phases of clinical trials for several cancer types. Early phase 1 studies evaluated its safety and preliminary activity in patients with advanced or metastatic solid tumors, helping establish a recommended phase 2 dose.
In phase 2 trials, prexasertib has shown activity in high-grade serous ovarian carcinoma (HGSOC), particularly in patients whose cancer had recurred and was resistant to platinum-based chemotherapy. In one study, prexasertib shrank tumors in a third of participants with recurrent HGSOC without BRCA gene mutations, and their disease did not progress for a median of 7.5 months.
Prexasertib has also been studied in:
- Squamous cell carcinoma, including head and neck and anal cancer, showing response rates in some patients.
- Triple-negative breast cancer, where monotherapy showed activity in BRCA wild-type patients.
- Acute lymphoblastic leukemia, with potential efficacy indicated in preclinical studies.
- Prostate cancer.
- Endometrial adenocarcinoma.
- Urothelial cancers.
Potential Side Effects and Administration
Like many cancer therapies, prexasertib is associated with potential side effects, primarily due to its impact on rapidly dividing cells, including healthy ones. The most commonly reported severe side effects are hematologic, affecting blood cell counts:
- Neutropenia (low levels of neutrophils, a type of white blood cell)
- Leukopenia (low white blood cell count)
- Thrombocytopenia (low platelet count)
- Anemia (low red blood cell count)
Neutropenia, especially grade 4, is often transient and manageable. Febrile neutropenia, a fever combined with low neutrophil count, has also been reported.
Non-hematologic side effects can include fatigue, nausea, headache, diarrhea, and anorexia, which are mild to moderate in severity. Prexasertib is administered intravenously (IV) as an infusion, often on day 1 and day 15 of a 28-day cycle, or once every 14 days. Patients undergoing treatment are closely monitored for these side effects, and supportive measures, such as granulocyte colony-stimulating factor (G-CSF) for neutropenia, may be used to manage them. Patients should consult with their healthcare professionals for guidance.