Berzosertib is an investigational drug currently undergoing clinical research for cancer treatment. It interferes with specific cellular processes that cancer cells rely on for survival and proliferation. As an investigational drug, it is not yet available for general medical use.
How Berzosertib Works
Berzosertib functions as a selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein kinase. ATR is an enzyme that detects DNA damage within cells, forming part of the cell’s DNA damage response (DDR) pathway. When DNA is damaged, ATR initiates a signaling cascade, including the ATR-checkpoint kinase 1 (Chk1) pathway, which pauses cell division to allow for DNA repair.
By inhibiting ATR activity, berzosertib prevents cancer cells from effectively repairing their damaged DNA, particularly during replication stress. This interference leads to an accumulation of DNA damage within rapidly dividing cancer cells, ultimately leading to their death. This mechanism makes berzosertib effective when combined with other therapies that cause DNA damage, such as chemotherapy or radiation, enhancing their effectiveness against cancer cells.
Conditions Under Investigation
Berzosertib is being investigated for its potential in treating various types of cancer, particularly those with existing DNA repair defects or high levels of replication stress. Its mechanism of action, which targets DNA damage response, makes it a candidate for cancers where these pathways are already compromised. Research has explored its use in ovarian cancer, where it has shown results in early trials.
Studies have also assessed berzosertib in small cell lung cancer, with early phase I/II data supporting its investigation. It has also been explored in other solid tumors, including those with specific genetic mutations like succinate dehydrogenase (SDH)-mutant gastrointestinal stromal tumors (GIST). In these GIST cases, patients experienced prolonged disease control, indicating vulnerability to ATR inhibition.
Current Status and Clinical Progress
Berzosertib has advanced through various phases of clinical development. It was the first ATR inhibitor evaluated in a randomized clinical trial for any tumor type. Early phase 1 trial results indicated outcomes, with some patients experiencing stabilization of their cancer or tumor shrinkage when treated with berzosertib alone or in combination with platinum chemotherapy.
In small cell lung cancer, a US National Cancer Institute-led Phase II clinical study met its primary objective, showing a confirmed objective response rate of 36%. However, a subsequent company-sponsored Phase II trial (DDRiver SCLC 250) for relapsed, platinum-resistant small cell lung cancer was discontinued after an interim analysis indicated a low probability of success. Despite this, Merck continues to explore berzosertib in other combinations and clinical settings, including ongoing external studies.
Potential Side Effects and Safety
Clinical trials have monitored the safety profile of berzosertib, both as a standalone therapy and in combination with other anti-cancer drugs. The drug has been reported as well-tolerated in studies. Common side effects observed can vary depending on the specific trial, dosage, and combination therapy used.
The full spectrum of potential side effects is still being characterized through ongoing research. Patients receiving berzosertib are under close medical supervision to monitor for any adverse reactions. This monitoring ensures that safety data is continually collected and assessed as the drug progresses through clinical development.