Merck KGaA's ATR cancer drug cleared for further trials after phase 1 trial success

DNA sequence

Merck KGaA’s ATR inhibitor cancer drug has been cleared for further clinical trials after it showed encouraging activity in a phase 1 study. 

The drug known as berzosertib works by blocking a key DNA repair protein called ATR and could be used in patients who have not responded to other drugs targeting cancer cells’ DNA damage repair systems. 

Short for ataxia telangiectasia and Rad3-related kinase, ATR inhibition is also being investigated by rival companies such as AstraZeneca and Bayer in pre-clinical studies.

Damage to DNA is the root cause of cancer but causes a fundamental weakness in tumours as cancer cells can be killed by further damaging the DNA or attacking their ability to repair it. 

A team at the Institute of Cancer Research London, and the Royal Marsden NHS Foundation Trust led a trial of berzosertib either on its own or with chemotherapy in 40 patients with very advanced tumours in hospitals across the world. 

As well as establishing safe doses, ICR said researchers found berzosertib stopped tumours growing in more than half of patients given the drug either on its own or with chemotherapy – 20 out of 38 patients whose treatment response could be measured. 

The drug’s benefit in blocking DNA repair was even more marked in patients also given chemotherapy, which works by causing DNA damage. In these patients, 15 out of 21, or 71% saw their disease stabilise – suggesting that chemotherapy boosted sensitivity to berzosertib. 

ICR said one patient with advanced bowel cancer whose tumour contained faults in key DNA repair genes including CHEK1 and ARID1A responded remarkably well to berzosertib on its own, seeing his tumours disappear and staying cancer free for more than two years. 

Another woman with advanced ovarian cancer whose disease had come back after treatment with a drug blocking PARP, another key DNA repair protein, received the combination treatment and saw her tumours shrink. 

ICR said that the drug is now moving forward into further trials and could be developed into a targeted treatment and help overcome resistance to other precision drugs such as poly (ADP-ribose) polymerase (PARP) inhibitors that target DNA repair. 

Results are published in the Journal of Clinical Oncology and the trial was funded by Merck KGaA, Darmstadt, Germany, the manufacturer of the drug.

Funded by research grants from several charities, as well as royalties and other funding bodies, the ICR led research in the mid-90s that led to the PARP inhibitor olaparib.

This was the first in its class to be approved in uses including ovarian and breast cancer and is marketed by AstraZeneca and Merck & Co as Lynparza.