Interfering with DNA Repair Shows Potential as Precision Cancer Treatment

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Genomic Health's Oncotype DX Genomic Prostate Score (GPS) test will be evaluated for the prostate cancer drug pipeline of Johnson & Johnson’s Janssen Pharmaceuticals through a research collaboration. [Source: National Cancer Institute

A new precision drug, currently under development in the U.K., that stops cancer from repairing its DNA has shown promise in an early-stage clinical trial, highlighting the potential of a new class of drugs known as ATR inhibitors.

The drug candidate, recently tested in humans for the first time, was shown to be well tolerated and stopped the growth of tumors in more than half of the treated patients, as described in a paper titled, “First-in-Human Trial of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors,” published in Cancer Discovery.

Patient enrolled in the trial had a range of advanced, heavily pre-treated cancers including breast, bowel, and prostate tumors. The researchers said they were encouraged by the fact that the new drug showed promising clinical benefit in a Phase I trial in patients who were extremely sick.

The trial, led by the Institute of Cancer Research (ICR), London, and the Royal Marsden NHS Foundation Trust, involved 21 patients with advanced solid tumors with defects in various genes that help coordinate DNA repair. Eleven patients had tumors with defects or deletions affecting the ATM gene.

The aim of the trial was to evaluate the safety of the ATR inhibitor BAY1895344 (manufactured by Bayer) and to identify the maximum tolerated dose that could be safely given to a group of cancer patients who had already previously been treated with multiple other drugs. The researchers found that the drug was well tolerated by patients effective against advanced cancers with defects in the ATM gene.

“Targeting the ataxia telangiectasia and Rad3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling,” the investigators wrote.

“We report the dose-escalation portion of the Phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5–80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. The most common adverse events were manageable and reversible hematological toxicities.

“Partial responses were achieved in four patients and stable disease in eight patients. The median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses greater than or equal to 40 mg BID.

“Overall, BAY 1895344 is well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency.”

The most common side effect reported was anemia, which was managed with the help of blood transfusions and did not usually require the treatment to be stopped.

The researchers also analyzed the biochemical and pharmacological effects of the drug, and were able to show that it exercised its effects in patients by increasing damage to DNA.

The new study supports further investigation of a treatment strategy that targets the DNA repair protein ATR, especially in patients whose cancers already have certain defects in DNA repair genes like ATM or BRCA1, weakening their ability to cope with DNA damage, according to the scientists.

“It is very promising to see patients responding in an early-stage trial like this, and we are looking forward to further clinical trials to test the drug’s efficacy,” said study leader Johann de Bono, MRCP, professor of experimental cancer medicine at the ICR and consultant medical oncologist at the Royal Marsden NHS Foundation Trust.

“One of our main goals is to find new targeted treatments and drug combinations that can tackle cancer evolution and drug resistance and this will be the main focus of research in our pioneering new Centre for Cancer Drug Discovery,” added Paul Workman, FRS, chief executive and president of the ICR.

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