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PARP inhibitor is most effective in ovarian cancer patients with DNA repair mutations

10 May 2021
Appeared in BioNews 1094

New research suggests mutations in multiple DNA repair genes can determine how well ovarian cancer patients will respond to the PARP inhibitor, rucaparib.

The authors of the study performed analyses on data from pre-treatment biopsies of tumours used in a phase 2 trial of rucaparib, to see if they could identify biomarkers that could predict a patient's response to treatment.  

'PARP inhibitors are a drug class that has become an important therapeutic for ovarian and some other cancers. This study looked at pre-treatment biopsies to define predictors of response to treatment and mechanisms of resistance (within the cancer cells), which is critical to understanding best use of these therapies,' said lead author Dr Elizabeth Swisher, professor of Obstetrics and Gynecology at the University of Washington School of Medicine, Seattle. 

The international study took place across 64 sites and recruited 491 ovarian cancer patients who had not received a PARP inhibitor as treatment for their cancer before. Patients were treated with oral rucaparib at 600 mg twice daily, and were aware of which treatment they were being given. Details of the study are published in Nature Communications.

Cancers caused by somatic and inherited BRCA1 and BRCA2 mutations are already understood to be responsive to treatment with PARP inhibitors, including breast, ovarian, pancreatic and prostate cancers. The researchers found that the presence of high-level BRCA1 promotor methylation as well as mutations in other DNA repair genes, RAD51C and RAD51D in the tumours, was also predictive of response to rucaparib. This was the first time this had been demonstrated in a phase 2 trial, having previously only been shown in pre-clinical trials. 

PARP inhibitors 'target the Achilles heel of cancers which have certain types of defects in DNA repair', Dr Swisher explained. PARP proteins normally help to prevent the accumulation of DNA damage in cancer cells with faulty DNA repair. When PARP proteins are blocked from performing this function, DNA errors build up, ultimately leading to the death of these cancer cells. 

The researchers also compared the outcomes of patients known to be responsive to platinum-based chemotherapy they had received, with those that had developed platinum-resistance in their cancer. They found patients with platinum-resistance also became resistant to rucaparib, rendering PARP inhibitors less effective. The authors therefore concluded that rucaparib 'should be considered in earlier lines of therapy, before the emergence of platinum resistance'. 

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