Rucaparib: targeting DNA repair and a patient’s perspective

​

Inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) kill BRCA-deficient tumours, and have significant activity in single agent and combination therapy. Professor Herbie Newell, of Newcastle University (with Hilary Calvert, Nicola Curtin, Barbara Durkacz, Bernard Golding, Roger Griffin and Ruth Plummer), was part of the team responsible for making the PARP inhibitor rucaparib.

In December 2016, the FDA fast-tracked rucaparib (Rubraca®) into the clinic to treat women with advanced ovarian cancer who have received two or more prior chemotherapies and whose tumours have a BRCA gene mutation. Here Herbie explains the start of the story.

“In the late 1980s, temozolomide, a DNA-methylating agent, was the drug of the moment. We reasoned that a PARP inhibitor should make temozolomide, as well as some other drugs and ionising radiation, more active by inhibiting DNA repair. There was lots of scepticism from pharma as they said a PARP inhibitor wouldn’t be a standalone drug and would increase toxicity; consequently there was no major commercial interest. Nevertheless, in a collaboration between the Cancer Research Unit and the School of Chemistry, we established a drug discovery group in Newcastle in 1990 to make and test PARP inhibitors. Rucaparib was subsequently identified in collaboration with Agouron and Pfizer GRD, and is now being developed and marketed by Clovis Oncology.

The critical breakthrough for PARP inhibitors was the recognition of single agent activity in cells defective for homologous recombination repair, as found in BRCA-deficient tumours (reported independently in Nature in 2005 by two UK teams). With the help of the CRUK Centre for Drug Development, rucaparib went into phase 1 trials in 2003, and went on to stimulate high levels of commercial interest in PARP inhibitors in multiple companies. The FDA approved rucaparib in December 2016, having previously identified it as a breakthrough drug.”

In 2003, Professor Ruth Plummer, now the chair of the New Agents Committee, wrote the prescription for the first patient in the world to be treated by rucaparib, the first ever cancer patient to be treated by a PARP inhibitor. “It was always clear we had a drug that did something. We have some patients whose scans are currently clear and have been for some years now. It’s fantastic – really great. The patient from our first trial doesn’t even come to clinic now – he’s been discharged!”

 ​