PARP Inhibitor Shows Strong Anti-Tumor Activity with Few Side Effects

Last Updated: 2009-06-24 17:00:13 -0400 (Reuters Health)

By Anthony J. Brown, MD

NEW YORK (Reuters Health) - Olaparib, a new orally active PARP inhibitor, shows potent anti-tumor activity against cancers with BRCA mutations and causes few of the side effects seen with conventional chemotherapy, according to a report in the June 24th Online First issue of The New England Journal of Medicine.

"This was the first study to show that single agent PARP inhibitors...in the absence of chemotherapy have a high level of antitumor activity in selected patients with ovarian, breast and prostate cancers," senior author Dr. Johann S. de Bono, from Royal Marsden NHS Foundation Trust, Surrey, UK, told Reuters Health.

The current phase I trial featured 60 cancer patients, including 22 who were BRCA1 or BRCA2 mutation carriers and 1 patient who had a family history of BRCA-related cancer, but did not undergo mutation testing. Olaparib was increased from a dose of 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously, the report indicates.

A reversible dose-limiting toxicity occurred in 1 of 8 patients treated with 400 mg twice daily (grade 3 mood alteration and fatigue) and in 2 of 5 patients given 600 mg twice daily (grade 3 somnolence and grade 4 thrombocytopenia), the authors note.

In a substudy confined to BRCA1 or BRCA2 mutation carriers, olaparib, at a dose of 200 mg twice daily, was generally well tolerated, associated with few side effects, and showed antitumor activity. By contrast, the drug was not active in patients who were not BRCA mutation carriers.

"PARP inhibitors are going to be very important anticancer drugs in the future for multiple types of cancer with a DNA repair defect," Dr. de Bono predicted.

He said that the key question now is "how do we recognize cancers that are sensitive to these drugs and have this defect?"

Source:

N Engl J Med 2009;361.


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