BRCA-targeting drug has benefit in prostate cancer

PHILADELPHIA, PA—Men with prostate cancer benefit from treatment with the pioneering drug olaparib, which is the first cancer drug to target inherited mutations. These major trial results were presented at the American Association for Cancer Research (AACR) Annual Meeting 2015.

Olaparib was licensed in December for women with ovarian cancer and inherited BRCA mutations, but the new research suggests it could also benefit men with genomic faults within their tumors.

Researchers stated that up to 30% of men with advanced prostate cancer had tumors with defects in repairing DNA, and these responded particularly well to olaparib.

The men most likely to benefit could be identified by genetic testing to look for mutations in genes responsible for DNA repair, including the BRCA genes and the gene ATM.

This investigator-initiated phase II trial, called TOPARP-A, was led by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and also involved several other institutions in the United Kingdom.

The work was funded by the Prostate Cancer Foundation, Stand Up To Cancer, Cancer Research UK, Prostate Cancer UK and the Movember Foundation, with support from the investigator-sponsored study collaboration between AstraZeneca and the National Cancer Research Network.

In the trial, researchers monitored the response of 49 men with treatment-resistant, advanced prostate cancer to olaparib. Sixteen patients (32.7%) responded to the drug, as defined by a set of clinical criteria.

Olaparib stopped prostate cancer growth, reduced levels of prostate-specific antigen (PSA) and of circulating tumor cell counts in the blood, and led to radiologic response on CT scans and MRI.

The response rate was much higher in patients whose tumors carried mutations to genes involved in repairing DNA.

Of the 16 patients with detectable DNA repair mutations, 14 responded to olaparib, which accounted for the large majority of patients who benefited from the drug. Most of these men, who all had terminal prostate cancer with limited treatment options, had disease control lasting much longer than expected in this group of patients.

The development of olaparib was underpinned by research at The Institute of Cancer Research (ICR) and clinical trials at The Royal Marsden, as well as other UK institutions. It has had particularly strong results in phase III trials in patients who inherited mutations to the BRCA genes, many of whom had breast or ovarian cancer.

The results will lead on to the start of TOPARP-B, a second part of the trial in which only men with detectable DNA repair mutations will receive olaparib. If the results of TOPARP-A are replicated in TOPARP-B, olaparib could become a treatment option for advanced prostate cancer.

"Our trial shows that olaparib is effective in men with defects in DNA repair genes who do not necessarily have an inherited risk of cancer and that we can pick up these defects in the clinic,” said trial chief investigator Professor Johann de Bono, MD, PhD, head of Drug Development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust. “This opens up the exciting possibility of delivering precise treatment for advanced prostate cancer, guided by genomic testing and based on the particular molecular characteristics of patients' tumors.”

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