ICR and The Royal Marsden prostate cancer study featured as a news item in Science

01 May 2015

Last week, the ICR press office issued a press release about the results of a phase III trial led by researchers at the ICR and The Royal Marsden. The results, which were presented at the AACR Annual Meeting in Philadelphia, found that men with prostate cancer benefit from treatment with olaparib, a drug licenced last December in Europe to treat ovarian cancer. The story has now been written up as a news item on the journal Science’s website following widespread national coverage last week.

Breast cancer drug may help men with prostate cancer

A new type of cancer drug originally aimed at women with rare, inherited forms of breast and ovarian cancer may also help a broader swath of patients, according to a small clinical study. The drug halted tumour growth in a third of men with a typically deadly form of advanced prostate cancer. Nearly all of those who responded had related mutations in their tumours, indicating the drug was targeting a common cell process, researchers reported here this week at the annual meeting of the American Association for Cancer Research (AACR).

The drug blocks an enzyme called poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP), which helps cells repair a certain type of DNA damage. Oncologists are mostly testing PARP inhibitors in ovarian and breast cancer patients born with mutations in BRCA1 or BRCA2, two of the most infamous cancer-related genes. These mutations raise a woman’s risk for breast and ovarian cancer, as well as a man’s risk of prostate cancer, because they disable proteins that repair DNA damage that can result in additional cancer-spurring mutations. But flaws in either gene also make tumour cells vulnerable to PARP inhibitors, because the drugs further impair tumour cells’ DNA repair machinery. This combination renders tumour cells unable to fix DNA damage and they die, an idea known as synthetic lethality.

In December, the first PARP inhibitor, AstraZeneca’s olaparib, received approval in the United States and Europe for ovarian cancer patients who had inherited a BRCA1 or BRCA2 mutation.

But some cancer patients who lack such mutations have also seen their tumours shrink in trials. A team led by Johann de Bono of the Institute of Cancer Research and The Royal Marsden, both in London, suspected that these patients had inherited errors in other DNA repair genes or had acquired mutations in BRCA or the other genes in a tumour as it formed or grew. Three years ago, a large sequencing project found that such DNA repair gene defects are common in advanced prostate tumours.

To test their hypothesis, de Bono’s group and collaborators, whose funding was independent from AstraZeneca, gave the drug to 50 men with metastatic castration-resistant prostate cancer, which means their tumours had stopped responding to drugs that block the hormones that drive prostate cancer growth. Of the 49 men who stayed in the trial, 33%, or 16 patients, responded to the drug, according to one of three measures – a drop in levels of tumour cells in the patient’s blood, a decline in blood levels of the biomarker prostate-specific antigen, or imaging scans that found their tumours shrank. When the researchers sequenced the patients’ tumour DNA, they found their hunch was correct: 14 of the 16 who responded had mutations in one or more of a dozen DNA repair genes in their tumours, and only two non-responders had these mutations, reported Joaquin Mateo, a clinical fellow in de Bono’s lab, at the AACR meeting (while three responders had inherited BRCA2 mutations, four had apparently new mutations in this gene). Most of these patients responded to the drug for at least six months (four for more than one year), while those without such mutations usually got worse within three months.

Although genetic tests of tumours are already used to determine whether certain drugs will work for several types of cancer, this is the first time researchers have found such a test for prostate cancer, de Bono’s group says. Olaparib could offer a new option for these men: The trial shows “this is a good swat at that disease,” said prostate cancer researcher William Nelson of Johns Hopkins University in Baltimore, Maryland, at an AACR press conference, adding that the prospect of genetic testing to identify prostate cancer patients who could benefit from olaparib “looks very promising.”

The results also suggest that women with ovarian and breast cancer who lack an inherited BRCA mutation might still respond to PARP inhibitors, if they have DNA repair mutations in their tumours, de Bono’s group says. Ursula Matulonis of the Dana-Farber Cancer Institute in Boston, who presented results at AACR from a trial of olaparib combined with another drug for breast and ovarian cancer patients, said at the press conference that her team plans to explore that possibility by DNA testing biopsies from the patients.

Posted in BiologyHealth