Research News

Third of men with treatment resistant prostate cancer respond to drug that targets gene defect, study finds

BMJ 2015; 351 doi: (Published 30 October 2015) Cite this as: BMJ 2015;351:h5783
  1. Susan Mayor
  1. 1London

One third of men with metastatic prostate cancer who do not respond to hormonal therapy show a response to olaparib, which targets inherited gene defects underlying the cancer in some people, says a study reported in the New England Journal of Medicine.1

The phase II trial included 50 men with metastatic prostate cancer that was resistant to androgen blockade. All of the men had previously been treated with docetaxel, and most (98%) had received abiraterone or enzalutamide. In the trial they were treated with olaparib tablets at a dose of 400 mg twice a day.

Olaparib inhibits the poly ADP ribose polymerase enzyme, which repairs damaged DNA. Cancers caused by BRCA1 or BRAC2 gene mutations, including some breast, ovarian, and prostate cancers, make particular use of this enzyme to repair damaged DNA, so blocking its action means that cancer cells are no longer able to divide and they die.

The study showed that 16 of the 49 patients who could be evaluated had a measurable response to treatment with olaparib (33% (95% confidence interval 20 to 48)). Response was defined as a reduction of at least 30% in tumour size, a reduction of at least 50% in the prostate specific antigen level, or a reduction in the circulating tumour cell count from five or more cells per 7.5 mL of blood to less than five. Twelve patients showed a response to olaparib for more than six months.

Genetic sequencing of samples from tumour biopsies found that 16 of 49 patients had mutations in DNA repair genes, including BRCA1/2. Of these 16 patients, 14 (88%) showed a response to olaparib. These included all seven patients with BRCA2 loss and four of five patients with ATM (ataxia telangiectasia mutated) aberrations.

“Our trial marks a significant step forward in the treatment of prostate cancer, showing that olaparib is highly effective at treating men with DNA repair defects in their tumours,” said Johann de Bono, lead author and the head of drug development at the Institute of Cancer Research in London, UK.

He added, “It also proves the principle that we can detect prostate cancers with specific targetable mutations using genomic sequencing to deliver more precise cancer care by matching treatment to those men most likely to benefit.”

A second part of the trial will now investigate olaparib treatment in men whose prostate cancers have detectable DNA repair mutations. Men with these mutations account for 25-30% of all sporadic, castration resistant prostate cancers.

The trial found that the most common grade 3 or 4 adverse events with the drug were anaemia (affecting 20% of patients) and fatigue (12%). It was supported by a wide range of funders including Cancer Research UK and AstraZeneca, the company that owns olaparib.


Cite this as: BMJ 2015;351:h5783


View Abstract

Log in

Log in through your institution


* For online subscription