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AstraZeneca’s Olaparib has become the first gene-targeted medicine to show benefits in metastatic castration resistant prostate cancer. Prostate cancer is the most common cancer among men, except for skin cancer, and metastatic prostate cancer has a 5-year survival rate of only 30%.

The drug has already been licensed to patients with ovarian and breast cancer harbouring BRCA mutations to slow or stop tumour growth. The TOPARP trial was led by teams at The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust.

Olaparib is an enzyme poly ADP ribose polymerase (PARP) inhibitor. The TOPARP trial set out to investigate clinically predictive biomarkers of PARP inhibitor sensitivity and identify the molecular signatures of tumour cells in responding and non-responding patients. Olaparib acts through inhibition of PARP enzymes involved in the DNA repair pathway of cancerous cells, leading to cell death.

The first TOPARP-A trial tested olaparib on advanced prostate cancer patients without initial identification of gene mutations within the tumour cells. After limited success, it was suggested that patients with mutations in DNA damage repair genes could benefit the most from the treatment. The second TOPARP-B trial was proposed to specifically target those patients harbouring mutations in DNA repair genes.

A total of 98 patients receiving treatment in 17 hospitals across the UK were recruited for the trial. The criteria included selecting patients with advanced prostate cancer only, those who had undergone previous heavy treatment with hormone therapy or chemotherapy, and those who’s tumour cells contained mutations in DNA repair genes.

The phase II trial showed promising results, with an overall of 47% of patients responding well to olaparib. Disease progression was halted for an average of 5.5 months, with the most common mutations lying in the BRCA genes, PALB2, CDK12, and ATM.

Over 80% of prostate cancer patients with BRCA gene mutations responded well to olaparib, and 40% remaining free from disease progression for more than a year. Over 50% of patients carrying PALB2 mutations and over 37% carrying ATM mutations responded well to olaparib. 20% of patients with other DNA repair gene alterations also responded well.

Following on from the successful results researchers suggested that routine tests should be carried out to identify DNA repair mutations in prostate cancer patients to select who may benefit most from using olaparib. Further studies at the ICR are seeking to discover ways of combining gene-targeted drugs with other medicines to keep cancer at bay for longer. With the Phase III trial for olaparib on the way, it is close to becoming the first genetically targeted treatment for prostate cancer.

The trial results were published in The Lancet Oncology, and funded by AstraZeneca, Cancer Research UK, Prostate Cancer UK, Movember, the Prostate Cancer Foundation, and the Experimental Cancer Medicine Centre (ECMC) Network.

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