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Targeting DNA repair in metastatic prostate cancer


Professor Richard Morgan, Anniversary Chair in Molecular Oncology.

One of the most significant challenges in treating cancer is its heterogeneous nature — it is a disease with highly variable origins, mutations, and behaviour, and consequently it also varies considerably with respect to its response to treatment.

Thus, for example, although some cancers will be sensitive to chemotherapy and/or radiotherapy, others will be highly resistant. An alternative approach to conventional chemotherapy and radiotherapy is the use of "molecular targeted therapy", which has developed rapidly over the last 20 years.

Molecular targeted therapy involves the use of drugs or antibodies that target specific proteins in the cancer cell. These proteins usually have important roles in cancer cells, for example in promoting cell division, but are generally less important in normal adult cells. Although targeted therapy has had a number of notable and dramatic successes in cancer treatment, a continuing problem is how to determine which cancers will be sensitive to these drugs, and hence which patients will derive the most benefit.

In the recent study "DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer" Joaquin Mateo and colleagues addressed the problem of identifying prostate cancer patients who would derive the greatest clinical benefit from olaparib, a drug that specifically targets a protein called PARP. PARP repairs DNA after it has been damaged, and generally cancer cells suffer DNA damage more frequently than normal cells, although this varies significantly between different tumours. Mateo and colleagues studied 50 patients with metastatic, castration-resistant prostate cancer: men whose disease has spread, and no longer responds to the standard therapy for this disease, which is to deprive the cancer cells of androgen through either removal of the testicles or by drugs that block androgen function.

These patients were treated with olaparib tablets at a dose of 400 mg twice daily, and the researchers measured the response to treatment by looking for a reduction of at least 50% in the prostate-specific antigen (PSA) level, or fewer tumour cells in the blood. The hypothesis tested by the researchers was that cancers showing a reduced ability to repair DNA damage would be more dependent on PARP, and thus more sensitive to olaparib. They therefore examined tumour samples for mutations or other genetic changes that stopped key DNA repair genes from working. Overall, 33% of the patients showed a response to olaparib treatment. However, 16 of the 50 patients were found to have cancers with mutations in DNA repair genes, and of these 14 (88%) had a response to olaparib. The authors concluded that the inactivation of DNA repair genes was a marker for olaparib sensitivity, and could form the basis of a test to select patients who would benefit from this treatment.

Although these findings are promising, there are a number of problems that need to be considered. Despite the very specific nature of olaparib, it still has side effects, as 20% of the patients suffered anaemia, and 12% suffered fatigue. However, the most significant barrier to the widespread clinical use of this test is an economic one. Although olaparib was previously shown to be effective in ovarian cancer, the National Institute for Health and Care Excellence (NICE) considers it to be too expensive, at £4,000/month, to justify its use in this malignancy. In addition, the cost of testing for mutations in DNA repair genes is significant. Difficult decisions therefore lie ahead on the road to the widespread use of olaparib for patients with metastatic prostate cancer.

Prof Richard Morgan, Professor of Molecular Oncology reacting to BBC News article.

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