Olaparib ‘Highly Effective’ In DNA Repair-Deficient Metastatic Prostate Cancer

Blocking poly(adenosine diphosphate–ribose) polymerase with olaparib elicits an anti-tumour response in a subset of men with metastatic prostate cancer

medwireNews: Previously-treated metastatic prostate cancer patients with tumours harbouring mutations in DNA repair genes could benefit from treatment with the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib, findings indicate.

In the phase II trial reported in The New England Journal of Medicine, 50 patients with metastatic, castration-resistant disease who had progressed after up to two regimens of chemotherapy were given open-label olaparib 400 mg twice daily.

After a median follow-up of 14.4 months, 16 (33%) of 49 evaluable study participants achieved a response, defined as an objective response as per RECIST 1.1 criteria, a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumour-cell count to below 5 cells per 7.5 mL of blood.

Whole-exome and transcriptome sequencing of fresh-frozen or archived (in six cases) biopsy samples showed that 16 patients had tumours with homozygous deletions, deleterious alterations or both in genes known to be involved in DNA repair, such as BRCA1,BRCA2,ATM and CHEK2.

Fourteen (88%) of the patients with DNA-repair defects had a response to the PARP inhibitor compared with just two (6%) of 33 mutation-negative patients, a significant difference, report Johann de Bono, from the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in Sutton, UK, and fellow investigators of the TOPARP-A trial.

Radiological progression-free survival was also significantly improved in men with tumours harbouring compared with those lacking the relevant aberrations, at a median of 9.8 versus 2.7 months. And overall survival was longer in men with than in those without alterations, although the difference only tended to significance.

The most frequent grade 3 or 4 adverse event attributed to olaparib therapy was anaemia (20%), followed by fatigue (12%), leukopenia (6%), thrombocytopenia (4%) and neutropenia (4%). The olaparib dose was reduced in 13 participants, while three discontinued treatment as a result of unacceptable toxicity.

“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”, Johann de Bono said in a press release.

“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.

“I hope it won’t be long before we are using olaparib in the clinic to treat prostate cancer, or before genomic stratification of cancers becomes a standard in this and other cancers.”

Reference

Mateo J, Carreira S, Sandhu S,et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.N Engl J Med2015; 373:1697–1708. doi: 10.1056/NEJMoa1506859

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