Olaparib Shows Metastatic Castration-Resistant Prostate Cancer Potential

PARP inhibitor therapy shows promise for the treatment of metastatic castration-resistant prostate cancer in men with DNA repair gene mutations

medwireNews: Olaparib was effective for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in almost a third of men, suggests results of the TOPARP-A trial reported at the American Association of Cancer Research meeting, held this week in Philadelphia, Pennsylvania, USA.

The overall response rate in the phase II trial of the PARP inhibitor was 32.7%, as defined by RECIST 1.1 objective response criteria and/or a prostate-specific antigen decrease of at least 50% and/or a circulating tumour cell count decrease from over 5 per 7.5 mL of blood to below 5 per 7.5 mL of blood.

In all, 11 of the 49 evaluated patients continued treatment for over 6 months and four patients did so for at least 1 year.

The patient population was unselected and all had previously received docetaxel alongside abiraterone and/or cabazitaxel for their mCRPC, said presenting author Joaquin Mateo, from The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust in London, UK, and team.

But next generation sequencing revealed that 32.7% of the patients had homozygous deletions and/or deleterious mutations in DNA repair genes, and 87.5% of these carriers responded to olaparib.

This included all seven patients showing somatic or germline loss of BRCA2 and four of the five patients with ATM truncations, but none of the patients showing PTEN loss or ERG rearrangements.

Writing in a press release, chief investigator Johann de Bono, also from The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, commented: "Our trial shows that olaparib is effective in men with defects in DNA repair genes who do not necessarily have an inherited risk of cancer - and that we can pick up these defects in the clinic.”

“This opens up the exciting possibility of delivering precise treatment for advanced prostate cancer, guided by genomic testing and based on the particular molecular characteristics of patients' tumours.”

Olaparib was associated with grade 3 or more symptoms of severe anaemia in 20% of patients and of fatigue in 12%, with a dose reduction necessary in 26% of the population.

TOPARP-B will now focus on assessing the efficacy of olaparib in men with known DNA repair mutations, the researchers conclude.


Mateo J, Sandhu S, Miranda S, et al. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. Presented at American Association of Cancer Research Annual Meeting; 2015 April 18-22; Philadelphia, Pennsylvania, USA

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