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2019 ASCO: TOPARP-B Finds Olaparib Shows Efficacy in Men With BRCA-Mutant Prostate Cancer

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Key Points

  • Overall, 47% of men with DNA repair defects in their tumors responded to olaparib, and the drug delayed progression for a median of 5.5 months.
  • 80% of men with BRCA1/2-mutated prostate cancer responded to olaparib.
  • 57% of patients with mutations in the PALB2 gene responded to olaparib.

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib may benefit some men with prostate cancer, according to findings from the phase II TOPARP-B trial presented by Mateo et al at the 2019 ASCO Annual Meeting (Abstract 5005).  

Olaparib previously showed activity against metastatic castration-resistant prostate cancer in the TOPARP-A trial, results of which were published in The New England Journal of Medicine by Mateo et al in 2015. In this follow-up study, researchers sought to investigate how effective the drug was in men with mutations in any genes known to have a role in repairing DNA—including BRCA1/2.

Methods

The researchers initially screened the tumors of 592 men and found 27% had alterations in one or more genes linked to repairing damaged DNA. After screening and evaluation, they enrolled 98 patients with DNA repair mutations onto the trial.

BRCA mutations were by far the most common mutation—found in 33% of the tumors with a DNA repair mutation. Other common DNA repair mutations were found in ATMCDK12CHEK2, and PALB2.

Results

Overall, 47% of men with DNA repair defects in their tumors responded to olaparib, and the drug delayed disease progression for a median of 5.5 months—2.7 months longer than previous trial, TOPARP-A, found in men with advanced prostate cancer who weren’t selected for treatment based on gene mutations.

Approximately 80% of men with BRCA1/2-mutated prostate cancer responded to olaparib, and even though men in the trial had advanced, heavily pretreated prostate cancer, olaparib delayed progression of the disease in these patients for a median of 8.3 months. About 35% were free of progression for more than 1 year.

Among patients with mutations in the PALB2 gene, 57% responded to olaparib—the next highest response after those with BRCA1 or BRCA2 mutations—and 25% of men with CDK12 mutations experienced a response.

A phase III trial of the drug is now underway.

Looking Ahead

Study author Johann de Bono, MD, PhD, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and consultant medical oncologist at The Royal Marsden, said in a press release, “Our study is exciting because it shows just how powerful genetic targeting and precision medicine can be. We have shown that by testing for DNA repair mutations we can select those patients with a high chance of responding well and for a long time to the targeted drug olaparib. We were delighted to see such strong responses in men with very advanced cancers where BRCA mutations and other faults in DNA repair genes were present within their tumours. The next phase of the trial is now underway and, if the results look as good as we hope, we should see olaparib starting to reach the clinic for men with prostate cancer in the next couple of years.”

Disclosure: The trial received funding from AstraZeneca, Cancer Research UK, the Prostate Cancer Foundation, Stand Up To Cancer, Prostate Cancer UK, and the Movember Foundation. It was supported by the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR), and the Experimental Cancer Medicine Centre (ECMC) network. For full disclosures of the study authors, visit coi.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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