# TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer

Source: https://onco.cc/key-papers/paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015/  
OnCo record `paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Fifty men whose prostate cancer had exhausted every standard treatment were given a PARP inhibitor and biopsied. A third responded, and almost all the responders were the ones with a broken DNA repair gene, including every man who had lost BRCA2.

## Summary

Joaquin Mateo, Johann de Bono and colleagues at the Institute of Cancer Research and the Royal Marsden ran a phase 2 trial of olaparib 400 mg twice daily in 50 heavily pre-treated men with metastatic castration-resistant prostate cancer, with a mandated tumour biopsy and targeted next-generation sequencing, exome and transcriptome analysis in every patient.

The design is why it matters. The trial was not restricted to men with known mutations; it treated everyone and then asked which ones responded. Sixteen of 49 evaluable men responded, and 14 of the 16 men with DNA repair defects did, with a biomarker specificity of 94 percent. That is a prospectively defined predictive biomarker read out of an unselected cohort, which is a stronger form of evidence than a biomarker-selected trial, and it is the trial PROfound was built from.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Also known as: TOPARP-A; Mateo 2015 olaparib prostate
- Tags: prostate-evidence
- Journal: New England Journal of Medicine
- Year: 2015
- DOI: 10.1056/nejmoa1506859
- Authors: Mateo J, Carreira S, Sandhu S, et al.
- Findings: 16 of 49 evaluable patients responded (33 percent; 95 percent confidence interval 20 to 48), with 12 receiving the study treatment for more than 6 months.; Next-generation sequencing identified homozygous deletions, deleterious mutations or both in DNA repair genes, including BRCA1 and BRCA2, ATM, Fanconi anaemia genes and CHEK2, in 16 of 49 evaluable patients (33 percent).; Of those 16, 14 (88 percent) responded to olaparib, including all 7 patients with BRCA2 loss (4 biallelic somatic, 3 germline) and 4 of 5 with ATM aberrations.; The specificity of the biomarker suite was 94 percent.; All patients had received docetaxel, 49 of 50 (98 percent) abiraterone or enzalutamide and 29 (58 percent) cabazitaxel; anaemia in 10 of 50 (20 percent) and fatigue in 6 (12 percent) were the most common grade 3 or 4 adverse events.
- What it means: The first molecularly stratified treatment in prostate cancer, and the proof that the synthetic lethality that works in ovarian and breast cancer works here too. Every PARP inhibitor now licensed in prostate cancer traces back to this trial.
- Caveats: 50 patients, single-arm, in a heavily pre-treated population; the response rate is not a survival benefit.; The composite response definition allowed objective response, a 50 percent prostate-specific antigen fall or circulating tumour cell conversion, which is broader than RECIST alone.; The ATM signal here (4 of 5 responding) was not confirmed in the larger randomised trials: TRITON3 found no benefit in the ATM subgroup.

## Sources

- N Engl J Med 2015: https://doi.org/10.1056/nejmoa1506859
- PubMed: https://pubmed.ncbi.nlm.nih.gov/26510020/
- ClinicalTrials.gov NCT01682772: https://clinicaltrials.gov/study/NCT01682772

## Connected records

- key papers: [Inherited DNA-repair gene mutations in men with metastatic prostate cancer](https://onco.cc/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/), [Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial](https://onco.cc/key-papers/paper-propel-lancet-oncol-2023/), [PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations](https://onco.cc/key-papers/paper-profound-nejm-2020/), [SU2C-PCF: integrative clinical genomics of advanced prostate cancer](https://onco.cc/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/), [TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration](https://onco.cc/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/)
- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [ATM](https://onco.cc/targets/atm/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/)
- drugs: [Olaparib](https://onco.cc/drugs/olaparib/)
- institutions: [The Institute of Cancer Research](https://onco.cc/institutions/icr-london/), [The Royal Marsden](https://onco.cc/institutions/royal-marsden/)
- terms: [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- people: [Johann de Bono](https://onco.cc/people/johann-de-bono/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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