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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.
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.
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.
This is the paper Europe PMC returns for registry id NCT03732820 with the most citations, so it is the natural first reading for anyone following the PROpel trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
Germline and tumour testing for homologous recombination repair genes is now standard in metastatic prostate cancer, and olaparib is approved for BRCA-mutated disease after a hormonal agent.
The trial behind the second PARP inhibitor licensed in prostate cancer, and the evidence that a somatic BRCA alteration predicts response as well as an inherited one. Together with TOPARP-A it is why tumour as well as germline sequencing is recommended in metastatic disease.
The evidence that made germline testing standard for every man with metastatic prostate cancer, whatever his family history. It changes his treatment, because PARP inhibitors and platinum work better in these tumours, and it changes his relatives' screening, because BRCA2 carries breast, ovarian and pancreatic risk as well.
The genomic definition of advanced prostate cancer, and the evidence that made molecular testing standard in it. The 19.3 percent DNA repair figure is the direct ancestor of PROfound, TRITON3, PROpel and TALAPRO-2, and the 8 percent germline figure is why a tumour result in this disease has implications for a man's relatives.
Shares TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations, Inherited DNA-repair gene mutations in men with metastatic prostate cancer, Synthetic lethality and the tag prostate-evidence.
Shares 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, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations, Inherited DNA-repair gene mutations in men with metastatic prostate cancer and the tag prostate-evidence.
Shares Johann de Bono, The Institute of Cancer Research, The Royal Marsden, 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 and the tag prostate-evidence.
Shares SU2C-PCF: integrative clinical genomics of advanced prostate cancer, Homologous recombination deficiency (HRD), Next-generation sequencing (NGS), 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 and the tag prostate-evidence.
Shares SU2C-PCF: integrative clinical genomics of advanced prostate cancer, Homologous recombination deficiency (HRD), Next-generation sequencing (NGS), 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 and the tag prostate-evidence.
Shares Johann de Bono, 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, Acquired resistance to every therapy, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.
Shares Johann de Bono, 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, Acquired resistance to every therapy, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.
Shares 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, Acquired resistance to every therapy, Metastatic castration-resistant prostate cancer, New England Journal of Medicine and the tag prostate-evidence.