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About one man in eight with prostate cancer that has spread carries an inherited DNA repair fault, and about one in five has one in the tumour. The drugs for those faults have moved to the beginning of treatment, but the test is still usually done near the end, when it is too late to use the result.
The evidence for testing is settled. Pritchard found presumed deleterious germline DNA repair mutations in 11.8 percent of 692 men with metastatic prostate cancer, against 4.6 percent in localised disease and 2.7 percent in a population without a cancer diagnosis, and found no relation to family history or age at diagnosis. Robinson found BRCA2, BRCA1 and ATM aberrations in 19.3 percent of 150 prospectively sequenced metastatic biopsies, and Chung found homologous recombination repair alterations in 23 percent of 3,476 routinely profiled tumours. Both germline and somatic BRCA alterations predict response to a PARP inhibitor, as TRITON2 showed.
What has changed is when the answer is needed. PARP inhibitors were licensed after an androgen receptor drug and a taxane; PROpel, TALAPRO-2 and MAGNITUDE moved them to first-line castration-resistant disease, and TALAPRO-3 and AMPLITUDE have moved them into hormone-sensitive disease. A result that arrives after two lines of treatment can no longer be acted on in the setting where the drug is licensed. The proposal is to make combined germline and tumour homologous recombination repair testing an automatic step triggered by the diagnosis of metastasis, in the same way a hormone receptor stain is triggered by a breast biopsy, with the result reported before the first systemic treatment is chosen and with the germline half routed to a family testing pathway.
UK and NHS specifics (the National Screening Committee position, NICE technology appraisals and their recommendation numbers, Cancer Drugs Fund status, magnetic resonance imaging and radiotherapy capacity, National Prostate Cancer Audit indicators and trial access) belong on the UK and NHS page for prostate cancer and are not restated here.
This is the paper Europe PMC returns for registry id NCT04821622 with the most citations, so it is the natural first reading for anyone following the TALAPRO-3 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.
This is the paper Europe PMC returns for registry id NCT03748641 with the most citations, so it is the natural first reading for anyone following the MAGNITUDE 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.
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.
This is the paper Europe PMC returns for registry id NCT03395197 with the most citations, so it is the natural first reading for anyone following the TALAPRO-2 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.
The randomised proof for PARP inhibition in BRCA-altered prostate cancer, and the clearest evidence that the homologous recombination repair gene list should not be used as a single yes-or-no test. ATM-altered disease needs a different answer, and does not yet have one.
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.
What a prostate cancer sequencing report looks like in practice, and the numerical basis for two clinical rules: do not expect checkpoint immunotherapy to work unless the tumour is mismatch repair deficient, and do not treat a CDK12 alteration as if it were a BRCA alteration.
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 SU2C-PCF: integrative clinical genomics of advanced prostate cancer, 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, Biomarkers are not validated or standardised and the tag prostate-evidence.
Shares Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, 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, Biomarkers are not validated or standardised and the tag prostate-evidence.
Shares Inherited DNA-repair gene mutations in men with metastatic prostate cancer, Inherited risk is mostly unidentified, 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, Germline (hereditary) testing and the tag prostate-evidence.
Shares SU2C-PCF: integrative clinical genomics of advanced prostate cancer, 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, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.
Shares Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, 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, Biomarkers are not validated or standardised, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.
Shares 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, Biomarkers are not validated or standardised, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.
Shares Non-metastatic castration-resistant prostate cancer, Metastatic hormone-sensitive prostate cancer, 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, Fragmented care and guideline gaps and the tag prostate-evidence.