{"entity":{"id":"idea-prostate-hrr-testing-at-metastatic-diagnosis","kind":"idea","name":"Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later","aka":["HRR testing at metastatic diagnosis","germline and tumour DNA repair testing timing prostate"],"tldr":"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.","summary":"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.\n\nWhat 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.\n\nWhat any of this means for someone treated in Britain, from the screening committee's position and the NICE appraisals to scanner and radiotherapy capacity, waiting times and how to reach a trial, is on the UK and NHS pathway page for prostate cancer.","asOf":"2026-09-25","links":[],"tags":["prostate-evidence"],"related":["idea-prev-reflex-germline-testing","prostate-roadmap","targeted-therapy-roadmap"],"cancers":["prostate","prostate-mhspc","prostate-mcrpc","prostate-nmcrpc"],"sections":["diagnostics","targeted-therapy","prevention"],"technologies":["germline-testing","ngs","liquid-biopsy"],"targets":["brca","atm","cdk12"],"drugs":["olaparib","rucaparib","niraparib","talazoparib"],"companies":["astrazeneca","johnson-johnson","pfizer","myriad-genetics","foundation-medicine"],"institutions":[],"pathways":[],"terms":["genome-wide-loss-of-heterozygosity"],"trials":[],"people":[],"bottlenecks":["b-hereditary-risk","b-biomarker-validation","b-care-fragmentation","b-knowledge-diffusion"],"keyPapers":["paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","paper-abida-triton2-rucaparib-brca-jco-2020","paper-fizazi-triton3-rucaparib-nejm-2023","paper-nct04821622-n-engl-j-med-2026"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Reflex germline and tumour homologous recombination repair testing at the moment of metastatic diagnosis, rather than on clinician request at castration resistance, increases the proportion of eligible men who receive a PARP inhibitor in the setting where it is licensed, increases the proportion of first-degree relatives who are offered cascade testing, and does so at a testing cost per actionable result lower than the cost of the current late pathway, which sequences men who never reach the relevant line.","rationale":"Three things make the timing argument rather than the testing argument the live one. First, carriers cannot be identified clinically: Pritchard showed mutation frequency does not differ by family history or age, so selective testing misses most of them. Second, the drug has moved: the licensed settings for PARP inhibition now start at first-line castration-resistant and, in TALAPRO-3 and AMPLITUDE, hormone-sensitive disease, which is before most men are currently tested. Third, the test result has a second use that is lost entirely by testing late, which is the 8 percent of men in the Stand Up To Cancer cohort with an actionable pathogenic germline alteration whose relatives carry breast, ovarian and pancreatic risk. Testing at metastatic diagnosis also takes place when tumour tissue is more likely to be available and adequate; TRITON3 screened 4,855 men to randomise 405, which is the cost of finding carriers late and one at a time.","test":"A stepped-wedge implementation trial across cancer networks, switching from clinician-requested testing to a reflex order fired by the coding of metastatic prostate cancer. Co-primary outcomes: the proportion of men with a homologous recombination repair result available before first-line systemic treatment is chosen, and the proportion of identified germline carriers whose first-degree relatives are offered testing within 12 months. Secondary outcomes: PARP inhibitor use in the licensed setting, turnaround time, tissue adequacy failure rate, and cost per actionable result against the current pathway. Two to three years, and it can be run inside an existing service rather than as a new trial infrastructure.","maturity":"early-clinical","actor":"clinic","cost":"medium","horizonYears":3},"route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/","neighbours":{"idea":[{"id":"idea-prev-reflex-germline-testing","kind":"idea","name":"Automatic germline testing for every cancer type where it changes care","route":"/ideas/idea-prev-reflex-germline-testing/"}],"roadmap":[{"id":"prostate-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/prostate-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","route":"/cancers/prostate-mhspc/"},{"id":"prostate-nmcrpc","kind":"cancer","name":"Non-metastatic castration-resistant prostate cancer","route":"/cancers/prostate-nmcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"prevention","kind":"section","name":"Prevention & Risk","route":"/fronts/prevention/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"term":[{"id":"genome-wide-loss-of-heterozygosity","kind":"term","name":"Genome-wide loss of heterozygosity (gLOH)","route":"/terms/genome-wide-loss-of-heterozygosity/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"cdk12","kind":"target","name":"CDK12","route":"/targets/cdk12/"}],"drug":[{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"rucaparib","kind":"drug","name":"Rucaparib","route":"/drugs/rucaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}],"company":[{"id":"astrazeneca","kind":"company","name":"AstraZeneca","route":"/companies/astrazeneca/"},{"id":"foundation-medicine","kind":"company","name":"Foundation Medicine (Roche)","route":"/companies/foundation-medicine/"},{"id":"johnson-johnson","kind":"company","name":"Johnson & Johnson","route":"/companies/johnson-johnson/"},{"id":"myriad-genetics","kind":"company","name":"Myriad Genetics","route":"/companies/myriad-genetics/"},{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-care-fragmentation","kind":"bottleneck","name":"Fragmented care and guideline gaps","route":"/bottlenecks/b-care-fragmentation/"},{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"},{"id":"b-knowledge-diffusion","kind":"bottleneck","name":"Knowledge reaches practice too slowly","route":"/bottlenecks/b-knowledge-diffusion/"}],"paper":[{"id":"paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","kind":"paper","name":"Inherited DNA-repair gene mutations in men with metastatic prostate cancer","route":"/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/"},{"id":"paper-magnitude-j-clin-oncol-2023","kind":"paper","name":"Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer","route":"/key-papers/paper-magnitude-j-clin-oncol-2023/"},{"id":"paper-propel-lancet-oncol-2023","kind":"paper","name":"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","route":"/key-papers/paper-propel-lancet-oncol-2023/"},{"id":"paper-nct04821622-n-engl-j-med-2026","kind":"paper","name":"PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer","route":"/key-papers/paper-nct04821622-n-engl-j-med-2026/"},{"id":"paper-profound-nejm-2020","kind":"paper","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","route":"/key-papers/paper-profound-nejm-2020/"},{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","kind":"paper","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/"},{"id":"paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","kind":"paper","name":"SU2C-PCF: integrative clinical genomics of advanced prostate cancer","route":"/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/"},{"id":"paper-talapro-2-lancet-2023","kind":"paper","name":"Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial","route":"/key-papers/paper-talapro-2-lancet-2023/"},{"id":"paper-abida-triton2-rucaparib-brca-jco-2020","kind":"paper","name":"TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","route":"/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/"},{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","kind":"paper","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/"}]}}