{"entity":{"id":"hrr-gene-mutation","kind":"biomarker","name":"Homologous recombination repair gene mutation in prostate cancer","aka":["HRR gene mutation","HRRm","HRR-mutated","homologous recombination repair mutation","DNA repair gene mutation","BRCA2 prostate","ATM prostate","CDK12 prostate"],"tldr":"A fault in one of the genes a cell uses to mend broken DNA. It decides whether a PARP inhibitor can be prescribed, but the list of genes that counts is different for each of the four approved routes, and the evidence behind them is mostly evidence about BRCA2.","summary":"Between a fifth and a quarter of metastatic prostate cancers carry an alteration in this gene set: BRCA2, BRCA1 and ATM aberrations alone were 19.3% of 150 castration-resistant tumours (Robinson 2015). About half of that is inherited: germline mutations in 20 DNA repair genes were present in 82 of 692 men with metastatic disease, 11.8%, led by BRCA2 at 5.3%, ATM at 1.6%, CHEK2 at 1.9% and BRCA1 at 0.9%, with no difference by family history or age at diagnosis (Pritchard 2016). The four approved routes ask for four different gene lists. Olaparib alone names 14 genes; olaparib with abiraterone names BRCA1 and BRCA2 only; rucaparib names BRCA1 and BRCA2 only; niraparib with abiraterone names BRCA2 alone in castration-sensitive disease and BRCA1 or BRCA2 in castration-resistant disease; talazoparib with enzalutamide names 12 genes, six of which are not on olaparib's list, including MLH1, a mismatch repair gene, and the label states that no FDA-approved test for detecting them with talazoparib is currently available. The response data do not spread evenly across those lists: in PROfound, confirmed objective response among men with a single-gene alteration and measurable disease was 24 of 43 with BRCA2 (56%), 3 of 30 with ATM (10%) and 2 of 34 with CDK12 (6%).","asOf":"2026-09-25","links":[{"label":"LYNPARZA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa"},{"label":"TALZENNA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fd147f-a77e-4a0b-9280-e82ecc41b4be"},{"label":"AKEEGA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8245a990-3268-4613-b5c5-9537858a1eb9"},{"label":"RUBRACA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e"},{"label":"Pritchard et al., N Engl J Med 2016: inherited DNA-repair gene mutations in 692 men with metastatic prostate cancer unselected for family history","url":"https://doi.org/10.1056/NEJMoa1603144"}],"tags":["biomarker","prostate"],"related":["brca-germline","brca-somatic","hrd-positive"],"cancers":["prostate","prostate-mcrpc","prostate-mhspc"],"sections":[],"technologies":["cgp","germline-testing","liquid-biopsy","parp-inhibitor"],"targets":["brca","atm","cdk12","palb2","chek2","rad51c","rad51d","bard1","brip1","parp"],"drugs":["olaparib","rucaparib","niraparib","talazoparib"],"companies":[],"institutions":[],"pathways":["homologous-recombination-repair","base-excision-repair-parp","synthetic-lethality-map","ddr"],"terms":["germline-vs-somatic","gbrca-mutation","hrd","brca-reversion-mutations","synthetic-lethality","vus","castration-resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015","paper-abida-triton2-rucaparib-brca-jco-2020","paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017","paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"target":"brca","measurement":"sequencing-variant","scoringRule":{"text":"A deleterious or suspected deleterious alteration in a homologous recombination repair gene on tumour tissue or, where the label allows it, on blood or plasma, reported gene by gene and with germline status stated separately, because the eligible gene list differs by medicine and by disease state.","quote":"Select patients for the treatment of HRR gene-mutated mCRPC with TALZENNA based on the presence of alterations in genes directly or indirectly involved in HRR (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C).","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fd147f-a77e-4a0b-9280-e82ecc41b4be","sourceLabel":"TALZENNA prescribing information, patient selection 2.1"},"thresholds":[{"value":"Deleterious or suspected deleterious germline or somatic mutation in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L","drugId":"olaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.","status":"current"},{"value":"Deleterious or suspected deleterious BRCA1 or BRCA2 mutation, with abiraterone and prednisone or prednisolone","drugId":"olaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=741ff3e3-dc1a-45a6-84e5-2481b27131aa","quote":"in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).","status":"current"},{"value":"Deleterious BRCA1 or BRCA2 mutation, germline and/or somatic","drugId":"rucaparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0295d202-1cfe-7659-e063-6294a90a476e","quote":"for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy.","status":"current"},{"value":"Deleterious or suspected deleterious BRCA2 mutation, with abiraterone acetate and prednisone","drugId":"niraparib","cancerId":"prostate-mhspc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8245a990-3268-4613-b5c5-9537858a1eb9","quote":"AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA2-mutated (BRCA2m) metastatic castration-sensitive prostate cancer (mCSPC).","status":"current"},{"value":"Deleterious or suspected deleterious BRCA1 or BRCA2 mutation, with abiraterone acetate and prednisone","drugId":"niraparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8245a990-3268-4613-b5c5-9537858a1eb9","quote":"AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).","status":"current"},{"value":"Mutation in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 or RAD51C, with enzalutamide","drugId":"talazoparib","cancerId":"prostate-mcrpc","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fd147f-a77e-4a0b-9280-e82ecc41b4be","quote":"TALZENNA is indicated in combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).","status":"current","note":"The label states that an FDA-approved test for the detection of HRR gene mutations for use with TALZENNA is not currently available."}],"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"This result decides whether a PARP inhibitor tablet is an option. Two things are worth asking about. First, which gene it is: the evidence is strongest for BRCA2 and much weaker for the others, so it is reasonable to ask what the chance of benefit is for your particular gene. Second, whether it is inherited: a tumour test cannot tell you, and a separate blood or saliva test is needed, which also matters for your children and your brothers and sisters."},"route":"/biomarkers/hrr-gene-mutation/","neighbours":{"biomarker":[{"id":"ctdna-tumour-fraction","kind":"biomarker","name":"Circulating tumour DNA fraction (and what a negative plasma result means)","route":"/biomarkers/ctdna-tumour-fraction/"},{"id":"brca-germline","kind":"biomarker","name":"Germline BRCA1/2 pathogenic variant (gBRCAm)","route":"/biomarkers/brca-germline/"},{"id":"hrd-positive","kind":"biomarker","name":"HRD-positive (genomic instability score)","route":"/biomarkers/hrd-positive/"},{"id":"brca-somatic","kind":"biomarker","name":"Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations","route":"/biomarkers/brca-somatic/"}],"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","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"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/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"bard1","kind":"target","name":"BARD1","route":"/targets/bard1/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"brip1","kind":"target","name":"BRIP1","route":"/targets/brip1/"},{"id":"cdk12","kind":"target","name":"CDK12","route":"/targets/cdk12/"},{"id":"chek2","kind":"target","name":"CHEK2","route":"/targets/chek2/"},{"id":"palb2","kind":"target","name":"PALB2","route":"/targets/palb2/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"rad51c","kind":"target","name":"RAD51C","route":"/targets/rad51c/"},{"id":"rad51d","kind":"target","name":"RAD51D","route":"/targets/rad51d/"}],"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/"}],"pathway":[{"id":"base-excision-repair-parp","kind":"pathway","name":"Base excision repair, PARP & alkylation damage","route":"/pathways/base-excision-repair-parp/"},{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"}],"term":[{"id":"brca-reversion-mutations","kind":"term","name":"BRCA reversion mutations","route":"/terms/brca-reversion-mutations/"},{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"gbrca-mutation","kind":"term","name":"Germline BRCA mutation (gBRCA)","route":"/terms/gbrca-mutation/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"},{"id":"vus","kind":"term","name":"Variant of uncertain significance (VUS)","route":"/terms/vus/"}],"paper":[{"id":"paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017","kind":"paper","name":"Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors","route":"/key-papers/paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017/"},{"id":"paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021","kind":"paper","name":"Association of clonal haematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference","route":"/key-papers/paper-jensen-clonal-haematopoiesis-cfdna-interference-prostate-jama-oncol-2021/"},{"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-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-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/"}]}}