{"entity":{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","kind":"paper","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","aka":["TRITON3","Fizazi 2023 rucaparib randomised"],"tldr":"The randomised confirmation that a PARP inhibitor beats the alternatives in men with a BRCA fault, nearly doubling the time before the cancer grew on scans. In men with an ATM fault instead, it did nothing.","summary":"Karim Fizazi and the TRITON3 investigators randomised 405 men with metastatic castration-resistant prostate cancer and a BRCA1, BRCA2 or ATM alteration, after progression on a second-generation androgen receptor pathway inhibitor, in a 2 to 1 ratio to rucaparib or a physician's choice control of docetaxel, abiraterone or enzalutamide.\n\nThe trial answers two questions. In the BRCA subgroup, imaging-based progression-free survival was 11.2 against 6.4 months, hazard ratio 0.50. In the exploratory ATM subgroup it was 8.1 against 6.8 months with a hazard ratio of 0.95, which is to say no effect. The lesson is that homologous recombination repair is not one biomarker: grouping ATM with BRCA in a single test result and treating on it will produce treatment that does not work. The screening figure is also worth noting: 4,855 men were prescreened or screened to randomise 405.","asOf":"2026-09-25","links":[{"label":"N Engl J Med 2023","url":"https://doi.org/10.1056/nejmoa2214676"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/36795891/"},{"label":"ClinicalTrials.gov NCT02975934","url":"https://clinicaltrials.gov/study/NCT02975934"}],"tags":["prostate-evidence"],"related":["paper-abida-triton2-rucaparib-brca-jco-2020","paper-profound-nejm-2020","paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016","prostate-roadmap"],"cancers":["prostate","prostate-mcrpc"],"sections":["targeted-therapy"],"technologies":[],"targets":["brca","atm"],"drugs":["rucaparib","docetaxel","abiraterone","enzalutamide"],"companies":["clovis-oncology"],"institutions":[],"pathways":[],"terms":["hrd","synthetic-lethality","genome-wide-loss-of-heterozygosity","radiographic-progression-free-survival"],"trials":[],"people":["karim-fizazi"],"bottlenecks":["b-biomarker-validation","b-trial-enrolment","b-resistance"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2023,"doi":"10.1056/nejmoa2214676","pmid":"36795891","authors":"Fizazi K, Piulats JM, Reaume MN, et al.","paperType":"rct","findings":["Of 4,855 men who underwent prescreening or screening, 270 were assigned to rucaparib and 135 to a control medication; 201 and 101 respectively had a BRCA alteration.","At 62 months, imaging-based progression-free survival in the BRCA subgroup was 11.2 months with rucaparib against 6.4 months with control (hazard ratio 0.50; 95 percent confidence interval 0.36 to 0.69).","In the intention-to-treat population it was 10.2 against 6.4 months (hazard ratio 0.61; 0.47 to 0.80; P less than 0.001 for both comparisons).","In the exploratory ATM subgroup, imaging-based progression-free survival was 8.1 months with rucaparib against 6.8 months with control (hazard ratio 0.95; 0.59 to 1.52).","The most frequent adverse events with rucaparib were fatigue and nausea."],"whatItMeans":"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.","caveats":["The primary endpoint is imaging-based progression-free survival, not overall survival; the control arm allowed another androgen receptor pathway inhibitor, which is a weak comparator after progression on one.","4,855 men screened for 405 randomised shows how much testing capacity a biomarker-selected trial in this disease consumes.","The ATM result is exploratory and the subgroup is small, but it points the same way as every other dataset in the field."],"changedPractice":true,"participants":405},"route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/","neighbours":{"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-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-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/"}],"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/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"}],"drug":[{"id":"abiraterone","kind":"drug","name":"Abiraterone acetate","route":"/drugs/abiraterone/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"enzalutamide","kind":"drug","name":"Enzalutamide","route":"/drugs/enzalutamide/"},{"id":"rucaparib","kind":"drug","name":"Rucaparib","route":"/drugs/rucaparib/"}],"company":[{"id":"clovis-oncology","kind":"company","name":"Clovis Oncology","route":"/companies/clovis-oncology/"}],"term":[{"id":"genome-wide-loss-of-heterozygosity","kind":"term","name":"Genome-wide loss of heterozygosity (gLOH)","route":"/terms/genome-wide-loss-of-heterozygosity/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"radiographic-progression-free-survival","kind":"term","name":"Radiographic progression-free survival (rPFS)","route":"/terms/radiographic-progression-free-survival/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"person":[{"id":"karim-fizazi","kind":"person","name":"Karim Fizazi","route":"/people/karim-fizazi/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-trial-enrolment","kind":"bottleneck","name":"Trials enrol too few, too slowly","route":"/bottlenecks/b-trial-enrolment/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"idea":[{"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","route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/"}]}}