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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.
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.
The 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.
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.
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.
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 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 Inherited DNA-repair gene mutations in men with metastatic prostate cancer, Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later, ATM and the tag prostate-evidence.
Shares Karim Fizazi, Radiographic progression-free survival (rPFS), Enzalutamide, 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 Radiographic progression-free survival (rPFS), Abiraterone acetate, Enzalutamide, 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 Karim Fizazi, Radiographic progression-free survival (rPFS), Enzalutamide, 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 Radiographic progression-free survival (rPFS), Abiraterone acetate, Enzalutamide, 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 Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, Abiraterone acetate, Enzalutamide, 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 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, Docetaxel, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.