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In men with metastatic castration-resistant prostate cancer carrying BRCA1, BRCA2 or ATM alterations who had progressed on hormonal therapy, the PARP inhibitor olaparib delayed progression and lengthened survival compared with another hormonal agent.
Phase 3 trial of 387 men with metastatic castration-resistant prostate cancer progressing on enzalutamide or abiraterone, with alterations in BRCA1, BRCA2 or ATM (cohort A) or 12 other homologous recombination genes (cohort B), randomised 2:1 to olaparib or physician's choice of enzalutamide or abiraterone.
In cohort A median progression-free survival was 7.4 versus 3.6 months (hazard ratio 0.34) and median overall survival 19.1 versus 14.7 months (hazard ratio 0.69 despite crossover); benefit was driven mainly by BRCA2.
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 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.
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.
The first molecularly stratified treatment in prostate cancer, and the proof that the synthetic lethality that works in ovarian and breast cancer works here too. Every PARP inhibitor now licensed in prostate cancer traces back to this trial.
Shares CDK12, TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later.
Shares TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer, TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer, Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later, ATM.
Shares CDK12, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, Base excision repair, PARP & alkylation damage, Synthetic lethality: paired dependencies.
Shares ATM, Germline BRCA mutation (gBRCA), Double-strand break repair: HR versus end joining, Homologous recombination deficiency (HRD).
Shares Base excision repair, PARP & alkylation damage, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining, Homologous recombination deficiency (HRD).
Shares PROfound, ATM, Homologous recombination deficiency (HRD), PARP.
Shares TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, Base excision repair, PARP & alkylation damage, Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later.
Shares Germline BRCA mutation (gBRCA), Double-strand break repair: HR versus end joining, Homologous recombination deficiency (HRD), Germline vs somatic mutations.