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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.
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%).
In plain words · DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
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.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
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.
“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).”
TALZENNA prescribing information, patient selection 2.1| Threshold | Drug | Cancer | Regulator | Source |
|---|---|---|---|---|
| Deleterious or suspected deleterious germline or somatic mutation in ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L | Olaparib | Metastatic castration-resistant prostate cancer | FDA | label |
| Deleterious or suspected deleterious BRCA1 or BRCA2 mutation, with abiraterone and prednisone or prednisolone | Olaparib | Metastatic castration-resistant prostate cancer | FDA | label |
| Deleterious BRCA1 or BRCA2 mutation, germline and/or somatic | Rucaparib | Metastatic castration-resistant prostate cancer | FDA | label |
| Deleterious or suspected deleterious BRCA2 mutation, with abiraterone acetate and prednisone | Niraparib | Metastatic hormone-sensitive prostate cancer | FDA | label |
| Deleterious or suspected deleterious BRCA1 or BRCA2 mutation, with abiraterone acetate and prednisone | Niraparib | Metastatic castration-resistant prostate cancer | FDA | label |
| Mutation in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2 or RAD51C, with enzalutamide The label states that an FDA-approved test for the detection of HRR gene mutations for use with TALZENNA is not currently available. | Talazoparib | Metastatic castration-resistant prostate cancer | FDA | label |
Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.
It identifies a way that a good test produces a wrong answer, and it names the fix. Any plasma repair-gene result used to decide on a PARP inhibitor should be run with a paired blood control, or an older man may be treated for a marrow clone rather than for his prostate cancer.
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.
It establishes that PARP inhibitor resistance in prostate cancer is a restored repair pathway rather than a bypass, which is why platinum and PARP inhibitors lose activity together, and it is the argument for sampling plasma rather than one lesion at progression.
The evidence that made germline testing standard for every man with metastatic prostate cancer, whatever his family history. It changes his treatment, because PARP inhibitors and platinum work better in these tumours, and it changes his relatives' screening, because BRCA2 carries breast, ovarian and pancreatic risk as well.
The genomic definition of advanced prostate cancer, and the evidence that made molecular testing standard in it. The 19.3 percent DNA repair figure is the direct ancestor of PROfound, TRITON3, PROpel and TALAPRO-2, and the 8 percent germline figure is why a tumour result in this disease has implications for a man's relatives.
Shares Metastatic hormone-sensitive prostate cancer, Castration-resistant prostate cancer (CRPC), Comprehensive genomic profiling, Prostate cancer and the tags biomarker, prostate.
Shares Comprehensive genomic profiling, Prostate cancer and the tags biomarker, prostate.
Shares Metastatic castration-resistant prostate cancer, Prostate cancer and the tags biomarker, prostate.
Shares CDK12, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, Rucaparib, Synthetic lethality.
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 Liquid biopsy (ctDNA) and the tag biomarker.
Shares Circulating tumour DNA fraction (and what a negative plasma result means), Metastatic hormone-sensitive prostate cancer, Castration-resistant prostate cancer (CRPC), Metastatic castration-resistant prostate cancer and the tag biomarker.