Variant cheat sheet · metastatic prostate cancer
BRCA2 in metastatic castration-resistant prostate cancer
Free clinical reference. Educational use only — not a substitute for professional medical advice.
TL;DR
BRCA2 (and the broader HRR panel: BRCA1, ATM, CHEK2, PALB2, RAD51 family) in mCRPC is AMP/ASCO/CAP Tier I-A for olaparib (PROfound, post-androgen receptor-targeted therapy), talazoparib + enzalutamide (TALAPRO-2, first-line mCRPC), and niraparib + abiraterone (MAGNITUDE, BRCA-positive 1L). Germline + somatic testing is standard at mCRPC diagnosis.
Biology
BRCA2 loss in prostate cancer recapitulates the synthetic-lethal vulnerability seen in BRCA-mutant breast and ovarian cancers. PARP inhibition prevents single-strand break repair; without competent homologous recombination, the cell accumulates lethal double-strand breaks. BRCA2 mutations also drive aggressive disease biology and shorter time to castration resistance, independent of treatment response.
Epidemiology
Germline BRCA2 mutations occur in roughly 5-8% of mCRPC and somatic mutations add a few percent more. The broader HRR-gene panel positivity rate is ~20-25% of mCRPC, depending on testing scope.
Detection
- Germline testing at mCRPC diagnosis (NCCN guidance — licensed content, not paraphrased here).
- Somatic NGS on tumor or plasma ctDNA: FoundationOne CDx, Tempus xT, Caris MI Profile, Guardant360 CDx.
- HRD-by-genomic-scar assays less established in prostate than ovarian; gene-level mutations remain the actionable readout.
FDA-approved targeted therapies
| Drug | Indication | Line | Tier |
|---|---|---|---|
| Olaparib | HRR-mutant mCRPC, post-androgen receptor-targeted therapy (PROfound) | 2L+ mCRPC | I-A |
| Talazoparib + enzalutamide | HRR-mutant mCRPC, 1L (TALAPRO-2) | 1L mCRPC | I-A |
| Niraparib + abiraterone | BRCA1/2-positive mCRPC, 1L (MAGNITUDE) | 1L mCRPC | I-A |
| Rucaparib | BRCA1/2-mutant mCRPC, post-androgen-receptor-targeted therapy (TRITON3) | 2L+ mCRPC | I-A |
Tier = AMP/ASCO/CAP 2017 (Li MM et al., J Mol Diagn 2017). Drug names link to openFDA labels where available. Synthetic data; consult primary sources before treatment.
Frequently asked questions
- BRCA1 vs BRCA2 in prostate — same approach?
- BRCA2 mutations are more common and more uniformly responsive to PARP inhibitors than BRCA1 in mCRPC. The label-level indications cover both, but BRCA2 has the deeper response data. Other HRR genes (ATM, CHEK2) have weaker single-agent PARP response signals; combination approaches are more relevant.
- Combination 1L or PARP monotherapy 2L?
- TALAPRO-2 and MAGNITUDE moved PARP into 1L mCRPC for HRR-mutant patients in combination with androgen-receptor-targeted therapy. Whether to use a combo upfront vs sequential monotherapy depends on the specific HRR alteration (BRCA2 favors combo most strongly), comorbidities, and AE tolerance.
- Should every mCRPC patient get genomic testing?
- Yes. Germline plus somatic HRR-panel testing is now standard at mCRPC diagnosis. The actionable yield (a PARP-inhibitor-eligible biomarker) is high enough to justify panel testing in every case.