Treatment of Metastatic Castration-Resistant Prostate Cancer with Deleterious BRCA1/2 Mutation
Clinical Scenario
This protocol applies to patients with metastatic castration-resistant prostate cancer (mCRPC) — defined by disease progression at castrate testosterone levels below 50 ng/dL with confirmed distant metastases (M1) — who carry a deleterious BRCA1/2 mutation, either germline or somatic.
Patients with BRCA1/2 alterations carry an adverse prognosis in the mCRPC setting and demonstrate limited response to many standard treatments. Mutation status — confirmed through germline or somatic testing — is therefore a decisive factor that directly determines the treatment pathway in this population.
Treatment Approach (Partial Overview)
Current evidence strongly prioritises a PARP inhibitor-based combination regimen in this setting, paired with an androgen receptor pathway inhibitor, alongside ongoing androgen deprivation therapy. Multiple approved combinations exist within this class — the complete options, sequencing considerations, and regimen details are available in the full protocol.
Treatment Goals
Key efficacy endpoints for this protocol are a PSA decline of ≥50% and radiographic progression-free survival (rPFS).
References
- In case of a known BRCA alteration, the use of a PARP inhibitor should always be prioritised as these patients harbour an adverse prognosis and don't respond well to most other treatments.
- PARP inhibitor use significantly improves rPFS and OS in these patients.
- The combination of PARP inhibitor plus ARPI in patients with BRCA1/2 (or ATM) mutations in the first-line as opposed to the use of PARP inhibitor monotherapy or the sequential use of these agents is supported by a randomised phase II trial (BRCAAway) albeit with low patient numbers and thus a low level of evidence.