This protocol covers male patients with metastatic castration-resistant prostate cancer (mCRPC) — defined by castrate testosterone below 50 ng/dL with M1 disease progression — who carry a deleterious BRCA1/2 mutation (germline or somatic) and whose prior first-line PARP inhibitor plus androgen receptor pathway inhibitor (ARPI) combination, with ongoing androgen deprivation therapy, has not achieved adequate disease control.
A confirmed deleterious BRCA1/2 mutation places these patients in a distinct subgroup with an adverse prognosis. Patients with BRCA alterations do not respond well to most other treatments, making targeted treatment sequencing especially important. PARP inhibitor-based strategies are supported by evidence of improved radiographic progression-free survival and overall survival in this population.
The previous treatment consisted of a PARP inhibitor (olaparib, niraparib, or talazoparib) combined with an ARPI (abiraterone acetate or enzalutamide), together with ongoing androgen deprivation therapy. That regimen did not achieve the target goals of a ≥50% PSA decline and durable radiographic progression-free survival. This protocol defines the next therapeutic step following that failure.
The full protocol outlines targeted monotherapy and chemotherapy options selected according to mutation status and the specific prior treatments received. The complete decision algorithm, drug selection criteria, and clinical conditions remain in the full protocol.
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.
The FDA approved olaparib for patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.
Rucaparib has been approved by the FDA for patients with deleterious BRCA mutations (germline and/or somatic) who have been treated with ARPI and a taxane-based chemotherapy.
Patients with mCRPC and alterations in DDR genes are more sensitive to platinum chemotherapy than unselected patients.
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