Second-Line Treatment for BRCA2-Mutated Metastatic Prostate Cancer After ADT+Enzalutamide Progression
Olaparib is the recommended second-line treatment for patients with BRCA2-mutated metastatic castration-resistant prostate cancer who have progressed on ADT plus enzalutamide. 1
Primary Recommendation: PARP Inhibitor Therapy
Olaparib should be initiated as the next treatment step for this BRCA2-mutated patient, providing a median PFS gain of 3.8 months (HR 0.25-0.47) compared to switching to another androgen receptor pathway inhibitor like abiraterone. 1 The ESMO 2023 guidelines specifically recommend olaparib for adult patients with mCRPC and BRCA1/2 mutations (germline and/or somatic) who have progressed following prior therapy that included a novel hormonal agent, with an ESMO-MCBS score of 3. 1
Key Evidence Supporting Olaparib
- The PROfound trial demonstrated that olaparib in BRCA1/2-mutated patients achieved a median OS of 11.5 months with an OS gain of 2.6 months (HR 0.63-1.49) compared to continuing enzalutamide or abiraterone. 1
- While quality of life benefit was not demonstrated overall, the survival advantage and disease control make this the optimal choice for BRCA2-mutated disease. 1
Alternative Option: Rucaparib
Rucaparib represents an alternative PARP inhibitor option for patients with deleterious BRCA mutations who have been treated with androgen receptor-directed therapy, demonstrating an objective response rate of 43.5% with a median duration of response of 6.4 months (ESMO-MCBS score: 3). 1 However, this was evaluated in a single-arm trial (TRITON2), making the evidence less robust than olaparib's randomized data. 1
Treatment Sequencing Considerations
If Patient Has NOT Received Prior Docetaxel
If this patient has not yet received docetaxel chemotherapy, there are two reasonable approaches:
- Proceed directly to olaparib to capitalize on the BRCA2 mutation and PARP inhibitor sensitivity. 1, 2
- Consider docetaxel first, which provides a median OS of 16.3 months with an OS gain of 2.9 months (HR 0.79) and improved quality of life, then reserve olaparib for subsequent progression. 1, 2
The NCCN and ASCO support moving to chemotherapy rather than sequential ARPIs after ARPI failure based on the CARD trial, but the presence of a BRCA2 mutation creates a unique opportunity for targeted therapy. 2
If Patient HAS Received Prior Docetaxel
If docetaxel was already administered (either in the hormone-sensitive or castration-resistant setting), olaparib becomes the clear next choice given the BRCA2 mutation. 1, 2
Essential Concurrent Management
Continue ADT indefinitely with LHRH agonist/antagonist to maintain castrate testosterone levels (<50 ng/dL) throughout olaparib therapy and all subsequent treatments. 2, 3 This is a critical component that must not be discontinued.
Subsequent Treatment Options After Olaparib Failure
When disease progresses on olaparib, treatment options depend on prior therapy exposure:
If Docetaxel-Naïve at Olaparib Failure
- Docetaxel chemotherapy becomes the preferred next option, providing survival benefit and quality of life improvement. 1, 2
If Docetaxel-Exposed Before or During Olaparib
- 177Lu-PSMA-617 for PSMA-positive disease (highest ESMO-MCBS score of 4), providing median OS of 15.3 months versus 11.3 months (OS gain: 4.0 months; HR 0.62). 2, 3
- Cabazitaxel with prednisone/prednisolone, providing median OS of 12.7 months with OS gain of 2.4 months (HR 0.70). 1, 2
Critical Monitoring Requirements
- PSA levels should be monitored regularly to assess treatment response. 2, 3
- Periodic imaging studies are essential for evaluating disease progression. 2, 3
- Testosterone verification must confirm maintenance of castrate levels throughout treatment. 2, 3
- PSMA PET imaging should be obtained to determine eligibility for 177Lu-PSMA-617 in future treatment lines. 2, 3
Important Clinical Pitfalls to Avoid
Do not switch to abiraterone after enzalutamide failure in this BRCA2-mutated patient, as cross-resistance between ARPIs is well-established and the CARD trial demonstrated superior outcomes with cabazitaxel over ARPI switching (median PFS 8.0 vs 3.7 months). 1, 2 The presence of a BRCA2 mutation makes PARP inhibition the biologically rational choice.
Do not discontinue ADT at any point during subsequent therapies, as maintaining castrate testosterone levels remains essential even when adding targeted agents or chemotherapy. 2, 3
Ensure comprehensive molecular testing was performed to confirm BRCA2 mutation status (germline and/or somatic) and to identify other potentially actionable alterations. 2, 4