What is the next step in managing a patient with metastatic castration-resistant prostate cancer (CRPC) who has progressed on both abiraterone (Zytiga) and enzalutamide (Xtandi) and is positive for a BRCA2 mutation?

Management of Metastatic CRPC Post-Progression on Abiraterone and Enzalutamide with BRCA2 Mutation

For a patient with metastatic CRPC harboring a BRCA2 mutation who has progressed on both abiraterone and enzalutamide, olaparib monotherapy (300 mg twice daily) is the preferred next-line treatment, demonstrating superior overall survival (HR 0.69, median OS 19.1 vs 14.7 months) specifically in BRCA1/2-mutated patients. 1, 2

Primary Treatment Recommendation: PARP Inhibitor Monotherapy

• Olaparib 300 mg twice daily is FDA-approved and guideline-recommended for patients with mCRPC and BRCA2 mutations who have progressed following prior therapy with a novel hormonal agent (abiraterone or enzalutamide). 1

• The PROfound trial specifically demonstrated that patients with BRCA2 mutations experienced significant OS benefit with olaparib (HR 0.59; 95% CI 0.37-0.95), with median radiographic PFS of 7.4 months versus 3.6 months compared to switching to alternative ARPI (HR 0.34; 95% CI 0.25-0.47). 1, 3

• BRCA2 mutations show the most robust response to PARP inhibition among all HRR gene alterations, with efficacy in PROfound driven primarily by BRCA1/2-mutated patients rather than other HRR genes like ATM. 1, 2

• Rucaparib is an alternative PARP inhibitor option showing 43.5% objective response rate with median duration of response of 6.4 months in BRCA-mutated mCRPC patients treated with prior androgen receptor-directed therapy. 1

Alternative Treatment Options Based on Prior Therapy

If Docetaxel-Naïve:

• Docetaxel chemotherapy every 3 weeks with prednisone is a reasonable alternative, particularly if the patient has not received prior taxane therapy, showing median OS of 16.3 months with OS gain of 2.9 months (HR 0.79). 1

• Cabazitaxel may be considered if docetaxel was previously used in the castration-sensitive setting, demonstrating median OS of 11.0 months with OS gain of 2.6 months versus alternative ARPI (HR 0.64). 1

If Prior Docetaxel Exposure:

• Cabazitaxel 25 mg/m² every 3 weeks with prednisone showed superior outcomes compared to switching ARPIs in the CARD trial (median PFS 3.7 months gain, median OS 2.6 months gain). 1

• 177Lu-PSMA-617 radioligand therapy should be strongly considered if PSMA-positive disease is confirmed on imaging and patient has received both prior ARPI and taxane, showing improved radiographic PFS (HR 0.40, medians 8.7 vs 3.4 months) and OS (HR 0.62, medians 15.3 vs 11.3 months). 2, 4, 5

Critical Implementation Steps

Genetic Testing Confirmation:

• Confirm BRCA2 mutation status through both germline and somatic tumor testing using next-generation sequencing if not already performed, as treatment eligibility requires documented deleterious or suspected deleterious mutations. 1

• Somatic analysis using circulating tumor DNA (ctDNA) is acceptable for treatment selection when tissue is unavailable. 6

• Refer to genetic counseling for assessment of hereditary cancer syndrome implications and family risk counseling. 1

Additional Biomarker Assessment:

• Evaluate MSI-H/dMMR status if not previously done, as pembrolizumab may be considered for MSI-H/dMMR mCRPC (category 2A recommendation) after progression on docetaxel and/or novel hormone therapy. 1

• Consider PSMA PET imaging to assess eligibility for 177Lu-PSMA-617 therapy in later treatment lines. 2, 5

Treatment Sequencing Algorithm

First Priority: Olaparib 300 mg twice daily (if no prior PARP inhibitor exposure) 1, 2

Second Priority (if olaparib contraindicated or unavailable):

• Docetaxel chemotherapy (if taxane-naïve) 1, 5
• Cabazitaxel chemotherapy (if prior docetaxel in hormone-sensitive setting) 1, 5

Third Priority (after PARP inhibitor and taxane exposure):

• 177Lu-PSMA-617 (if PSMA-positive on imaging) 2, 5
• Radium-223 (if symptomatic bone-only disease without visceral metastases, showing median OS 11.3 months with OS gain of 3.6 months) 1

Critical Pitfalls to Avoid

• Do not discontinue ADT when initiating olaparib or any subsequent therapy; all novel agents are studied with concurrent ADT as backbone therapy. 2

• Avoid sequential ARPI therapy (switching from abiraterone to enzalutamide or vice versa) in patients with BRCA2 mutations, as PARP inhibition provides superior outcomes compared to alternative ARPI. 1, 3

• Do not rely solely on primary tumor profiling; molecular drivers can change as disease progresses through treatments, requiring repeat testing at castration resistance. 2

• Monitor for specific olaparib toxicities including anemia (potentially requiring transfusion), fatigue, nausea/vomiting, thrombocytopenia, and rare but serious adverse effects including thromboembolic events and drug-induced pneumonitis. 1, 3

Expected Outcomes and Monitoring

• Continue olaparib until clinical or radiographic progression or intolerance, recognizing that PSA progression alone may not indicate treatment failure. 1

• Monitor with radiologic imaging (CT, bone scan) every 8-12 weeks, PSA tests, and clinical exams, as bone imaging may reveal progression even when PSA remains stable. 1

• Expected median time on olaparib therapy is approximately 7.4 months based on radiographic PFS data, though individual responses vary significantly in BRCA2-mutated patients. 3

• Quality of life considerations: olaparib showed no overall QoL benefit in PROfound, though progression-free survival and time to pain progression were improved. 1