What treatment options are available for a patient with metastatic castrate-resistant prostate cancer (mCRPC) and a CHEK2 mutation, who has had a rising Prostate-Specific Antigen (PSA) level during Pluvicto (Lutetium-177) treatment, after prior treatments with docetaxel chemotherapy, Zytiga (abiraterone), and orchiectomy?

Treatment Options for mCRPC with Rising PSA During Lu-177-PSMA Therapy

Given progression on Lu-177-PSMA therapy with heterogeneous PSMA expression and a CHEK2 mutation, you should consider cabazitaxel chemotherapy as the next line of treatment, as this patient has exhausted multiple prior therapies including docetaxel, abiraterone, and radionuclide therapy. 1

Clinical Context and Treatment Sequencing

This patient represents Index Patient 5 from the AUA guidelines: symptomatic mCRPC with good performance status and prior docetaxel chemotherapy, now with additional progression through multiple subsequent lines including abiraterone and Lu-177-PSMA. 1

Key Prognostic Considerations

The heterogeneous PSMA expression on PET imaging (some lesions PSMA-positive, others PSMA-negative) is a critical finding that explains the treatment failure with Lu-177-PSMA therapy. 2 This heterogeneity indicates:

• PSMA-negative clones are driving disease progression 2
• Further PSMA-targeted therapy is unlikely to be effective 3
• Systemic cytotoxic therapy targeting all tumor cells regardless of PSMA expression is needed 1

Primary Treatment Recommendation: Cabazitaxel

Cabazitaxel is FDA-approved specifically for mCRPC patients who have progressed after docetaxel-based chemotherapy and represents the standard of care in this setting. 1 The drug demonstrated survival benefit in the post-docetaxel population, which directly applies to your patient. 1

Rationale for Cabazitaxel

• Proven overall survival benefit in post-docetaxel mCRPC 1
• Works independently of PSMA expression, addressing the heterogeneous disease 1
• Effective against both bone and visceral metastases 1
• Does not require specific biomarker expression for efficacy 1

Alternative Considerations

Second-Generation Androgen Receptor Inhibitors

Enzalutamide could be considered if not previously used, though the patient's prior abiraterone exposure and CHEK2 mutation status suggest potential cross-resistance. 1 However, given the aggressive progression through multiple lines, cytotoxic chemotherapy is more appropriate. 1

PARP Inhibitors and the CHEK2 Mutation

The CHEK2 mutation is a DNA damage repair defect that theoretically could predict response to PARP inhibitors (olaparib, rucaparib). However:

• PARP inhibitors are primarily FDA-approved for BRCA1/2 and ATM mutations 4
• CHEK2 mutations have less robust evidence for PARP inhibitor response compared to BRCA mutations
• Consider genetic counseling and tumor genomic profiling to identify additional actionable mutations 4

Re-challenge with Lu-177-PSMA

Re-challenge with Lu-177-PSMA is NOT recommended in this case because:

• PSA rose during active treatment (primary resistance) 2, 3
• Heterogeneous PSMA expression indicates PSMA-negative clones are dominant 2
• Re-challenge is only effective in patients who initially responded and then progressed after a treatment-free interval 5

Clinical Pitfalls to Avoid

Common Mistakes

• Do not continue Lu-177-PSMA beyond progression: Rising PSA during treatment indicates primary resistance, and continuing therapy exposes the patient to toxicity without benefit 2, 3

• Do not delay systemic chemotherapy: The presence of visceral metastases (if any develop) and rising PSA indicate aggressive disease requiring prompt intervention 3, 6

• Do not assume all DNA repair mutations respond equally to PARP inhibitors: CHEK2 is not equivalent to BRCA1/2 in terms of PARP inhibitor sensitivity 4

Monitoring During Treatment

• PSA should not be the sole endpoint: Clinical and radiographic progression are more meaningful than PSA changes alone 1
• Monitor for bone marrow suppression with cabazitaxel (anemia, thrombocytopenia, neutropenia) 1
• Assess pain control and quality of life measures regularly 1, 4

Supportive Care Considerations

Bone health management remains critical given the bone-only disease history:

• Continue bone-targeted therapy (denosumab or zoledronic acid) 4
• Optimize pain management with multimodal approach 4
• Consider palliative radiation for symptomatic bone lesions 4

Future Treatment Planning

After cabazitaxel progression, consider:

• Clinical trial enrollment given limited standard options 1
• Comprehensive genomic profiling if not already done to identify targetable alterations beyond CHEK2 4
• Palliative care integration for symptom management and quality of life optimization 4

The key principle is that this patient has exhausted hormonal therapies and first-line chemotherapy, with documented resistance to PSMA-targeted therapy, making cabazitaxel the evidence-based next step. 1