What is the best treatment for metastatic castration-resistant prostate cancer (mCRPC) that is progressing after 6 infusions of Pluvicto (lutetium-177 vipivotide tetraxetan) in a patient with good health?

Treatment for mCRPC Progressing After 6 Pluvicto Infusions

For a patient in good health with mCRPC progressing after 6 infusions of Pluvicto (lutetium-177 vipivotide tetraxetan), the best treatment depends critically on prior therapy exposure: if the patient has received both docetaxel and a novel hormone therapy (abiraterone or enzalutamide), cabazitaxel 25 mg/m² every 3 weeks with prednisone plus primary prophylactic G-CSF is the definitive next treatment based on Level 1 evidence from the CARD trial. 1, 2

Treatment Algorithm Based on Prior Therapy

If Patient Received Prior Docetaxel AND Novel Hormone Therapy (Abiraterone or Enzalutamide)

Cabazitaxel is the category 1 preferred option based on the CARD trial, which demonstrated superior outcomes compared to switching between hormone therapies. 1, 2

• Cabazitaxel 25 mg/m² every 3 weeks with prednisone/prednisolone 10 mg daily plus primary prophylactic G-CSF significantly improved radiographic progression-free survival (8.0 vs 3.7 months; HR 0.54, p<0.0001) and overall survival (13.6 vs 11.0 months; HR 0.64, p=0.008) compared to switching to alternate hormone therapy. 1

• Do not switch from abiraterone to enzalutamide (or vice versa) as this is no longer a preferred strategy due to demonstrated cross-resistance between these agents and lack of evidence for meaningful survival benefit with sequential use. 1, 3

• Cabazitaxel remains effective even after taxane exposure, making it viable when other agents fail. 3

If Patient Received Novel Hormone Therapy WITHOUT Prior Docetaxel

Docetaxel-based chemotherapy is the standard recommendation, particularly for symptomatic disease or visceral metastases. 1, 4

• The recommended dose of docetaxel is 75 mg/m² administered intravenously over 1 hour every 3 weeks for metastatic castration-resistant prostate cancer. 4

• Prednisone 5 mg orally twice daily is administered continuously with docetaxel. 4

• A dose of 100 mg/m² in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality. 4

If Patient Has NOT Received Docetaxel OR Novel Hormone Therapy

This scenario is unlikely given Pluvicto is typically reserved for heavily pre-treated patients, but if it occurs:

• Novel hormone therapy (abiraterone or enzalutamide) should be offered to patients with good performance status. 5

• Docetaxel chemotherapy is appropriate for symptomatic patients with metastatic castration-resistant disease and good performance status. 5

Alternative and Specialized Options

Radium-223 for Bone-Predominant Disease

Radium-223 is a category 1 option specifically for patients with good performance status, symptomatic bone-predominant disease, and NO visceral metastases. 1, 3, 6

• Radium-223 improves overall survival while specifically targeting bone metastases. 1, 3

• Do not use radium-223 in patients with visceral metastases—it is contraindicated and ineffective in this setting. 1

• Radium-223 can be used in combination with other systemic therapies or as monotherapy depending on clinical context. 1

Re-treatment with Pluvicto

While not explicitly addressed in the guidelines, progression after 6 infusions of Pluvicto suggests the disease has developed resistance to PSMA-directed radioligand therapy. 6, 7

• The TheraP trial demonstrated Lu-177-PSMA-617 had superior PSA response rates (66%) compared to cabazitaxel (37%), but this was in the initial treatment setting, not after progression. 1

Critical Monitoring and Management

Performance Status Considerations

For patients with good performance status (ECOG 0-1) after Pluvicto progression:

• First choice is cabazitaxel if prior docetaxel and novel hormone therapy exposure. 1

• Alternative is docetaxel if no prior chemotherapy. 1, 4

• Radium-223 specifically for symptomatic bone disease without visceral metastases. 1, 3

Monitoring Requirements

• Regular monitoring of liver function, potassium levels, and blood pressure is mandatory with all hormonal therapies. 3

• Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of chemotherapy. 4

• Do not administer docetaxel to patients with neutrophil counts <1500 cells/mm³. 4

• Monitor blood counts frequently as neutropenia may be severe and result in infection. 4

• PSA response should be evaluated regularly, but treatment decisions should not be based solely on PSA changes—use radiologic imaging to detect progression. 3

Common Pitfalls to Avoid

Do not delay chemotherapy in symptomatic patients with good performance status—these patients derive the most benefit from docetaxel or cabazitaxel. 1

Do not continue sequential novel hormone therapy expecting substantial benefit—the CARD trial definitively showed cabazitaxel superiority over this approach in post-docetaxel, post-hormone therapy patients. 1, 2

Avoid docetaxel in patients with bilirubin > upper limit of normal (ULN), or AST/ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN, as these patients are at increased risk for severe toxicity and treatment-related mortality. 4

Additional Considerations

Continuation of Androgen Deprivation Therapy

Continue androgen-deprivation therapy indefinitely for patients with mCRPC. 6

Clinical Trials

For patients with limited standard options, clinical trials should be actively considered throughout the treatment course. 1, 6

Palliative Care Integration

Concurrent palliative care consultation should be offered to address bone pain, fatigue, and quality of life concerns. 2

• Palliative radiotherapy remains an option for controlling localized bone pain. 2