What are the next treatment options for a patient with metastatic prostate cancer who has completed 6 infusions of Pluvicto (Lutetium-177 vipivotide tetraxetan)?

Treatment Options After Completing 6 Pluvicto Infusions for Metastatic Prostate Cancer

After completing 6 cycles of Pluvicto (177Lu-PSMA-617), patients with responding disease and high-volume residual tumor burden may benefit from extended therapy with additional Pluvicto cycles, while those with progressive disease should transition to alternative systemic therapies including rechallenge with androgen receptor pathway inhibitors, taxane chemotherapy, or clinical trial enrollment.

Extended Pluvicto Therapy for Responders

For patients who demonstrated response to the initial 6 cycles but retain high-volume residual disease (defined by CHAARTED criteria as ≥4 bone metastases with ≥1 outside spine/pelvis, or visceral metastases), continuation beyond 6 cycles is a viable option. 1

• Extended therapy with additional Pluvicto cycles (median 10 cycles, range 7-16) achieved further PSA decline of 33% in 81% of responding patients with high-volume residual disease 1
• Grade ≥3 hematological toxicity occurred in only 15% of patients during extended treatment, with grade ≥3 nephrotoxicity in 4%, demonstrating acceptable safety 1
• Median progression-free survival was 19 months and overall survival was 29 months with extended therapy 1
• Response assessment with PSMA PET/CT should be performed every 2-3 cycles during extended treatment 1

Alternative Systemic Therapies for Progressive Disease

Androgen Receptor Pathway Inhibitors

If patients have not previously received all available androgen receptor pathway inhibitors, these remain standard options for metastatic castration-resistant prostate cancer. 2, 3

• Abiraterone or enzalutamide are recommended for chemotherapy-naïve or minimally pretreated metastatic CRPC 2
• Novel agents including apalutamide and darolutamide represent additional options if not previously used 3
• Sequential use of different androgen receptor inhibitors may provide benefit even after progression on one agent 4

Taxane-Based Chemotherapy

For patients who have not exhausted taxane options, docetaxel or cabazitaxel remain viable choices. 4, 2

• Docetaxel at 75 mg/m² every 3 weeks for 6 cycles is recommended for metastatic CRPC 4, 2
• Cabazitaxel should be considered if docetaxel was previously used but not cabazitaxel 5

Targeted Therapies Based on Molecular Alterations

Olaparib is recommended for patients with BRCA1/2 or other homologous recombination repair gene alterations who have progressed after androgen receptor axis inhibitors. 3

• Molecular testing for BRCA1/2 and other DNA repair gene mutations should guide targeted therapy selection 3

Bone-Directed Therapies

For patients with bone-predominant disease and pain, radium-223 is an option, particularly if no visceral metastases are present. 2

• Radium-223 is recommended for symptomatic bone metastases without visceral involvement 2
• Denosumab or zoledronic acid should be continued or initiated for patients at high risk of skeletal-related events 2
• Single-fraction external beam radiotherapy provides effective palliation for painful bone metastases 2

Clinical Trial Enrollment

Clinical trial enrollment is strongly recommended for all patients after standard therapies, as second-line and subsequent treatment data remain limited. 4

Monitoring and Supportive Care Considerations

• PSA and clinical assessment should continue regularly, though PSA may be less reliable in patients with neuroendocrine differentiation 2
• Routine imaging surveillance is not mandatory without PSA rise or cancer-related symptoms 2
• Monitor for long-term ADT side effects including osteoporosis and metabolic syndrome 2
• MRI of the spine is recommended for patients with vertebral metastases to detect subclinical cord compression 2

Common Pitfalls to Avoid

• Do not automatically discontinue Pluvicto after 6 cycles in responding patients with high-volume residual disease—extended therapy has demonstrated safety and efficacy 1
• Do not overlook molecular testing for BRCA1/2 and homologous recombination repair genes—this guides eligibility for PARP inhibitors 3
• Do not use radium-223 in patients with visceral metastases—it is contraindicated in this population 2
• Do not assume all neurologic symptoms after Pluvicto are treatment-related—dysgeusia and dizziness are most common (12% and 6% respectively), but severe neurologic events are rare 6