What is the most effective treatment for recurrent metastatic castration-resistant prostate cancer that generates Prostate-Specific Membrane Antigen (PSMA)?

177Lu-PSMA-617 is the Most Effective Treatment for Recurrent Metastatic Castration-Resistant Prostate Cancer that Generates PSMA

For patients with metastatic castration-resistant prostate cancer (mCRPC) that generates PSMA and who have received prior treatment with androgen receptor pathway inhibitors and taxane chemotherapy, 177Lu-PSMA-617 is the most effective treatment option, significantly prolonging overall survival compared to standard of care.

Evidence-Based Treatment Algorithm for mCRPC with PSMA Expression

Diagnostic Confirmation

• PSMA expression must be confirmed using PET imaging with either Ga-68 PSMA-11, F-18 piflufolastat, or F-18 flotufolastat before initiating 177Lu-PSMA-617 therapy 1
• Patients should not have PSMA non-expressing lesions, which would indicate poor response to PSMA-targeted therapy 1

First-Line Treatment for mCRPC

• For initial management of mCRPC, standard options include:
  • Abiraterone plus prednisone 1
  • Enzalutamide 1
  • Docetaxel chemotherapy 1, 2
  • Sipuleucel-T immunotherapy (for asymptomatic/minimally symptomatic disease) 1

Second-Line Treatment for mCRPC

• After progression on first-line therapy:
  • If not previously used, consider novel hormonal agents (abiraterone, enzalutamide) 1
  • Cabazitaxel chemotherapy after docetaxel failure 1, 3
  • For patients with BRCA1/2 alterations, consider olaparib 1

177Lu-PSMA-617 Therapy (Optimal Treatment for PSMA-Positive mCRPC)

• 177Lu-PSMA-617 is indicated for patients who have:

  • Confirmed PSMA-positive disease on PET imaging 1
  • Previous treatment with at least one androgen receptor pathway inhibitor 1
  • Previous treatment with at least one taxane regimen 1, 4

• The VISION trial demonstrated that 177Lu-PSMA-617 plus standard care significantly improved:

  • Overall survival (median 15.3 vs. 11.3 months; HR 0.62) 4
  • Imaging-based progression-free survival (median 8.7 vs. 3.4 months; HR 0.40) 4

• Dosing and administration:

  • 7.4 GBq every 6 weeks for four to six cycles 4
  • Requires multidisciplinary collaboration and radioprotection precautions 1
  • Blood counts, renal and hepatic function should be checked before each cycle 1

Alternative Options When 177Lu-PSMA-617 is Not Available or Appropriate

Cabazitaxel Chemotherapy

• Cabazitaxel 25 mg/m² every 3 weeks plus prednisone is effective after prior docetaxel and androgen receptor pathway inhibitor therapy 3
• In the CARD trial, cabazitaxel showed superior radiographic progression-free survival compared to abiraterone or enzalutamide (8.0 vs. 3.7 months; HR 0.54) 3
• Primary prophylaxis with G-CSF is recommended to reduce neutropenia risk 3

Clinical Considerations and Monitoring

• Regular monitoring of PSA levels every 3-4 weeks initially to assess response 5
• Imaging follow-up with CT scans and bone scintigraphy to evaluate treatment response 5
• Quality of life was not adversely affected with 177Lu-PSMA-617 despite higher incidence of grade 3 or above adverse events (52.7% vs. 38.0%) 4

Emerging Therapies

• Alpha-emitter PSMA-targeted therapies (e.g., Actinium-225) are under investigation for patients who progress on 177Lu-PSMA-617 6
• Combination approaches with immunotherapy are being evaluated in clinical trials 7
• PARP inhibitors show promise for specific molecular subtypes of mCRPC 7

Common Pitfalls to Avoid

• Failure to confirm PSMA expression before initiating 177Lu-PSMA-617 therapy 1, 8
• Not checking for PSMA non-expressing lesions, which predict poor response to PSMA-targeted therapy 1
• Inadequate monitoring of hematologic parameters during treatment 1
• Delaying PSMA-targeted therapy until after multiple lines of treatment, when disease burden is high and response rates may be lower 6

177Lu-PSMA-617 represents a paradigm shift in the treatment of mCRPC, offering a targeted approach with proven survival benefits for patients with PSMA-expressing disease who have progressed on standard therapies 4, 6.