What is the status of targeting Fibroblast Activation Protein (FAP) and Prostate-Specific Membrane Antigen (PSMA) in cancer treatment?

Current Status of FAP and PSMA Targeting in Cancer Treatment

PSMA-targeted therapy with 177Lu-PSMA-617 is now FDA-approved for metastatic castration-resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition and taxane-based chemotherapy, while FAP targeting remains investigational with limited clinical utility due to lower expression levels in prostate cancer.

PSMA Targeting: Established Clinical Role

PSMA (Prostate-Specific Membrane Antigen) targeting has evolved from a diagnostic tool to an approved therapeutic approach in prostate cancer management:

Diagnostic Applications

• PSMA PET imaging has demonstrated superior diagnostic performance compared to conventional imaging in:
  • Intermediate to high-risk primary prostate cancer
  • Biochemical recurrence after definitive therapy
  • Delineation of metastatic disease extent 1
  • Patient selection for PSMA-targeted radioligand therapy

Therapeutic Applications

• 177Lu-PSMA-617 (PLUVICTO) received FDA approval for:

  • PSMA-positive mCRPC patients
  • Who have progressed after androgen receptor pathway inhibition
  • And have received taxane-based chemotherapy 2

• The VISION trial demonstrated significant clinical benefits:

  • Improved overall survival: 15.3 vs 11.3 months (HR 0.62) 2
  • 4-month absolute survival advantage compared to standard of care 3
  • Now recommended as a treatment option by ESMO (Level I, A evidence) 1

Patient Selection for PSMA Therapy

• Patient eligibility requires:
  • Confirmed PSMA expression on PET imaging
  • No PSMA-negative lesions 1
  • Prior treatment with androgen receptor pathway inhibitors and taxane-based chemotherapy 2

FAP Targeting: Emerging Research Area

Fibroblast Activation Protein (FAP) targeting is still in early investigational stages for prostate cancer:

Current Status

• FAP is expressed by carcinoma-associated fibroblasts in the tumor microenvironment 4
• FAP expression in CRPC is significantly lower than PSMA expression (median immunoscores 14 vs 72) 4
• Only 58% of PSMA-negative tumors exhibit FAP positivity 4

Potential Applications

• FAP targeting may have potential utility in:
  • PSMA-negative prostate cancer variants (e.g., small cell carcinoma) 4
  • Patients with heterogeneous tumor phenotypes 5
  • As a complementary approach to PSMA targeting 6

Limitations

• Low FAP expression levels in CRPC may limit the utility of FAP-targeted imaging and therapy 4
• FAPi PET typically shows lower uptake than PSMA PET in metastatic lesions (median SUVmax 9.6 vs 14.5) 4
• Currently no FDA-approved FAP-targeted diagnostics or therapeutics

Clinical Implications and Future Directions

Current Treatment Algorithm

1. For patients with mCRPC who have progressed after androgen receptor pathway inhibitors and docetaxel:

   • 177Lu-PSMA-617 is recommended for those with PSMA-positive disease on PET imaging 1, 2
   • Cabazitaxel remains an alternative option 1

2. Patient selection is critical:

   • PSMA expression must be confirmed by PSMA PET imaging
   • Absence of PSMA-negative lesions is important for optimal response 1

Future Research Needs

• Development of FAP-targeted therapies for PSMA-negative prostate cancer
• Investigation of combination approaches targeting both PSMA and FAP
• Exploration of other molecular targets for heterogeneous or treatment-resistant disease

Practical Considerations

• PSMA PET imaging has become an essential tool for staging and treatment selection in advanced prostate cancer
• Multidisciplinary expertise (medical oncology, nuclear medicine, radiation oncology) is required for optimal implementation of PSMA-targeted theranostics 1
• FAP targeting may eventually complement PSMA-based approaches but requires further clinical validation

In conclusion, while PSMA targeting has established clinical utility in both diagnosis and treatment of advanced prostate cancer, FAP targeting remains investigational with potential applications in PSMA-negative disease that warrant further research.