FOLH1 (PSMA)

  • FOLH1 (folate hydrolase 1) encodes prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II.1
  • Gene Location: Chromosome 11 (11p11.12).1

Biology

  • PSMA is a type II transmembrane glycoprotein with glutamate carboxypeptidase activity on substrates including folate. It is expressed in normal prostate, nervous system, and kidney and is overexpressed on prostate cancer cells.1,2
  • Theranostic rationale: high PSMA expression on prostate cancer with restricted normal-tissue expression allows PSMA PET to identify target-positive disease and PSMA-directed radioligands such as lutetium Lu 177 vipivotide tetraxetan to deliver beta radiation to PSMA-positive cells and the surrounding microenvironment.2,3,4
  • High PSMA expression is an independent marker of poor prognosis. Tumors with DNA damage repair defects, such as BRCA2 alterations, show higher PSMA expression.2,5

Etiology and Epidemiology

  • PSMA-positive disease is common in advanced prostate cancer: in VISION, 95.1% (954 of 1003) of men with mCRPC had at least 1 PSMA-positive lesion and 86.6% met full PSMA PET eligibility criteria; in PSMAfore, 92% (505 of 547) met criteria.2,3
  • Heterogeneity: on IHC, membranous PSMA was undetectable in 42% of castration-sensitive and 27% of castration-resistant tissues, and PSMA-negative foci were common within PSMA-expressing tumors; expression was lowest in liver metastases.5
  • Neuroendocrine disease: FOLH1 expression is suppressed in neuroendocrine prostate cancer, which limits PSMA imaging and therapy in that setting.6

Testing

When to Test:

  • Before PSMA-directed radioligand therapy in metastatic disease, mAPMN/S or castration-resistant. SNMMI recommends PSMA PET within 3 months of starting treatment and repeating it after progression or intervening therapy.7,8

Testing Methodologies:

  • PSMA PET: trial eligibility required at least 1 lesion with uptake greater than normal liver. VISION and PSMAfore excluded patients with any PSMA-negative lesion meeting size criteria (organ 1 cm or larger, lymph node 2.5 cm or larger short axis, bone with soft-tissue component 1 cm or larger); PSMAddition required at least 1 metastatic lesion on conventional imaging.7
  • Agents labeled for selecting patients for PSMA-directed therapy: Locametz and Illuccix (gallium Ga 68 gozetotide). The Pluvicto label also allows another approved PSMA PET product. Gozellix, Pylarify, Pylarify TruVu (piflufolastat F 18), and Posluma (flotufolastat F 18) are approved for staging and suspected recurrence but are not labeled for therapy selection.7,9
  • Contrast CT or MRI helps identify PSMA-negative disease that would not be targeted.8

Guideline Recommendations

  • SNMMI (2023): lutetium Lu 177 vipivotide tetraxetan is appropriate in mCRPC after chemotherapy and ARPI; either 68Ga-PSMA-11 or 18F-DCFPyL PET may be used for selection. This statement predates the 2025 and 2026 label expansions.8
  • EANM/SNMMI and EAU-EANM: PSMA imaging should be performed before considering PSMA radioligand therapy.4,10
  • NCCN (Prostate Cancer, V.5.2026): PSMA PET is used to determine eligibility for PSMA-directed radioligand therapy.11

Targeted Therapy

Approved Agents

Lutetium Lu 177 Vipivotide Tetraxetan (Pluvicto)

FDA-Approved Indication:

  • With ARPI therapy for PSMA-positive mAPMN/S prostate cancer (July 31, 2026).7
  • PSMA-positive metastatic androgen pathway modulation-resistant prostate cancer after ARPI therapy, in patients appropriate to delay taxane chemotherapy (2025) or after prior taxane chemotherapy (2022).7

Mechanism of Action:

  • Radioligand that binds PSMA and delivers beta-particle radiation from lutetium-177, inducing DNA damage in PSMA-expressing cells and neighboring cells.2,7

Drug Information: Learn more about Lutetium Lu 177 Vipivotide Tetraxetan ›

Patient Resources: https://us.pluvicto.com/

References

  1. NCBI Gene. FOLH1 folate hydrolase 1 [Homo sapiens]. Gene ID 2346. Accessed October 2026.
  2. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
  3. Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore). Lancet. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2
  4. Kratochwil C, Fendler WP, Eiber M, et al. Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging. 2023;50(9):2830-2845. doi:10.1007/s00259-023-06255-8
  5. Paschalis A, Sheehan B, Riisnaes R, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur Urol. 2019;76(4):469-478. doi:10.1016/j.eururo.2019.06.030
  6. Bakht MK, Derecichei I, Li Y, et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr Relat Cancer. 2019;26(2):131-146. doi:10.1530/ERC-18-0226
  7. Pluvicto (lutetium Lu 177 vipivotide tetraxetan) injection. Prescribing information. Novartis Pharmaceuticals Corporation; revised 07/2026. Accessed October 2026.
  8. Hope TA, Antonarakis ES, Bodei L, et al. SNMMI consensus statement on patient selection and appropriate use of 177Lu-PSMA-617 radionuclide therapy. J Nucl Med. 2023;64(9):1417-1423. doi:10.2967/jnumed.123.265952
  9. Locametz, Illuccix, Gozellix, Pylarify, Pylarify TruVu, and Posluma. Prescribing information. DailyMed. Accessed October 2026.
  10. Fanti S, Briganti A, Emmett L, et al. EAU-EANM consensus statements on the role of prostate-specific membrane antigen positron emission tomography/computed tomography in patients with prostate cancer and with respect to [177Lu]Lu-PSMA radioligand therapy. Eur Urol Oncol. 2022;5(5):530-536. doi:10.1016/j.euo.2022.05.003
  11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.