Molecular Imaging and Targeted Radionuclide Therapy with PSMA Pharmaceuticals

The role that molecular radiotherapy with alpha- and beta-emitting PSMA-targeted radio-pharmaceuticals is expected to play in the treatment of metastatic castrate resistant prostate cancer (mCRPC) was reviewed at the 2021 ASTRO annual meeting by Ephraim Parent, MD, PhD, radiologist at the Mayo Clinic, Jacksonville, FL.

Prostate-specific membrane antigen (PSMA) is a membrane-bound metallopeptidase overexpressed at high levels in 90-100% of prostate cancer lesions, Dr Parent explained. PSMA expression levels increase with higher prostate cancer stage and grade, except in neuroendocrine prostate cancer. PSMA has two unique enzymatic functions, folate hydrolase function and glutamatergic neurotransmission, and it can be recycled in a manner similar to other membrane-bound receptors through clathrin-coated pits. PSMA is also expressed in the neovasculature of many different malignancies such as glioblastoma, but not in normal tissue.

Dr Parent explained that most PSMA-targeted radioligands contain a urea-based scaffold by which they bind to PSMA. Changes in imaging and therapeutic payload affect the affinity of the overall PSMA ligand to bind to the receptor, subsequently affecting delivery and physiological uptake. He emphasized the importance of the chemical linker between the DOTA chelator and the urea pharmacophore and its effect on internalization potency. As an example, he recalled that 177Lu-PSMA-617, the radioligand agent shown to be highly effective in the recently reported VISION trial,1 has been shown to be highly specifically internalized at up to 17.51 ± 3.99 percentage injected activity/106 LNCaP cells.2

At the time of the meeting, two PSMA-targeted PET imaging agents had been approved by the FDA: Gallium-68 PSMA-11 (68Ga-PSMA-11)3 and piflufolastat F 18 (also known as 18F-DCFPyL)4 The two agents differ in how they are expressed, although the differences between them are “subtle,” and “to all intents and purposes they operate similarly to each other and to the same target tissue,” Dr Parent noted. The accuracy of both has been studied widely. As an example, one large study of 68Ga-PSMA-11 in 2005 prostate cancer patients with biochemical recurrence of disease after either radical prostatectomy (RP), definitive radiation therapy (RT), or RP with post-operative RT identified an optimal SUVmax threshold of 7.5 for differentiating false positive from true positive lesions.5 Despite a sensitivity of 69% and specificity of 80%, however, the study investigators pointed out a large overlap between the SUVmax of true positive and false positive lesions that limited the reliability of this threshold to predict prostate cancer.

68Ga-PSMA-11 scans are comparable with those of fluciclovine F-18 (18F-fluciclovine) at higher PSA levels, Dr Parent noted. At low PSA levels, where physicians are likely to be seeking to identify a single oligometastatic lesion, however, detection rates are significantly higher with 18F-fluciclovine PET/CT imaging.6 This will only apply in about 10% of cases, Dr Parent advised, but PSMA scans also have the advantage of being tied to therapy, he pointed out.

The effect of androgen deprivation therapy (ADT) on the detection efficacy of PSMA ligand PET/CT is still under investigation, Dr Parent explained. Highly variable changes in PSMA expression have been reported in response to ADT ranging from increases to moderate decreases, and no true consensus exists about the clinical effect of ADT on PSMA PET imaging, he cautioned. One hypothesis proposed that PSMA is decreased in patients with metastatic castration-sensitive prostate cancer (mCSPC) patients due to the strong antiproliferative effect of ADT in the early (castration-sensitive) stages of the disease, and that the observed PSMA increased uptake in mCRPC may be due to the slower treatment response of second- or third-line treatment. Dr Parent recommends that despite an effect of ADT on PSMA PET, as a general practice, it is not necessary to start ADT before PSMA PET.

Short-term ADT in mCRPC may increase tumor detection rates. Low PSMA expression after ADT has been associated with progression of mCRPC during ADT, possibly due to mutation or amplification of the androgen receptor or to neuroendocrine differentiation, Dr Parent advised. The increase in PSMA uptake seen in some lesions during long-term ADT, despite complete or incomplete PSA remission, may correlate with those cell clones that become castration resistant first, he suggested. However, “we don’t know how long ADT needs to be paused to increase the sensitivity of PSMA ligand imaging in clinical practice,” he acknowledged. He stressed the importance of this in identifying patients for PSMA-targeted therapy.

According to current European Association of Nuclear Medicine (EANM) procedure guidelines,7 177Lu- PSMA-617 can be utilized in patients with mCRPC who have exhausted or are ineligible for approved alternative options and have adequate uptake of PSMA ligands on the basis of pre-therapy imaging, Dr Parent explained. Despite this recommendation, Dr Parent stressed caution because of a minority of patients who have discordant hypermetabolic disease. These patients will have ≥1 hypermetabolic (FDG) lesions, with or without PSMA expression.

A case-series study in 56 patients with mCRPC who underwent both 68Ga-PSMA and 18F-FDG PET/CT showed that 23% had ≥1 PSMA-negative/FDG-positive lesion and that PSA levels and Gleason scores were high in these patients.8 This is important, because mCRPC patients with discordant FDG-avid disease in patients who progress after conventional therapies have a worse outcome, Dr Parent stressed, noting that in a study of 50 mCRPC patients who had progressed after abiraterone and/or enzalutamide, overall survival (OS) in those with low PSMA expression or PSMA-negative/FDG-positive lesions was 2.6 months compared with 13.5 months in patients with PSMA-positive lesions who received 177Lu-PSMA-617.9 In a different group of mCRPC patients who all received 177Lu-PSMA-617, median OS was 6.0 months in patients with PSMA-negative/FDG-positive lesions compared with 16.0 months in those patients without any FDG+/ PSMA− lesions.10 Dr Parent emphasized the importance of correctly identifying patients who are good candidates for PSMA-targeted therapy, although assessment of FDG PET/ CT may only be reasonable for initial staging before PSMA radioligand therapy, he added.

Dr Parent recalled that the TheraP phase 2 treatment trial of 177Lu-PSMA-617 excluded patients with PSMA- negative/FDG-positive lesions,11 whereas the phase 3 VISION trial using the same agent excluded patients with PSMA-negative tumors based on node and bone lesion size.1 Both trials reported positive outcomes, but those in the TheraP trial appeared superior to those in the VISION trial, emphasizing the importance of ordering PSMA (and FDG) PET before selecting patients for treatment with 177Lu-PSMA-617, Dr Parent emphasized. “PSMA radioligand therapy for prostate cancer without PSMA PET should not be accepted,” he declared, describing this statement as “standing up for precision medicine.”13 Treatment may also be appropriate in patients with bone disease, he added.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

References

  1. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. DOI: 10.1056/NEJMoa2107322
  2. Benešová M, Schäfer M, Bauder-Wüst U, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med. 2015;56:914–920. DOI: 10.2967/ jnumed.114.147413
  3. FDA approves First PSMA-targeted PET imaging drug for men with prostate cancer. Food and Drug Administration (FDA). December 1, 2020. https://www.fda.gov/news-events/ press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate- cancer
  4. FDA approves first PSMA-Targeted PET imaging drug for men with prostate cancer. December 1, 2020. https://www.fda.gov/news-events/press-announcements/fda- approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer
  5. Abghari-Gerst M, Armstrong WR, Nguyen K, et al. A comprehensive assessment of 68Ga- PSMA-11 PET in biochemically recurrent prostate cancer: Results from a prospective multi- center study in 2005 patients. J Nucl Med. Published online July 29, 2021. DOI: 10.2967/ jnumed.121.262412
  6. Calais J, Ceci F, Eiber M, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single- centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;20(9):1286-1294. DOI: 10.1016/S1470-2045(19)30415-2
  7. Kratochwil C, Fendler WP, Eiber M, et al. EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT). Eur J Nucl Med Mol Imaging. 2019;46(12):2536-2544. DOI: 10.1007/s00259-019-04485-3
  8. Chen R, Wang Y, Zhu Y, et al. The added value of 18 F-FDG PET/CT compared to 68 Ga- PSMA PET/CT in patients with castration-resistant prostate cancer. Nucl Med. Published online April 23, 2021. DOI: 10.2967/jnumed.121.262250
  9. Thang SP, Violet J, Sandhu S,, et al. Poor outcomes for patients with metastatic castration-resistant prostate cancer with low prostate-specific membrane antigen (PSMA) expression deemed ineligible for 177Lu-labelled PSMA radioligand therapy. Eur Urol Oncol. 2019;2(6):670-676. DOI: 10.1016/j.euo.2018.11.007
  10. Michalski K, Ruf J, Goetz C, et al. Prognostic implications of dual tracer PET/CT: PSMA ligand and [18F]FDG PET/CT in patients undergoing [177Lu]PSMA radioligand therapy. Eur J Nucl Med Mol Imaging. 2021;48(6):2024-2030. DOI: 10.1007/s00259-020-05160-8
  11. Hofman MS, Emmett L, Violet J, et al. TheraP: a randomized phase 2 trial of ¹⁷⁷Lu- PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration- resistant prostate cancer (Clinical Trial Protocol ANZUP 1603). BJU Int. 2019;124 (suppl 1):5-13. DOI: 10.1111/bju.14876
  12. Hofman MS, Emmett L, Sandhu S, et al; Australian and New Zealand Urogenital and Prostate Cancer Trials Group [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. DOI: 10.1016/s0140-6736(21)00237-3
  13. Srinivas S, Iagaru A. To scan or not to scan: an unnecessary dilemma for PSMA: radioligand therapy. J Nucl Med. 2021;62(11):1487-1488. DOI: 10.2967/jnumed.121.263035