Introduction: Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. Methods: A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15^th of July 2022) to search for prospective trials on FAP TRT. Results: In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD. Conclusion: To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [¹⁷⁷Lu]Lu-FAPI-04, [⁹⁰Y]Y-FAPI-46, [¹⁷⁷Lu]Lu-FAP-2286, [¹⁷⁷Lu]Lu-DOTA.SA.FAPI and [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂. In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.

Purpose: [177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC. Patients and Methods: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS. Results: All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III–IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease. Conclusions: 177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.

Rationale: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for ¹⁷⁷ Lu-PSMA-617 and ¹⁷⁷ Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter ⁸⁹ Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of ⁸⁹ Zr-PSMA-617 and ⁸⁹ Zr-PSMA-I&T to those of ¹⁷⁷ Lu-PSMA-617 and ¹⁷⁷ Lu-PSMA-I&T, respectively, in a PSMA ⁺ xenograft model. Moreover, we provide the first human ⁸⁹ Zr-PSMA-617 images. Materials and methods: PSMA ligands were labeled with 50-55 MBq [ ⁸⁹ Zr]ZrCl ₄ using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA ⁺ and PSMA ⁻ xenografts received 0.6 µg (0.6–1 MBq) of ⁸⁹ Zr-PSMA-617, ⁸⁹ Zr-PSMA-I&T, ¹⁷⁷ Lu-PSMA-617, or ¹⁷⁷ Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq ⁸⁹ Zr-PSMA-617 followed by PET/CT imaging. Results: ⁸⁹ Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective ¹⁷⁷ Lu-labeled counterparts with high tumor accumulation in the PSMA ⁺ xenografts. However, using a dose estimation model for ¹⁷⁷ Lu, absorbed radiation dose in bone and kidneys differed among the ¹⁷⁷ Lu-PSMA and ⁸⁹ Zr-PSMA tracers. ⁸⁹ Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection. Conclusion: PSMA-617 and PSMA-I&T were successfully labeled with ⁸⁹ Zr and demonstrated high uptake in PSMA ⁺ xenografts, which enabled PET up to 168 h post-injection. The biodistribution of ⁸⁹ Zr-PSMA-I&T and ⁸⁹ Zr-PSMA-617 resembled that of ¹⁷⁷ Lu-PSMA-I&T and ¹⁷⁷ Lu-PSMA-617, respectively. The first patient ⁸⁹ Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.

Fluorine 18 prostate-specific membrane antigen 1007 PET/CT showed good sensitivity and moderate specificity for the detection of clinically significant prostate cancer, effectively ruling this out in 93% of participants with Prostate Imaging Reporting and Data System category 3 lesions.