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Defining the Position of [177Lu]Lu-PSMA Radioligand Therapy in the Treatment Landscape of Metastatic Castration-Resistant Prostate Cancer: A Meta-analysis of Clinical Trials

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Abstract

Background

In recent years, theranostics has become a promising approach for treating metastatic castration-resistant prostate cancer (mCRPC), with trials investigating targeted radioligand therapy, particularly using prostate-specific membrane antigen labeled with lutetium-177 ([177Lu]Lu-PSMA). The proper position of [177Lu]Lu-PSMA in the therapeutic algorithm of mCRPC is yet to be identified.

Design, Setting, and Participants

We conducted a systematic review and meta-analysis of phase II/III randomized controlled trials to assess the efficacy of [177Lu]Lu-PSMA in treating mCRPC. Study endpoints included radiographic progression-free survival (rPFS), prostate-specific antigen-PFS, objective response rate, and overall survival.

Outcome Measurements and Statistical Analysis

Data were extracted according to the PRISMA statement. Summary hazard ratios (HRs) were calculated using random- or fixed-effects models. Statistical analyses were performed with RevMan software (v.5.2.3).

Results

[177Lu]Lu-PSMA reduced the risk of rPFS (HR 0.55; 95% confidence interval [CI] 0.43–0.71; p < 0.00001) and prostate-specific antigen-PFS (HR 0.53; 95% CI 0.41–0.67; p < 0.00001), and improved the objective response rate compared with control therapies (response rate 3.55; 95% CI 1.91–6.60; p < 0.0001), whereas no significant cumulative effect on overall survival was documented (HR 0.92; 95% CI 0.65–1.31; p = 0.63). Notably, in a dedicated subanalysis, comparable effects on rPFS were observed when [177Lu]Lu-PSMA was compared with active therapy.

Conclusion

[177Lu]Lu-PSMA has a favorable impact on the radiographic and biochemical control of mCRPC and represents a potential treatment in a scenario where other valuable options are available. Further efforts are required to identify clinical and molecular markers necessary for proper patient stratification.

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Author notes

  1. Chiara Ciccarese and Matteo Bauckneht authors share the first co-authorship.

Authors and Affiliations

  1. Medical Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy

    Chiara Ciccarese, Giampaolo Tortora & Roberto Iacovelli

  2. Faculty of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy

    Chiara Ciccarese, Viria Beccia, Giampaolo Tortora, Lucia Leccisotti, Alessandro Giordano & Roberto Iacovelli

  3. Department of Health Sciences (DISSAL), University of Genova, 16132, Genoa, Italy

    Matteo Bauckneht, Francesco Lanfranchi & Gianmario Sambuceti

  4. Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, University of Genova, 16132, Genoa, Italy

    Matteo Bauckneht & Gianmario Sambuceti

  5. Nuclear Medicine Unit, Department of Radiology and Oncological Radiotherapy, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy

    Luca Zagaria, Germano Perotti, Giada Pinterpe, Fortuna Migliaccio, Lucia Leccisotti & Alessandro Giordano

  6. Medical Oncology 1, IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy

    Giuseppe Fornarini

  7. Unit of Oncology, Santa Chiara Regional Hospital, APSS, Trento, Italy

    Orazio Caffo

Authors
  1. Chiara Ciccarese
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Corresponding author

Correspondence to Matteo Bauckneht.

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Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Chiara Ciccarese has received speaker honoraria from Astellas, BMS, EISAI, IPSEN, Janssen, MSD, Novartis, Pfizer, and Sanofi. Matteo Bauckneht has received speaker honoraria from Novartis and GE Healthcare. Giampaolo Tortora is an advisory board member for BMS and Novartis. Luca Zagaria has received speaker honoraria from Novartis. Orazio Caffo has received speaker honoraria from Astellas, Astra Zeneca, Bayer, Janssen, Ipsen, MSD, Novartis, Pfizer, and Recordati. Roberto Iacovelli is an advisory board member for Astellas, BMS, EISAI, IPSEN, Janssen, MSD, Novartis, Pfizer, and Sanofi and a consultant for Astellas, EISAI, MSD, and Pfizer. Giuseppe Fornarini, Viria Beccia, Francesco Lanfranchi, Germano Perotti, Giada Pinterpe, Fortuna Migliaccio, Lucia Leccisotti, Gianmario Sambuceti, and Alessandro Giordano declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Availability of data and material

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Authors' contributions

Conceptualization: C.C., M.B., and R.I. Data curation: L.Z., G.F., V.B., F.L., G.P., G.P., F.M., G.T., L.L., G.S., A.G., and O.C. Formal analysis: C.C., M.B., and R.I. Investigation: C.C., and M.B. Methodology: all authors. Software: C.C. and R.I. Writing - original draft: C.C., M.B., and R.I. Writing - review & editing: all authors.

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Ciccarese, C., Bauckneht, M., Zagaria, L. et al. Defining the Position of [177Lu]Lu-PSMA Radioligand Therapy in the Treatment Landscape of Metastatic Castration-Resistant Prostate Cancer: A Meta-analysis of Clinical Trials. Targ Oncol 20, 103–112 (2025). https://doi.org/10.1007/s11523-024-01117-1

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