Optimizing salvage radiotherapy in prostate cancer: the emerging role of prostate-specific membrane antigen positron emission tomography/computed tomography

We are grateful to accept the invitation to provide this commentary on the recently published article entitled “Impact of prostate-specific membrane antigen positron emission tomography/computed tomography on prostate cancer salvage radiotherapy management: results from a prospective multicenter randomized phase 3 trial (PSMA-SRT NCT03582774)” (1).

Conventional imaging tests rarely detect disease with serum prostate-specific antigen (PSA) values of <1.0 ng/mL (2-5). Armstrong et al. (1) published a robust and highly topical paper on the utility of prostate-specific membrane antigen positron emission tomography (PSMA-PET) for initial staging and restaging of prostate cancer, particularly for detecting recurrent prostate cancer at low PSA levels (5-7). This important trial adds to the salvage radiotherapy (SRT) literature an important analysis of how PSMA-PET-guided SRT could allow an individualization of the treatments taking into account volume adaptation, dose escalation, as well as an intensification of the systemic treatment, estimating that this could improve 5-year progression-free survival by 20% (1).

The use of SRT has been debated in recent years. Attempts have been made to establish risk groups based on different factors in an attempt to stratify patient risk and thus individualize the indication for SRT. The European Association of Urology (EAU) guideline has established risk groups in this sense based on PSA doubling time (PSA-DT) and pathological International Society of Urological Pathology (ISUP) grade group <4 (8-10). According to this classification, it has also been shown that in patients classified as high-risk PSMA-PET detects more metastatic disease (11).

The first point in favour of the PSMA-SRT NCT03582774 trial is that it is a prospective, multicentre, randomized, controlled, open-label, phase III clinical trial unlike most of the retrospective published studies on the impact of PSMA-PET on SRT management.

The participants enrolled on this study were patients who undergo SRT for prostate cancer biochemical relapse (BCR) after radical prostatectomy and PSA >0.1 ng/mL. Investigational arm included patients with PSMA-PET scan prior to SRT planning vs. patients who received SRT without PSMA-PET (control arm). It is important to highlight that at the time of enrolment, fluciclovine-PET was Food and Drug Administration (FDA) approved as standard of care in the BCR field and was allowed in the control arm. Up to 43% of patients in the control arm underwent fluciclovine PET/computed tomography (CT), potentially affecting the interpretation of the results, taking into account that it is not currently considered a standard but whose results clearly improve the detection of tumour disease in the control arm with respect to conventional imaging tests such as bone-scan or CT-scan, less sensitive and specific (12).

Of a total of 193 patients, 103 patients were included in the investigational arm. All patients were planned standard treatment without PSMA-PET information. Changes in planned treatment were recorded as major, minor, or no change. In the investigational arm, 45% more major changes were detected and these included any treatment escalations. Seventy-two percent of these changes were due to the PSMA-PET in the intervention arm. It is important to note that they defined major changes as the addition of advanced systemic treatment, the modification of androgen deprivation therapy (ADT) for 3 months, the variation of the target volumes of radiotherapy treatment, and the addition of a simultaneous-integrated boost (SIB) to the standard radiotherapy treatment. On the other hand, treatment escalation was defined as adding a new radiotherapy treatment volume, increasing the prescribed radiation dose, as well as adding advanced systemic treatment with or without ADT.

The authors also assessed the relationship of these changes in management and PSMA-PET. They analyzed different variables, but only PSMA-PET had a significant impact on the frequency of changes in therapeutic management, both for treatment intensification and for not offering SRT due to evidence of distant metastases. On the one hand, evidence of localized disease allowed dose escalation and/or a change in volume contouring, or the addition of systemic treatment, a situation that occurred in 36% vs. 12% in the experimental arm and the control arm, respectively.

In this paper, SRT treatment was omitted in 9% of the patients who presented a negative PSMA-PET. Several authors have found progression-free survival benefit in favour of SRT in those patients with negative PSMA-PET or with disease located in the surgical bed (prostatic fossa) despite receiving less extensive radiotherapy and lower rates of additional ADT than those with distant disease (13). Similarly, several studies have shown that patients with negative PSMA-PET who do not receive SRT have worse oncologic outcomes compared to those who do (13-16). Interestingly, omission of SRT for ADT ± androgen receptor pathway inhibitor (ARPI) was considered as an escalation or a de-escalation strategy, rending the interpretation of what is a relevant strategy difficult to define. Currently, according to the indications of international clinical guidelines, SRT is recommended as standard treatment in these patients with PSMA-PET, positive or negative, and its omission is suboptimal and may influence the results of the primary endpoint of the study. Similarly, it has been demonstrated from a phase III trial that SRT prolongs time to treatment failure in patients with post-radical prostatectomy PSA failure when compared to hormonal treatment alone (17), highlighting the fact that SRT omission could lead to a loss of chances to be cured in both arms. At this moment, the value of PSMA-PET findings for the indication of systemic treatment is still unclear since the clinical trials that gave the indication for the systemic treatments currently indicated in advanced disease used conventional imaging tests and have not been validated with molecular imaging tests.

Evidence of distant metastatic disease in advance imaging could led to important changes in the therapeutic approach, avoiding local SRT and intensifying systemic and/or local ablative treatment. Ten percent of patients received systemic treatment and/or stereotactic body radiation therapy due to loco-regional or distant disease detection (vs. 1% in the control arm).

Multiple papers have analyzed the role of treatment intensification with both ADT and SRT. Regarding the use of ADT, Ghadjar et al. (18) reviewed several studies, including the prospective RTOG 9601 and GETUG-AFU-16, and concluded that the use of ADT produced a benefit in overall and biochemical progression-free survival, without significantly increasing side effects. Thus, the use of ADT was recommended in patients with aggressive characteristics to improve oncological outcomes, specifically in patients with a PSA level before SRT of ≥0.7 ng/mL. In patients without persistent PSA after prostatectomy and PSA levels of <0.7 ng/mL, ADT should be considered if they present other risk factors such as Gleason score ≥8 and negative surgical margins. Recently, similar findings were showed in an ICECaP study proposing a risk score for patients receiving SRT with or without hormonal treatment, using three standard-of-care clinico-pathological risk factors providing refined prognostic information for individual patient counselling (19). With this in mind, the SPPORT clinical trial (20) wanted to analyze the benefit of adding short-term ADT to radiation of the surgical bed, and of adding short-term ADT to radiation of the pelvic bed and lymph node areas. However, there is no evidence of the optimal approach if advanced imaging tests are used in pre-treatment staging and possible treatment changes associated with their use.

In conclusion, taking into account the above and according to the indications of international clinical guidelines, we can summarize that SRT is recommended as standard treatment in these patients with PSMA-PET, and its omission is suboptimal and may influence the results of the primary objective of the study, PFS, a debatable objective not being consider as a surrogate end-point for survival. Karpinski et al. compared the prognostic value of the PSMA-PET according to PROMISE (PPP) with respect to other nomograms demonstrating that the PPP was able to stratify patients into high and low risk in terms of overall survival being better or at least equal with respect to other risk stratification tools (21). However, the exclusive use of PSMA-PET may be insufficient and relying on genomic scans may help to define a tailored strategy for those patients regarding dose/volume adaptations and/or ADT use (22,23).

Undoubtedly, the published data are of great value, although the data that will probably be presented this year concerning the primary objective as well as the toxicity associated with the treatments administered in those patients in whom an intensification based on advanced imaging tests has been carried out are lacking in order to be able to comprehensively assess the results obtained.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-188/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-188/coif). E.G.d.P. receives payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Johnson & Johnson, Astrazeneca, and Adventia; and support for attending meetings and/or travel from Astellas, Johnson & Johnson, Astrazeneca, and Adventia. F.L.C. receives consulting fees from Astellas, Bayer, Johnson & Johnson, and Recordati; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Bayer, Johnson & Johnson, Recordati, Accord, and Ipsen; and support for attending meetings and/or travel from Astellas, Bayer, Johnson & Johnson, and Recordati. P.S. receives payment or honoraria from Astellas, Bayer, Janssen, Sanofi, Ipsen, Takeda, Recordati, Fering, and Accord Healthcare; and support for attending meetings and/or travel from Astrazeneca, Astellas, Janssen, and Roche. F.C. receives grants or contracts from any entity from Sponsored Research, and Janssen; consulting fees from Janssen, and Astrazeneca; payment or honoraria from Janssen, Roche Farma, Astrazeneca, and Astellas; and support for attending meetings and/or travel from Astrazeneca, Astellas, Janssen, from Roche Farma. The authors have no other conflicts of interest to declare.

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References

1. Armstrong WR, Kishan AU, Booker KM, et al. Impact of prostate-specific membrane antigen positron emission tomography/computed tomography on prostate cancer salvage radiotherapy management: results from a prospective multicenter randomized phase 3 trial (PSMA-SRT NCT03582774). Eur Urol 2024;86:52-60. Erratum in: Eur Urol 2025;87:97-9. [Crossref] [PubMed]
2. Kane CJ, Amling CL, Johnstone PA, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology 2003;61:607-11. [Crossref] [PubMed]
3. Woo S, Han S, Kim TH, et al. Prognostic Value of Pretreatment MRI in Patients With Prostate Cancer Treated With Radiation Therapy: A Systematic Review and Meta-Analysis. AJR Am J Roentgenol 2020;214:597-604. [Crossref] [PubMed]
4. Taneja SS. Imaging in the diagnosis and management of prostate cancer. Rev Urol 2004;6:101-13. [PubMed]
5. Zhu M, Liang Z, Feng T, et al. Up-to-Date Imaging and Diagnostic Techniques for Prostate Cancer: A Literature Review. Diagnostics (Basel) 2023;13:2283. [Crossref] [PubMed]
6. Calais J, Ceci F, Eiber M, et al. (18)F-fluciclovine PET-CT and (68)Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol 2019;20:1286-94. [Crossref] [PubMed]
7. Olivier P, Giraudet AL, Skanjeti A, et al. Phase III Study of (18)F-PSMA-1007 Versus (18)F-Fluorocholine PET/CT for Localization of Prostate Cancer Biochemical Recurrence: A Prospective, Randomized, Crossover Multicenter Study. J Nucl Med 2023;64:579-85. [Crossref] [PubMed]
8. Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2024;86:148-63. [Crossref] [PubMed]
9. Roberts MJ, Chatfield MD, Hruby G, et al. Event-free survival after radical prostatectomy according to prostate-specific membrane antigen-positron emission tomography and European Association of Urology biochemical recurrence risk groups. BJU Int 2022;130:32-9. [Crossref] [PubMed]
10. Scharl S, Zamboglou C, Strouthos I, et al. European association of urology risk stratification predicts outcome in patients receiving PSMA-PET-planned salvage radiotherapy for biochemical recurrence following radical prostatectomy. Radiother Oncol 2024;194:110215. [Crossref] [PubMed]
11. Ferdinandus J, Fendler WP, Farolfi A, et al. PSMA PET Validates Higher Rates of Metastatic Disease for European Association of Urology Biochemical Recurrence Risk Groups: An International Multicenter Study. J Nucl Med 2022;63:76-80. [Crossref] [PubMed]
12. Jani AB, Schreibmann E, Goyal S, et al. (18)F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial. Lancet 2021;397:1895-904. [Crossref] [PubMed]
13. Emmett L, Tang R, Nandurkar R, et al. 3-Year Freedom from Progression After (68)Ga-PSMA PET/CT-Triaged Management in Men with Biochemical Recurrence After Radical Prostatectomy: Results of a Prospective Multicenter Trial. J Nucl Med 2020;61:866-72. [Crossref] [PubMed]
14. Bernardino RM, Lajkosz K, Yin LB, et al. Association of Free-to-Total PSA Ratio and (18)F-DCFPyL Prostate-Specific Membrane Antigen PET/CT Findings in Patients with Biochemical Recurrence After Radical Prostatectomy: A Prospective Single-Center Study. J Nucl Med 2024;65:1731-9. [Crossref] [PubMed]
15. Emmett L, Metser U, Bauman G, et al. Prospective, Multisite, International Comparison of (18)F-Fluoromethylcholine PET/CT, Multiparametric MRI, and (68)Ga-HBED-CC PSMA-11 PET/CT in Men with High-Risk Features and Biochemical Failure After Radical Prostatectomy: Clinical Performance and Patient Outcomes. J Nucl Med 2019;60:794-800. [Crossref] [PubMed]
16. Hope TA, Eiber M, Armstrong WR, et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection: A Multicenter Prospective Phase 3 Imaging Trial. JAMA Oncol 2021;7:1635-42. [Crossref] [PubMed]
17. Yokomizo A, Wakabayashi M, Satoh T, et al. Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised, Multicentre, Open-label, Phase 3 Trial (JCOG0401) Eur Urol 2020;77:689-98. [Crossref] [PubMed]
18. Ghadjar P, Aebersold DM, Albrecht C, et al. Use of androgen deprivation and salvage radiation therapy for patients with prostate cancer and biochemical recurrence after prostatectomy. Strahlenther Onkol 2018;194:619-26. [Crossref] [PubMed]
19. Pommier P, Xie W, Ravi P, et al. Prognostic factors in post-prostatectomy salvage radiotherapy setting with and without hormonotherapy: An individual patient data analysis of randomized trials from ICECaP database. Radiother Oncol 2024;201:110532. [Crossref] [PubMed]
20. Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial. Lancet 2022;399:1886-901. [Crossref] [PubMed]
21. Karpinski MJ, Hüsing J, Claassen K, et al. Combining PSMA-PET and PROMISE to re-define disease stage and risk in patients with prostate cancer: a multicentre retrospective study. Lancet Oncol 2024;25:1188-201. [Crossref] [PubMed]
22. Dal Pra A, Ghadjar P, Ryu HM, et al. Predicting dose response to prostate cancer radiotherapy: validation of a radiation signature in the randomized phase III NRG/RTOG 0126 and SAKK 09/10 trials. Ann Oncol 2025;36:572-82. [Crossref] [PubMed]
23. Feng FY, Huang HC, Spratt DE, et al. Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial. JAMA Oncol 2021;7:544-52. [Crossref] [PubMed]