[¹⁷⁷Lu]Lu-PSMA-617 and PD-1 blockade: lessons from the PRINCE trial

The PRINCE trial (NCT03658447) was the first clinical study to investigate multiple cycles of radioligand therapy (RLT), using [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto^®), in combination with Programmed cell death protein 1 (PD-1) blockade in patients with metastatic castration-resistant prostate cancer (mCRPC) (1). In this single-arm phase Ib/II study, 37 patients with progression after one or more androgen receptor pathway inhibitors (ARPI), and with or without prior docetaxel chemotherapy, received [¹⁷⁷Lu]Lu-PSMA-617 every 6 weeks (6 cycles maximum). Pembrolizumab was given every 3 weeks (35 doses maximum) starting 2–4 days prior to [¹⁷⁷Lu]Lu-PSMA-617. This combination treatment was well tolerated, and there were no grade 4 events, although 11/37 (30%) developed immune-related adverse events. Prostate-specific antigen (PSA) declines 50% from baseline (PSA50) were observed in 76% of patients (28/37), however 46% (17/37) had profound PSA declines >90% from baseline, and 19% (7/37) paused [¹⁷⁷Lu]Lu-PSMA-617 treatment due to exceptional response. Median radiographic progression-free survival (rPFS) and overall survival (OS) were 11.2 and 20.8 months, respectively. Despite these favorable early outcome indicators, rPFS and OS rates were low at 24 months, suggesting that disease control was not sustained. Sandhu et al. concluded that the clinical outcomes were comparable to [¹⁷⁷Lu]Lu-PSMA-617 monotherapy in the VISION (NCT03511664) and TheraP (NCT03392428) trials, suggesting that RLT seemed to be the main driver of response, but that pembrolizumab may have benefited a subset (2,3). However, it should be recognized that the patient populations differed in terms of eligibility criteria and disease characteristics among these three trials, and hence comparisons should be interpreted with caution. Moreover, the single-arm design of the PRINCE trial precludes definitive conclusions regarding the contribution of pembrolizumab.

The goal of this trial was to enhance the therapeutic efficacy of [¹⁷⁷Lu]Lu-PSMA-617 by combining it with PD-1 blockade in an attempt to concurrently augment anti-tumor immunity. Indeed, previous trials for other cancer types have demonstrated encouraging results using a similar approach. The Phase III PACIFIC trial (NCT02125461) evaluated chemoradiotherapy with or without subsequent durvalumab in patients with non-small cell lung cancer. This trial demonstrated significantly prolonged PFS and OS in those receiving durvalumab (4,5). Similarly, patients with esophageal or gastroesophageal junction cancer treated with nivolumab following neoadjuvant chemoradiotherapy and surgery also had significantly improved disease-free survival and OS (CheckMate 577; NCT02743494) (6,7). More recently, pembrolizumab has been evaluated in combination with chemoradiotherapy in patients with muscle-invasive bladder cancer undergoing bladder-preserving treatment. While a small, non-randomized trial, this showed an encouraging 2-year metastasis-free survival and OS of 81% and 83%, respectively (8). These studies collectively demonstrate the potential clinical benefits of combining radiation with PD-1 blockade. In addition, these combinations have appeared pragmatic and safe.

However, other trials have similarly observed little additional clinical benefit using immune checkpoint blockade in combination with radiation therapy in patients with prostate cancer. As opposed to the PRINCE trial, in which PD-1 blockade was added to standard [¹⁷⁷Lu]Lu-PSMA-617 treatment, Aggarwal et al. evaluated multiple cycles of PD-1 blockade with a single dose of [¹⁷⁷Lu]Lu-PSMA-617 in a phase I trial (NCT03805594). Because radiotherapy can induce immunogenic cell death, increase the infiltration and maturation of antigen-presenting cells and CD8⁺ T cells (9), conceivably, it could help make an immunologically “cold” tumor immune microenvironment (TIME) more amenable to treatment with immunotherapies, including PD-1 blockade (10). This was the rationale for this study’s treatment design using a single dose of [¹⁷⁷Lu]Lu-PSMA-617. The authors identified a PSA50 response in 56% of patients (19/43) and a median rPFS of 6.9 months, both less than what has been observed with standard [¹⁷⁷Lu]Lu-PSMA-617 monotherapy (11). In another trial, the EVOLUTION trial (NCT05150236), patients with mCRPC received [¹⁷⁷Lu]Lu-PSMA-617 with or without combined PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. While patients receiving the combination experienced slightly improved PSA50 responses (75% vs. 67%) and median PSA PFS (7.6 vs. 7.1 months) compared to those treated with [¹⁷⁷Lu]Lu-PSMA-617 monotherapy arm, the combination was associated with markedly increased grade 3–4 treatment-related adverse events (TRAE; 75% vs. 29%) and treatment-related deaths (12).

Given that trials combining external beam radiation therapy with PD-1 blockade for other tumor types have been effective, why have trials for prostate cancer combining PD-1 blockade with [¹⁷⁷Lu]Lu-PSMA-617 not been as effective? Certainly this is due, at least in part, to the immunosuppressive TIME of prostate cancer, in which there are typically few infiltrating lymphocytes and for which immune checkpoint blockade (using PD-1 and/or CTLA-4 blockade) as monotherapy has shown limited efficacy (13,14). This is not the case for non-small cell lung cancer or bladder cancer, cancers for which PD-1 blockade has demonstrated single-agent efficacy. In addition, it is possible that the biologically delivered dose or type of (ß-emitting ¹⁷⁷Lu versus external beam) radiation being delivered affects the efficacy of the combination. For example, differences in tumor burden or tumor heterogeneity of PSMA expression could lead to differences in radiation dose delivered to tumor by radioligand therapy compared to external beam radiation therapy. Alternatively, the type of radiation or sequence of therapy could have different effects on other cells of the tumor immune microenvironment. For example, administration of a pan-cancer targeting RLT, [¹⁷⁷Lu]Lu-NM600, to prostate tumor-bearing mice increased the recruitment of immunosuppressive Tregs and myeloid-derived suppressive cells (MDSCs), populations that are more radioresistant (15,16). In contrast, delivery of an α-emitter, [²²⁵Ac]Ac-NM600, led to depletion of these immunosuppressive populations (15,16). Treatment of prostate-tumor bearing mice with another ß-emitter, [⁹⁰Y]Y-NM600, led to a relative depletion of CD8⁺ T cells and retention of Tregs whose suppressive function was increased in the presence of PD-1 blockade (17). In contrast, two groups have independently demonstrated that PD-1 blockade augmented the efficacy of α-emitting ²²⁵Ac-labeled RLT targeting PSMA in a murine model of prostate cancer (18,19).

Activation of tumor-infiltrating Tregs following PD-1 blockade has also been observed in cancer patients with hyperprogressive disease following anti-PD-1 therapy (20). In fact, results from NCT03805594 demonstrated that Tregs expanded following a single dose of [¹⁷⁷Lu]Lu-PSMA-617, and the activation marker 4-1BB was frequently upregulated on circulating Tregs, monocytes, and neutrophils post-treatment (11,21). This suggests that activation of immunosuppressive Tregs might be occurring in patients following [¹⁷⁷Lu]Lu-PSMA-617 and PD-1 blockade (22,23). Clinical trials to overcome this potential limitation are underway. For example, PRESERVE-006 (NCT05682443) is an ongoing phase I/II trial evaluating [¹⁷⁷Lu]Lu-PSMA-617 in combination with a Treg-depleting anti-CTLA-4 antibody in patients with mCRPC. While early, this trial has demonstrated safety (no grade 4-5 TRAE) and some evidence of efficacy with PSA50 responses observed (24). Another ongoing phase I/II trial (NCT04946370) is evaluating the therapeutic efficacy of [²²⁵Ac]Ac-J591, an alpha-emitter linked to a PSMA-targeting antibody, with PD-1 blockade and an ARPI in patients with mCRPC who had progressed following prior ARPI treatment. Encouraging preliminary results showed that all (12/12) patients experienced PSA decline, and 4/12 remained on trial without progression beyond 6 months (25).

While immune checkpoint blockade has been most explored as an immunotherapy agent in combination with RLT for prostate cancer, other immunotherapy approaches may be preferred to increase the efficacy of RLT. In particular, anti-tumor vaccines have demonstrated modest efficacy in prostate cancer, and sipuleucel-T is an autologous cellular vaccine that is FDA-approved for the treatment of mCRPC (26). We have found that the anti-tumor efficacy of [⁹⁰Y]Y-NM600 is improved if activated tumor-specific CD8⁺ T cells are present prior to RLT; this could be achieved by administering cancer vaccines prior to RLT in murine models of prostate cancer (27). Consistent with this finding, a single-institution retrospective study of mCRPC patients treated with [¹⁷⁷Lu]Lu-PSMA-617 showed that those who had been previously treated with an investigational anti-tumor DNA vaccine had significantly greater PSA50 response and OS compared to those who had not been treated with an anti-tumor vaccine (28). Similarly, another retrospective study reported that patients who had received sipuleucel-T prior to [¹⁷⁷Lu]Lu-PSMA-617 also achieved a higher-than-expected PSA50 response rate of 60% and median PFS of 15.2 months (29). Given the ongoing clinical evaluation of anti-tumor vaccines and other T-cell activating therapies in prostate cancer, notably CAR-T and bispecific T-cell engagers (BiTEs), combining these approaches with RLT is a rational strategy to augment T cell responses, while limiting the activation of immunosuppressive populations (30,31).

As the first trial to evaluate multiple cycles of RLT with PD-1 blockade, the PRINCE trial aimed to leverage the immunomodulatory effects of RLT by combining it with PD-1 blockade to augment T cell-mediated anti-tumor responses. Yet, the modest improvement in clinical outcomes suggests that PD-1 blockade alone may be insufficient to overcome the various mechanisms of immune resistance found within the prostate TIME. A strength of the PRINCE trial was its comprehensive translational evaluation of other markers, including ctDNA, tumor mutational burden, DNA damage repair mutations, PET imaging parameter, serial biopsies, and immune microenvironment profiling. These and other ongoing evaluations could help in the design of future combination strategies, or understanding the best sequence of therapies. In fact, future combinations of radioligand therapies with immunotherapy agents should be guided by the specific mechanisms of immune resistance learned by these types of analyses that may limit therapeutic efficacy, rather than simply prioritizing PD-1 blockade because of its clinical availability and established safety profile. Emerging evidence indicates that other immunotherapies capable of activating tumor-specific CD8⁺ T cells, and/or depleting immunosuppressive cell populations, may provide greater therapeutic benefit when combined with RLT.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0141/prf

Funding: This study was supported by NRSA award (T32 CA009135 to D.S.) and NIH (F31 CA305954 to D.S., P50 CA269011 to D.G.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0141/coif). D.S. received funding from NRSA (T32 CA009135) and NIH (F31 CA305954). D.G.M. received funding from NIH (P50 CA269011). D.G.M. served on the Scientific Advisory Board for PharmaJet and received stock options. D.G.M. has patents issued related to work on DNA vaccines as treatment for prostate cancer – none licensed at this time. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Sandhu S, Joshua AM, Emmett L, et al. 177LuLu-PSMA-617 in combination with pembrolizumab for treatment of metastatic castration resistant prostate cancer (PRINCE): a single-arm, phase 1b/2 study. Lancet Oncol 2026;27:470-9. [Crossref] [PubMed]
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;385:1091-103. [Crossref] [PubMed]
3. Hofman MS, Emmett L, Sandhu S, et al. 177LuLu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021;397:797-804. [Crossref] [PubMed]
4. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
5. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018;379:2342-50. [Crossref] [PubMed]
6. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
7. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
8. Economides MP, O'Donnell PH, Alva AS, et al. Pembrolizumab in Combination With Gemcitabine and Concurrent Hypofractionated Radiation Therapy as Bladder-sparing Treatment for Muscle-invasive Urothelial Cancer of the Bladder: A Multicenter Phase 2 Trial. Eur Urol 2026;S0302-2838(26)02034-8. [Crossref] [PubMed]
9. Sun Q, Li J, Ding Z, et al. Radiopharmaceuticals heat anti-tumor immunity. Theranostics 2023;13:767-86. [Crossref] [PubMed]
10. Kerr CP, Grudzinski JJ, Nguyen TP, et al. Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment. Pharmaceutics 2022;15:128. [Crossref] [PubMed]
11. Aggarwal R, Starzinski S, de Kouchkovsky I, et al. Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. Lancet Oncol 2023;24:1266-76. [Crossref] [PubMed]
12. Sandhu S, Subramaniam S, Thomas H, et al. 177Lu-PSMA-617 with ipilimumab (ipi) and nivolumab (nivo) in metastatic castration-resistant prostate cancer (mCRPC): An investigator-initiated phase 2 trial (EVOLUTION; ANZUP2001). J Clin Oncol 2025;43:5016.
13. Powles T, Yuen KC, Gillessen S, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med 2022;28:144-53. [Crossref] [PubMed]
14. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol 2020;38:395-405. [Crossref] [PubMed]
15. Ferreira CA, Potluri HK, Mahmoudian M, et al. Immunomodulatory effects of alpha vs beta radiopharmaceutical therapy in murine prostate cancer. Front Immunol 2025;16:1563387. [Crossref] [PubMed]
16. Ferreira CA, Potluri HK, Tantawy AA, et al. Enhanced Antitumor Efficacy of 225Ac-NM600 Compared to 177Lu-NM600 in Prostate Cancer Models. Int J Radiat Oncol Biol Phys 2026;125:566-75. [Crossref] [PubMed]
17. Potluri HK, Ferreira CA, Grudzinski J, et al. Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors. J Immunother Cancer 2022;10:e005060. [Crossref] [PubMed]
18. Sun J, Yang J, Guo J, et al. Dual-targeted alpha therapy mitigates prostate cancer and boosts immune checkpoint blockade therapy. J Control Release 2025;382:113686. [Crossref] [PubMed]
19. Czernin J, Current K, Mona CE, et al. Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer. J Nucl Med 2021;62:228-31. [Crossref] [PubMed]
20. Kamada T, Togashi Y, Tay C, et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A 2019;116:9999-10008. [Crossref] [PubMed]
21. Muralidhar A, Law K, Fan Z, et al. 674 Multi-omic single-cell assessment of castration-resistant prostate cancer patients receiving 177Lu-PSMA-617 and pembrolizumab shows timing of radioligand therapy alters immune response. J Immunother Cancer 2025;13:
22. Freeman ZT, Nirschl TR, Hovelson DH, et al. A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target. J Clin Invest 2020;130:1405-16. [Crossref] [PubMed]
23. Vinay DS, Kwon BS. 4-1BB signaling beyond T cells. Cell Mol Immunol 2011;8:281-4. [Crossref] [PubMed]
24. Wise DR, Zhang T, Tutrone R, et al. Phase 1 study of gotistobart (BNT316/ONC-392) in combination with lutetium Lu 177 vipivotide tetraxetan (Lu 177) in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2025;43:5067.
25. Holmes A, Thomas C, Fajardo AR, et al. 1606P Mature follow up of phase I dose finding trial of pembrolizumab (pembro) with AR inhibitors (ARI) and priming tumour-targeted radiation with anti-PSMA alpha emitter 225Ac-J591. Ann Oncol 2024;35:S968.
26. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22. [Crossref] [PubMed]
27. Shim D, Mouton C, Moseman JE, et al. Activation of tumor-specific CD8+ T cells prior to radiopharmaceutical therapy improves antitumor response. J Immunother Cancer 2026;14:e015261. [Crossref] [PubMed]
28. Tan B, Shim D, Lee C, et al. Immunological Priming Improves Efficacy of 177Lu-PSMA-617 in mCRPC: A Retrospective Cohort Study. J Nucl Med 2026;67:261187.
29. Shore ND, George DJ, Heath EI, et al. Outcomes of [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) after sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC): A real-world prostate cancer disease observation (PRECISION) data platform analysis. J Clin Oncol 2026;44:88.
30. Simão DC, Zarrabi KK, Mendes JL, et al. Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer. Cancers (Basel) 2023;15:1412. [Crossref] [PubMed]
31. Wooster ME, Stein MN. Chimeric antigen receptor T cell therapy in prostate cancer: racing to prime time. AME Clin Trials Rev 2026;4:10.