Combinations of treatments based on radiotherapy or radionuclides to enhance immunotherapy efficacy in advanced prostate cancer: a systematic review.

Background: Prostate cancer (PCa) has been considered an immunologically "cold tumor". Indeed, in advanced PCa, immune checkpoint inhibitors (ICIs) or anti-tumor vaccines have shown poor results in phase II and phase III trials with the exception of sipuleucel-T that showed a modest survival benefit. Radiotherapy and Targeted radioisotopes, such as ²²³Radium or ¹⁷⁷Lu-PSMA-617 monotherapy, contributed in prolonging the progression-free survival of PCa patients in second or third line. However, potential benefits of combination with immune therapies were inconstantly investigated and outcomes often were discordant.

Objective: Aim of this systematic review was to gather and analyze clinical evidence about benefits and risks of combining ionizing-radiation-based treatments with the main immunotherapies administed in clinical and experimental oncology for the setting of metastatic PCa.

Methods: We performed a systematic review according to the PRISMA-ScR criteria, investigating PubMed, Web of science, Embase and Medline databases from February 2000 to April 2024, searching for phase I to phase III clinical trials associating radiotherapy with immunotherapy (RT/IT) in metastatic PCa patients.

Conclusion: We observed that combination of Ipilimumab with stereotactic beam radiotherapy (SBRT) at the dose of 8 Gy performed about 12 days (range 2-21) before immunotherapy was liked with trials with a significative gain in progression-free survival. Furtherly, we described better objective responses when immunotherapies, were associated with SBRT than radionuclides An exception was ¹⁷⁷Lu-PSMA-617, which showed promising synergic results after few cycles of standard doses, suggesting a possible enhancing of immune system, in particular when associated with anti-PD1 (pembrolizumab). Due to the few data reported in literature, both for radiotherapy and radionuclides, however, future randomized trials should confirm these data.