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Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis




To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa.


Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with (NCT03543189).


Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post–HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders.


Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

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Fig. 1: Study design and systematically coordinated tissue biopsy system.
Fig. 2: Timing of pathologic response to treatment.
Fig. 3: Detection of human CD8 (yellow), CD4 (green), PCK (cian), FOXP3 (red), Ki67 (magenta) and PD-L1 (orange) in FFPE prostate cancer biopsies by IHC-IF.
Fig. 4: Quantification of CD4+ and CD8+ T cells in patients peripheral blood samples.

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The authors acknowledge Moffitt Cancer Center CLIA Tissue Imaging Lab for Multiplex Immune Panel Procedure and Quantitative Image Analysis.

Role of the funding source:

Bristol Myers Squibb (BMS) had no role in the study design, data collection, analysis, and interpretation, or writing of the study.

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Correspondence to Kosj Yamoah.

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Conflict of interest

J.Z. reports honorarium from AstraZeneca, Merck, Sanofi and Bayer for speaker programs and advisory boards. R.J. serves as an advisor for Pfizer and a speaker for Dava Oncology. R.L. is on Clinical trial protocol committee for Cold Genesys and BMS, and serves as a scientific advisor/consultant for BMS and Ferring. S.K. reports research funds from BMS and Astra Zeneca. The remaining authors declare that they have no conflict of interest.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Clinical trial: This Phase I/II trial is registered with (NCT03543189).

Author responsible for statistical analysis: Youngchul Kim, PhD;

Funded by: Bristol Myers Squibb

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Yuan, Z., Fernandez, D., Dhillon, J. et al. Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis. Prostate Cancer Prostatic Dis 24, 140–149 (2021).

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