187 - Combination of Nivolumab Immunotherapy with Radiation Therapy and Androgen Deprivation Therapy in the Management of Gleason Group 5 Prostate Cancer: Final Analysis of a Phase 2 Trial

J. M. Bryant¹, M. L. Sandoval¹, R. Putney¹, C. Caslini¹, E. Katende¹, A. Fink¹, P. Trivedi¹, S. M. Naqvi¹, Y. Kim², J. Zhang¹, J. Park¹, A. Serna¹, N. B. Lam¹, J. Pow-Sang¹, M. Poch¹, R. Li¹, B. Manley¹, A. O. Naghavi³, J. F. Torres-Roca³, D. Grass¹, S. Kim^1,4, K. Latifi³, D. C. Hunt¹, P. A. S. Johnstone¹, J. Dhillon¹, R. Jain¹, D. C. Fernandez⁵, and K. Yamoah³; ¹H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, ²H. Lee Moffitt Cancer Center and Research Institute, Department of Bioinformatics and Biostatistics, Tampa, FL, ³H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, ⁴Mayo Clinic, Jacksonville, FL, ⁵Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Purpose/Objective(s): Survival outcomes of grade group 5 (GG5) prostate cancer (PCa) after standard of care therapy (SOC) remain poor. Evidence suggests that high-dose rate brachytherapy (HDR) and androgen deprivation therapy (ADT) can serve as immune modulators. We determine whether the addition of a checkpoint inhibitor (ICI) to SOC would synergize to improve disease control for GG5 PCa patients with or without oligometastatic disease. Materials/

Methods: The single-arm phase 2 trial accrued 34 patients between 9/2018 and 4/2021 with a data cutoff date of 12/6/2023. Patients had to have GG5 PCa with >30% positive cores and receive ICI plus SOC regimen (ADT, HDR, and external beam RT [EBRT]). ICI (240 mg) was given every 2 weeks for 4 doses beginning 4 weeks prior to HDR. HDR consisted of 2 implants (1150 cGy). EBRT (4500 cGy/25 fractions) followed HDR. Biopsies were taken at time of diagnosis, HDR, and 1-month post HDR. Biopsy tumor samples underwent transcriptome profiling using the Decipher® Affymetrix platform. Major pathologic response (MPR) was defined as =1 positive cores. The primary endpoint was a 2-year freedom from biochemical recurrence (FFBR; as defined by NCCN) improvement to =90% from 75% with a one-sided alpha of 0.05 (binomial exact test). A separate contemporary control cohort consisted of all GG5 patients treated with trimodality between 1/2013 to 4/2021 that met study enrollment criteria. Additional statistical analyses consisted of Wilcoxon tests for transcriptome data, and Kaplan Meier log-rank (KM) and Cox univariable (UVA)/multivariable (MVA) analysis for clinical data.
Results: The primary endpoint was reached with a 2-year FFBR of 90.3% (p=0.031). Median follow up and ADT length was 38 and 18 months, respectively. The addition of nivolumab resulted in a median KM FFBR of 58.6 months (95% CI not reached) and there were no disease or treatment related deaths. Compared to contemporary controls (n=45), nivolumab demonstrated a 21.6% improvement in 3-year FFBR (90.4% vs. 68.8%, p=0.032). Nivolumab (p=0.009), >18 months of ADT (0.037), and stage IVB (p=0.030) were significant on 3-year FFBR MVA with control cohort. A higher Decipher® Ricketts Immunosuppression biomarker was associated with both early MPR (p=0.012) and 3-month radiographic response (p=0.021) for patients with intermediate/high Decipher® scores. Two patients (6.3%) experienced an acute grade 3 (autoimmune hepatitis and QT prolongation) toxicity related to nivolumab.
Conclusion: Nivolumab plus SOC for GG5 PCa demonstrated an improvement in 2-year FFBR to historic rate and was well tolerated. It was also associated with a 3-year FFBR improvement over a strictly defined external control cohort. Ricketts Immunosuppression was identified as a potential biomarker to predict favorable treatment response, contributing to the ongoing effort to optimize patient selection for ICI-based approaches. Our findings support further investigation with a larger randomized phase 2/3 study. Trial information: NCT03543189.