Abstract CT157: Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial
Authors: Bryant John Michael , Sandoval Maria , Putney Ryan , Caslini Corrado , Awasthi Shivanshu , Katende Esther , Fink Angelina , Naqvi Syeda Mahrukh H , Kim Youngchul , Zhang Jingsong , Park Jong , Serna Amparo , Pow-Sang Julio , Poch Michael , Li Roger , Manley Brandon , Naghavi Arash , Torres-Roca Javier , Grass G. Daniel , Kim Sungjune , Latifi Kujtim , Hunt Dylan , Johnstone Peter A. , Dhillon Jasreman , Jain Rohit , Fernandez Daniel , Yamoah Kosj 
Published: April 2023

Abstract
Survival outcomes of grade group 5 (GG5) prostate cancer (PCa) after standard of care therapy (SOC) remain poor. Evidence suggest that high dose rate brachytherapy (HDR) and androgen depravation therapy (ADT) can serve as immune modulators. We hypothesize that the combination of HDR, ADT, and immune checkpoint inhibitors (ICI) may synergize to improve immune response and disease control. Here we report an interim analysis of a single-center single-arm phase II trial exploring this novel combination therapy with nivolumab for GG5 PCa.
Patients were enrolled from 9/2018 to 4/2021 and required to have GG5 PCa with &gt; 30% positive cores and receive ICI plus SOC regimen, comprising ADT, external beam RT (EBRT), and HDR. ICI (240 mg) was administered every 2 weeks for 4 doses beginning 4 weeks prior to HDR. HDR consisted of two 1150 cGy implants. EBRT followed HDR and consisted of 4500 cGy in 25 fractions. Total ADT length and elective nodal radiotherapy were per physician discretion. Biopsies were taken at time of diagnosis, HDR, and 1-month post HDR. Biopsy tumor samples underwent genomic profiling. Major pathologic response (MPR) was defined as &lt; 17% positive cores. Wilcoxon test and Area Under the Curve (AUC) Receiver Operating Characteristics (ROC) curves were used for statistical analyses. Toxicity was evaluated according to CTCAE v5.0. The historic control cohort consisted of all patients treated with SOC between 1/2013 to 11/2021 and met all study inclusion/exclusion criteria. Cox regression was used to calculate 2-year (2Y) risk of metastasis with censorship at 24 months (m). Median follow up (mFUP) defined from diagnostic biopsy.
Of 34 patients who received 2 or more doses of ICI, 1 patient (3%) experienced a dose limiting toxicity of autoimmune hepatitis (AH). The incidence of all grade 3 toxicity related to ICI at 3 and 6 months were both 3% (n=1; AH and QT prolongation, respectively). There was no grade 4+ toxicity at 3 m, nor any grade 3+ toxicity at 6 m. Two subjects were withdrawn from study, leaving 32 evaluable for clinical outcomes. mFUP of ICI cohort was 32 m with a 2Y PSA failure rate of 6%. CD8A, STING, ANPEP, and multiple immune signatures were associated with an early MPR (p &lt; 0.05) with ICI. The Ricketts_Immunosuppression genomic signature strongly correlated with MPR to ICI (AUC = 0.7, p = 0.01). The control cohort consisted of 59 patients with a mFUP of 35 m and a 2Y PSA failure rate of 19%. ICI demonstrated an 88% reduction in 2Y risk of metastasis compared to controls (HR = 0.12, 95% CI, 0.02 - 1.0, p = 0.05).
Combination of ICI with SOC for GG5 PCa is safe and associated with a clinically significant improvement in disease control. Key genomic features were identified to predict for early MPR to ICI. Ricketts_Immunosuppression was identified as a potential biomarker for ICI-sensitive tumor subtypes. Final analyses are anticipated in late 2023. Clinical trial information: NCT03543189.
Citation Format: John Michael Bryant, Maria Sandoval, Ryan Putney, Corrado Caslini, Shivanshu Awasthi, Esther Katende, Angelina Fink, Syeda Mahrukh H Naqvi, Youngchul Kim, Jingsong Zhang, Jong Park, Amparo Serna, Julio Pow-Sang, Michael Poch, Roger Li, Brandon Manley, Arash Naghavi, Javier Torres-Roca, G. Daniel Grass, Sungjune Kim, Kujtim Latifi, Dylan Hunt, Peter A. Johnstone, Jasreman Dhillon, Rohit Jain, Daniel Fernandez, Kosj Yamoah. Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT157.