1478 Phase 1/2 trial of androgen deprivation, with or without pTVG-AR, and with or without nivolumab, in patients with newly diagnosed, high-risk prostate cancer

<h3>Background</h3> We have previously evaluated a DNA vaccine encoding the ligand-binding domain of the androgen receptor (AR, pTVG-AR) in patients with metastatic prostate cancer. In murine studies we have demonstrated that the anti-tumor efficacy of androgen deprivation (ADT) can be improved using pTVG-AR vaccination, and that anti-tumor efficacy of vaccination can be improved with concurrent PD-1 blockade. The current trial evaluates these approaches in patients with high-risk prostate cancer treated in the neoadjuvant setting before prostatectomy. <h3>Methods</h3> 24 patients with high-risk prostate cancer planning to undergo prostatectomy were randomized to receive neoadjuvant treatment over 12 weeks with either androgen deprivation alone with degarelix (Arm 1, n=6), androgen deprivation with pTVG-AR (Arm 2, n=9), or androgen deprivation, pTVG-AR and nivolumab (Arm 3, n=9), according to the schema in (figure 1). The primary endpoint was pathological complete response (pCR) or minimal residual disease (MRD). Secondary endpoints were 1-year PSA recurrence-free survival and residual tumor volume &lt; 0.25cc. Correlative endpoints included changes in tumor-infiltrating cell populations, systemic immune changes, and whether treatment elicited changes detectable by FLT PET/CT imaging. <h3>Results</h3> Of 24 patients who underwent prostatectomy, 1 achieved MRD and 3 had residual tumor volume &lt; 0.25cc, all in treatment Arm 2. The median time to PSA recurrence was 49 weeks in Arm 1, 47 weeks in Arm 3, and has not been reached in Arm 2 (p=0.037). At one year after surgery, 20% (1/5) patients in Arm 1, 100% (5/5) patients in Arm 2, and 33% (3/9) patients in Arm 3 remained free from PSA recurrence (p=0.033). Flow cytometry analysis of tissue demonstrated differences in tumor-infiltrating T cell populations, notably with reduced CD4+CTLA-4+ T cells in patients treated in Arm 2, and increases in T cells expressing LAG-3. Further measures of systemic immunity and analysis of FLT PET imaging are underway. <h3>Conclusions</h3> While this trial remains ongoing, results suggest that vaccination targeting AR with ADT might improve outcome for patients with high-risk prostate cancer. This was unexpectedly not improved with the addition of PD-1 blockade. Immune analyses and spatial transcriptomic analyses are ongoing to identify potential explanations for this finding. In addition, this trial has been amended to include two additional treatment arms to evaluate earlier administration of PD-1 blockade, and to use PD-1 and LAG-3 concurrent blockade. The treatment arm with the most pathological responses will be expanded by an additional 15 patients to gain further information about safety and efficacy. <h3>Acknowledgements</h3> Drug support was provided by Bristol Myers Squibb and Madison Vaccines, Inc. <h3>Trial Registration</h3> ClinicalTrials.gov: NCT04989946. <h3>Ethics Approval</h3> This study was approved by the University of Wisconsin Health Sciences IRB, approval number 2021-0575.