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Introduction: Many patients do not benefit from immunotherapies targeting immune checkpoints such as PD(L)-1 due to a variety of resistance mechanisms. The AhR pathway is downstream of the Trp-IDO/TDO-Kyn axis. High levels of immune-suppressive AhR-activating ligands, such as kynurenine derived from IDO1/TDO2-expressing tumors, have been implicated as a potential resistance mechanism and are associated with poor responses to PD-1 therapies. Compared with inhibition of IDO1/TDO2 alone, direct AhR inhibition can block the activation of this transcription factor and may better counteract immune suppression. BAY2416964 is a novel, oral AhR inhibitor currently in a Phase I clinical trial in patients with solid tumors. Preclinically, BAY2416964 can block the activation of AhR by kynurenine and relieve its immune-suppressive effects, thereby restoring anti-tumor T-cell activity, reducing the level of inhibitory myeloid-derived suppressor cells and regulatory T cells, and improving the effectiveness of PD-1 blockade. We have analyzed PK and biomarker data from the ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule for effective AhR inhibition. Methods: PK data were intensely sampled from patients in 10 different groups with different dosing regimens (once and twice daily) and various food-intake scenarios. AhR downstream target gene expression after ex vivo kynurenic acid stimulation of patients’ peripheral blood mononuclear cells (PBMCs) was assessed. A population PK (popPK) model was developed and calibrated to characterize the PK of BAY2416964 across treatment groups. This model accounts for the non-linear relationship between dose and bioavailability as well as the effect of food intake. Results: The preliminary popPK model identified a non-linear relationship between the BAY2416964 dose and its (relative) bioavailability which was dependent on the respective food condition. The popPK model was able to describe the clinical BAY2416964 plasma exposures from all dose groups, including the effect of food intake. Ex vivo analysis of PBMCs showed inhibition of kynurenic acid-induced AhR downstream gene expression (such as CYP1A1, CYP1B1), suggesting effective in vivo target engagement in the doses tested. Conclusion: This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial. Citation Format: Kyriakos Papadopoulos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, Yuko Ishii, David Schaer, Ilona Gutcher, Gabriele Leder, Radost Pencheva, Thomas Wagener, Christian Scheerans, Carsten Zieschang, Andrea Wagner, Spyros Stamatelos, Ecaterina Dumbrava. Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 [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 CT276.

148 Background: In ARASENS (NCT02799602), DARO in combination with ADT and DOC significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P2 q21d for 6 cycles). The effect of DARO on DOC PK was assessed by noncompartmental analysis from the first 25 patients with dense PK data and by population PK (PopPK) for all patients. DARO PK from ARASENS were compared with PK data from ARAMIS (NCT02200614; without DOC) to evaluate the impact of DOC on DARO PK. Results: Of 1306 randomized patients, 1305 were included in the full analysis set (DARO, n=651; PBO, n=654). The median treatment duration was longer with DARO vs PBO (41.0 vs 16.7 months) and more DARO-treated patients (45.9% vs 19.1%) were still receiving treatment at primary analysis cutoff (Oct 25, 2021). Almost all patients completed 6 cycles of DOC in both groups (DARO, 87.6%; PBO, 85.5%). The proportion of patients requiring DOC dose modification (interrupted/delayed or reduced) was similar between groups (DARO, 60.0%; PBO, 62.9%). TEAEs led to discontinuation/reduction of DOC in 8.0%/19.9% of DARO patients and 10.3%/19.5% of PBO patients. PopPK analysis indicated that DOC PK in ARASENS was generally consistent with that in the literature. A slight numeric increase in DOC exposure was observed in the DARO + DOC + ADT arm, with 15% higher maximum plasma concentration (geometric mean, 1.93 vs 1.68 µg/mL) and 6% higher area under the concentration-time curve (AUC0-tlast within an 8-hour sampling interval, 2.10 vs 1.99 µg·h/mL) vs PBO + DOC + ADT. This small numeric increase is likely not clinically relevant given the variability in DOC exposure (coefficient of variation, 23%–54%). PK meta-analysis of ARASENS and, which considered patients’ intrinsic characteristics as covariates (eg, age, body weight, region), indicated a 10% lower AUC0-12ss of DARO in patients receiving DOC vs those not receiving DOC, which is not considered clinically relevant. Conclusions: The combination of DARO + DOC + ADT increases overall survival with similar overall incidence of TEAEs and no observed drug-drug interactions between DARO and DOC. DARO can be effectively and safely administered with DOC in patients with mHSPC without clinically relevant changes in PK of DARO or DOC. Clinical trial information: NCT02799602 .