TRAMP study: A phase 2 trial of tumor necrosis factor-α blockade and AR inhibition in men with CRPC.

Le résumé fourni par la source

TPS5117 Background: Combining androgen receptor signaling inhibitors (ARSI) with androgen deprivation therapy (ADT) leads to improved clinical outcomes compared to ADT alone in patients with advanced prostate cancer (PC). However, treatment resistance and cancer progression invariably occur. Novel strategies to overcome resistance to AR pathway inhibition are needed. TNF-α is a “master regulator” of a pro-inflammatory cytokine cascade mediated through activation of the transcription factor nuclear factor kappa-B. TNF-α also mediates pro-survival signaling in tumor cells, elicits pro-tumor immune changes in the tumor microenvironment, and promotes tumor cell migration and metastases in PC models. Our group recently showed that TNF-α induces AR signaling and increases PC cell clonogenic growth, even in the presence of ARSIs. Pharmacologic inhibition and genetic ablation of TNF-α signaling subsequently rescued and thereby enhanced the activity of AR antagonists. Taken together, we hypothesize that the addition of TNF-α blockade to AR antagonist may overcome resistance and thus extend the duration of response to ARSI treatment. Methods: This Phase 2, single-center, single-arm trial aims to enroll 34 patients with castration-resistant prostate cancer (CRPC) and will employ a Bayesian continual reassessment method study design with early stopping rules for both toxicity and futility. Eligible patients must have progressing CRPC (defined as either a confirmed rising PSA ≥ 2 ng/ml or radiographic progression) and previously received at least 6 months of ARSI therapy in the hormone-sensitive setting. Prior taxane chemotherapy is allowed in the hormone-sensitive setting, but must be completed ≥ 6 months prior to enrollment. All patients will receive the TNF-α inhibitor golimumab (50mg SC monthly) for up to six months plus AR antagonist apalutamide (240mg PO daily). The primary endpoint is the rate of PSA50 (defined as ≥50% decline from baseline PSA) at 12 weeks. The null hypothesis is that the true response rate is 0.22 (ARN-509-001, NCT01171898), and the alternative hypothesis is that the true response rate is 0.44. Secondary endpoints include objective response rate, PSA progression-free survival (PFS), radiographic PFS, time to subsequent antineoplastic therapy, and overall survival. Correlative studies will quantify pre-treatment proinflammatory cytokines and classify ctDNA and metastatic tumor biopsies into 3 phenotypic categories based on AR activity levels (“high,” “weak/heterogeneous,” or “absent”) using quantitative gene expression and digital spatial profiling. We plan to evaluate treatment-induced changes and assess if AR activity is modulated by TNF- inhibition and determine whether the modulation is associated with improved clinical outcomes. The trial is open to enrollment. Clinical trial information: NCT05960578 .

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.