Phd in NETWORK ONCOLOGY AND PRECISION MEDICINE

Thesis title: Evaluation of Drug-Drug Interactions in Prostate Cancer patients during therapy with Abiraterone, Enzalutamide, Apalutamide or Darolutamide and Docetaxel using the Drug-PIN® software. An interim analysis of the DDI-AID study.

Background Androgen Receptor Pathway Inhibitors (ARPIs) such as abiraterone, enzalutamide, apalutamide, and darolutamide are widely used in metastatic Prostate Cancer. Given the advanced age and comorbidity burden typical of this population, polypharmacy is frequent and increases the risk of clinically relevant drug–drug interactions (DDIs). In clinical practice, DDIs are not routinely assessed, and there is a lack of knowledge on their impact on oncologic outcome (toxicity and survival). The Drug-PIN® software is the first intelligent system that analyze phenotypical data and DDIs, considering and integrating multiple dimensions of a multifactorial network. The DDI-AID study investigates the prevalence of DDIs and their potential association with clinical outcomes. Methods The study includes both retrospective and prospective cohorts of patients with mHSPC or mCRPC initiating ARPI therapy alongside at least one concomitant medication. Drug-PIN® scores were collected at baseline and after ARPI introduction to classify patients into low- or high-risk DDI categories. Primary endpoints were DDI prevalence, DDI correlation with treatment related adverse events and progression-free survival (PFS). Cox models were used for multivariate adjustment. Results This is an interim analysis reporting results from the first 132 cases. Baseline polypharmacy was common, with up to 50% of patients receiving ≥5 drugs. ARPI initiation significantly increased Drug-PIN® scores, particularly in the abiraterone and enzalutamide groups. After ARPI introduction, high-risk DDI profiles were observed in 33–38% of patients in these groups. DDI burden was significantly associated with PFS: median PFS was 30.8 months in the low-risk group versus 12.0 months in the high-risk group. Low-risk DDIs remained independently predictive of longer PFS in multivariate analysis (HR 0.53, p = 0,044). No significant differences in toxicity were observed between groups. Conclusions Interim findings suggest that DDIs are common in patients treated with ARPIs and may substantially reduce treatment effectiveness. Systematic DDIs assessment using tools such as Drug-PIN® may improve therapeutic outcomes. Full study completion and prospective validation will clarify underlying mechanisms and inform clinical practice.