Purpose of Review <p>Polypharmacy is highly prevalent among older adults with advanced cancer, particularly those with multimorbidity and limited life expectancy. The concurrent use of multiple medications increases the risk of potentially inappropriate medications (PIMs), drug–drug interactions, and adverse events, compromising quality of life and clinical outcomes. This systematic review aimed to examine current evidence on deprescribing for comorbidities in advanced cancer patients, identifying barriers and facilitators, frequent classes of PIMs, available tools to support deprescribing, and proposing a model to prioritise medications for discontinuation.</p> Recent Findings <p>Reported barriers to deprescribing included prognostic uncertainty, fragmented care, time constraints, patient resistance, and clinician reluctance. Facilitators comprised interdisciplinary collaboration, pharmacist-led reviews, validated tools (e.g., STOPP/START, Beers Criteria, OncPal, OncoSTRIP), and patient-centred communication. Frequently identified PIMs included statins, antihypertensives, proton pump inhibitors, anticholinergic agents, and vitamins. Deprescribing was most effective when integrated into routine workflows and guided by systematic, goal-concordant approaches.</p> Summary <p>Deprescribing in patients with advanced cancer and comorbidities is essential to mitigate the risks of polypharmacy. A structured, patient-centred process—supported by multidisciplinary teams and validated tools—is key to aligning pharmacological regimens with prognosis, functional status, and individual goals of care.</p>