Background: Polypharmacy (PP) is common in older adults starting cancer treatment and associated with increased risk of potential drug-drug interactions (PDI). PP and PDI may affect treatment-related outcomes in older patients. This study evaluates the association of PP and PDI with systemic treatment adverse outcomes in older adults with advanced cancer. Methods: This secondary analysis of prospectively collected data from the GAP 70+ Trial (NCT02054741; PI: Mohile) enrolled patients aged 70+ with advanced (i.e. incurable) cancer; had ≥1 geriatric assessment domain impairment; and planned to start a new chemotherapy regimen or another regimen with high risk of toxicity. PP was assessed prior to initiation of treatment and defined as concurrent use of ≥8 medications (meds). PDI among all drugs were reviewed prior to initiation of treatment using Lexi-Interact^® Online with category D and X considered “major PDI”. Study outcomes were assessed within 3 months of treatment initiation and included: 1) total number of Grade ≥2 toxicities according to National Cancer Institute Common Toxicity Criteria; 2) total number of Grade ≥3 toxicities; and 3) early treatment discontinuation due to toxicity. Multivariable linear and logistic regression models were used to examine the association of PP and PDI with treatment adverse-outcomes adjusted for age, gender, cancer type, comorbidity, physical function, social support, and study arm. Results: Among 718 participants, the mean age was 77 (range 70-96); 43% were females; and 57% had lung or gastrointestinal cancers. The median number of meds was 5 (range 0-24); 28% received ≥8 concurrent meds; and 25% had ≥1 major PDI. The mean number of Grade ≥2 toxicities for patients with PP was 9.8 versus 7.7 in patients without PP (adjusted β=1.87, standard error [SE]=0.71, P<0.01). The mean number of Grade ≥3 toxicities for patients with PP was 2.9 versus 2.2 in patients without PP (adjusted β=0.59, SE=0.29, P=0.04). Patients with ≥1 major PDI had 59% higher odds of early treatment discontinuation versus those without major PDI (adjusted odds ratio 1.59, 95% confidence interval=1.03-2.46, P=0.03). There was no significant association between PP and early treatment discontinuation. Major PDI were not significantly associated with toxicity (Ps>0.05). Conclusions: In a cohort of vulnerable older adults with advanced cancer, PP and PDI are associated with increased risk of systemic treatment adverse outcomes. Providing meaningful screening and interventional tools to optimize medication use may improve treatment outcomes in these patients. Funding:UG1CA18996, U01CA233167.