Background: QOL outcomes have been associated with specific genetic variants in neurotransmitter metabolism. One such variant associated with reduced symptoms in placebo studies is in the rs4680 SNP of Carboxy-O-Methyltransferase (COMT). This variant is associated with reduced COMT enzymatic activity, higher cerebral dopamine levels, and improved mood. The interaction between this germline variant and cancer-directed treatment on QOL is undefined. A priori, we hypothesized that the COMT rs4680 SNP would be associated with better pain and QOL patient reported outcomes (PROs), than wildtype (WT) COMT within the E3805 CHAARTED Trial. Methods: E3805 compared docetaxel + androgen deprivation therapy (ADT+D) vs ADT in patients with metastatic hormone sensitive prostate cancer (mHSPC). PROs were collected at baseline, 3, 6, 9, and 12 months. Blood samples were genotyped prior to treatment. We compared PROs between patients with COMT WT vs rs4680 SNP within treatment arms longitudinally. PROs include Brief Pain Inventory (BPI) classified as: no (0), minimal (1), or more (≥2) pain, and BPI interference (range 0-10, 0= no pain or interference), and the Functional Assessment of Cancer Therapy-Prostate (FACT-P, higher score= better QOL, clinically important difference (CID)= 6). Descriptive statistics were used to characterize QOL over time. Fisher’s exact test, Wilcoxon rank sum test and mixed effects models were used to evaluate the associations between SNP and QOL in each arm. Results: Of 790 participants, 550 with SNP data were included. In the ADT+D arm, SNPs were not associated with PROs at any time point. In contrast, in the ADT alone arm, when compared to WT, rs4680 was associated with less pain at 3 months, less interference at 3, 6 and 9 months, and better QOL at 6 months (met criteria for CID). Conclusions: The rs4680 SNP, often associated with higher cerebral dopamine levels and improved QOL, was associated with less pain and superior QOL among patients with mHSPC treated with ADT, but not chemohormonal therapy. This is the first hypothesis driven genotyping study to demonstrate that genetics are associated with QOL in patients with cancer, especially when treatment does not cause profound symptoms. Clinical trial information: NCT00309985.