Background: There are limited treatment options for patients with metastatic colorectal cancer (mCRC) who have progressed on standard therapies. A personalised approach to guide treatment selection would maximise efficacy whilst minimising unnecessary toxicity. Patient derived tumour organoids (PDTO) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. Drug sensitivity testing on PDTO models have the potential to guide personalised treatment in this clinical setting. Methods: FORECAST-1 is a feasibility study, sponsored by the Australian Gastro-Intestinal Trials Group, of PDTO-based drug sensitivity testing for 30 patients with mCRC that have failed ≥two lines of therapy. Established PDTOs underwent drug sensitivity screening including regorafenib, TAS102, oxaliplatin, irinotecan, 5FU, gemcitabine, pemetrexed and temozolomide. Patients underwent treatment at clinician’s discretion, with clinical response correlated with PDTO response. Results: Between September 2020 and December 2021, 30 patients were enrolled in the study with a median age of 59 years (range 36-71). All patients were ECOG 0-1 and eight patients had received prior TAS102 treatment. Fresh tumour biopsies were obtained from liver (N = 17), soft tissue/peritoneal metastases (N = 5), lung (N = 3), lymph node (N = 2), primary colon (N = 1), brain (N = 1) and bone (N = 1). 20/30 (67%) of patients had successful drug sensitivity screening performed at a median PDTO age of 62 days (range 42-128), nine PDTO cultures failed, and one is still undergoing culture. 15/17 (88%) of PDTO cultures obtained from a fresh liver biopsy were successfully cultured to drug sensitivity testing. 14/20 (70%) of PDTOs that underwent drug sensitivity testing identified therapies with intermediate to high likelihood of clinical response, including regorafenib (N = 7), TAS102 (N = 5), gemcitabine (N = 4), oxaliplatin (N = 3), irinotecan (N = 1), 5FU (N = 1) and temozolomide (N = 1). Subsequent anti-cancer treatment received by patients after study enrolment included TAS102 (N = 7), FOLFOX (N = 3), FOLFIRI+EGFR-inhibitor (N = 2), FOLFIRI (N = 2), regorafenib (N = 1), capecitabine (N = 1) and an immunotherapy based clinical trial (N = 2). As of February 2022, 11 patients remain on active anti-cancer therapy and 17 patients have died. Conclusions: Improving therapeutic selection in refractory mCRC patients remains an area of high clinical need. Two-thirds of patients achieved PDTO establishment to allow drug sensitivity testing in a timely manner. Of these further potentially efficacious treatments were able to be successfully identified. Methods to accelerate PDTO culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDTO sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.