Background: The phase-3, investigator-initiated, ORCHESTRA trial (NCT01792934) was conducted to prospectively evaluate overall survival (OS) benefit from tumor debulking in addition to standard palliative systemic therapy in patients with multiorgan metastatic colorectal cancer (mCRC). Local therapy of metastases is increasingly discussed as part of the treatment plan for patients with multiorgan mCRC in analogy to selected patients with oligometastatic disease for whom this is standard of care. Treatment decisions are made on a daily base in multidisciplinary teams (MDT) worldwide, but evidence of superiority for additional local therapy over systemic therapy alone based on a head-to-head comparison is lacking. Methods: Between May 2013 and May 2023, 454 patients were enrolled in 28 hospitals. Patients with multiorgan mCRC as described in Table, were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy at the start of first-line palliative systemic therapy according to the MDT. Upon clinical benefit after 3 or 4 cycles of respectively capecitabine or 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, 382 patients were randomized 1:1 to continuation with systemic therapy alone in the standard arm or to tumor debulking followed by restart of the systemic therapy in the experimental arm. The primary endpoint was OS, from the date of inclusion to the date of death. Secondary endpoints included progression free survival (PFS) and treatment related adverse events. OS and PFS were analyzed by means of multivariable Cox proportional hazards regression analysis where the variables used in the randomization process were included as covariates. Results: 382 patients were randomized to either receive standard palliative systemic therapy in the standard arm (N=192) or to receive additional tumor debulking to palliative systemic therapy in the experimental arm (N=190). Baseline characteristics of patients were in standard arm versus (vs) experimental arm: median age 64 vs 64 years, male 69% vs 67%, >2 organs involved 38% vs 40%, baseline LDH >250 U/L 17% vs 16%, baseline CEA >200 ng/ml 5% vs 8%. At data cut-off on April 4th, 2024, a total of 153 OS events were observed in the standard arm and 155 OS events in the experimental arm. Median follow up was 32.3 months. Median OS in the standard arm was 27.5 months versus 30.0 months in the experimental arm (adjusted HR 0.88 [95% CI 0.70-1.10] p=0.225). Median PFS in the standard arm was 10.4 months versus 10.5 months in the experimental arm (adjusted HR 0.83 [95% CI 0.67-1.02], p=0.076). Details on local treatment modalities being applied, including rate of successful radical debulking and related adverse events, will be presented at the meeting. Conclusions: Additional tumor debulking to standard first-line palliative systemic therapy failed to improve overall survival for patients with multiorgan metastatic colorectal cancer. The increasing use of local therapies for patients with mCRC needs further consideration. Clinical trial information: NCT01792934.