Background: Cytoreductive nephrectomy (CN) has been the standard of care in mRCC in the past twenty years, supported by randomized and large retrospective studies. However the efficacy of targeted therapies has challenged this standard. CARMENA was designed to answer the question of whether upfront CN should continue to be performed before sunitinib. Methods: CARMENA was a randomized phase III trial. Patients (pts) with synchronous mRCC, amenable to CN, were enrolled after confirmation of clear cell histology on biopsy if PS 0-1, absence of symptomatic brain metastasis, acceptable organ function and eligible for sunitinib therapy. Pts were randomized 1:1 to either CN followed by sunitinib (arm A) or sunitinib alone (arm B), and stratified by MSKCC risk groups. Sunitinib was given at 50 mg/d, 4/6wk with dose adaptation to routine practice. In arm A, sunitinib had to start 4 to 6 wk after surgery. Primary endpoint was overall survival (OS). A total of 576 pts had to be enrolled to demonstrate non inferiority hypothesis (H0: λE/λC > 1.20), with 80% power at a 1-sided significance level of 5%. Results: 450 pts were included from 9/09 to 9/17, 226 and 224 in arm A and B, respectively. Median age was 62, ECOG-PS was 0 in 56% and 1 in 44%. MSKCC risk groups were intermediate/poor in 55.6/44.4% (arm A) and in 58.5/41.5% (arm B). In arm A, 6.7% did not have CN and 22.5% never received sunitinib. In arm B, 4.9 % never received sunitinib and 17% had secondary nephrectomy. At the time of the analysis, 326 deaths have been observed with a median follow-up of 50.9 mo. OS was not inferior in arm B, overall as well as by MSKCC risk groups (table). No difference in response rate and PFS was observed. Safety of sunitinib was as expected in both arms. Conclusions: Sunitinib alone is not inferior to CN followed by sunitinib in synchronous mRCC both in intermediate and poor MSKCC risk groups. CN should not be anymore the standard of care when medical treatment is required. Clinical trial information: NCT00930033