The mechanisms underlying metastatic latency in renal cell carcinoma (RCC) remain poorly understood. This study evaluated two large independent cohorts for differences in tumor biology between patients who developed metastases early (≤1 year after nephrectomy) and those with late-onset (>
3 years). In the discovery cohort (n = 161), late-metastatic RCC (late-mRCC) was associated with clear cell histology (88.9% vs 78.7%), lower pathological stage (pT1-2
40.3% vs 18.0%), and favorable histopathological features including low grade (40.0% vs 2.3%), less sarcomatoid (5.6% vs 21.8%), and reduced necrosis (37.7% vs 78.3%
all p <
.02). Late-mRCC tumors exhibited increased angiogenesis (63.5% vs 19.4%) and reduced inflammation (78.8% vs 50.0%
all p <
.02) profiles. Genomic driver analyses revealed comparable rates of PBRM1 and SETD2 loss in both late- and early-mRCC, while BAP1 loss was significantly less common in late-mRCC (7.5% vs 27.1%
p <
.02). In multivariable models, BAP1/PBRM1/SETD2 status and tumor necrosis emerged as key discriminators of late-mRCC. These findings were confirmed in the second cohort (n = 307). Late-mRCC was enriched for fatty acid oxidation and angiogenesis pathways, supporting a less aggressive phenotype. This was further evidenced by a lower engraftment rate in murine models (0% vs 36.5%
p <
.001) and significantly longer overall survival from the time of metastasis (median survival doubled, p <
.001). Interestingly, late-mRCC shared genomic and phenotypic features with RCC that metastasizes to the pancreas, suggesting a common underlying biology that influences both metastatic latency and pancreatic tropism. Overall, these findings advocate for recognition of late-mRCC, due to its distinct biology and improved prognosis.