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While organ‐confined prostate cancer (PCa) is mostly therapeutically manageable, metastatic progression of PCa remains an unmet clinical challenge. Resistance to anoikis, a form of cell death initiated by cell detachment from the surrounding extracellular matrix, is one of the cellular processes critical for PCa progression towards aggressive disease. Therefore, further understanding of anoikis regulation in PCa might provide therapeutic opportunities. Here, we discover that PCa tumours with concomitant inhibition of two tumour suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having < 50% 5‐year secondary‐therapy‐free patient survival. Functionally, overexpression of PME‐1, a methylesterase for the catalytic PP2A‐C subunit, inhibits anoikis in PTEN‐deficient PCa cells. In vivo, PME‐1 inhibition increased apoptosis in in ovo PCa tumour xenografts, and attenuated PCa cell survival in zebrafish circulation. Molecularly, PME‐1‐deficient PC3 cells display increased trimethylation at lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3), a phenotype known to correlate with increased apoptosis sensitivity. In summary, our results demonstrate that PME‐1 supports anoikis resistance in PTEN‐deficient PCa cells. Clinically, these results identify PME‐1 as a candidate biomarker for a subset of particularly aggressive PTEN‐deficient PCa. A subset of prostate cancer (PCa) tumours present simultaneous inactivation of two tumour suppressor phosphatases; phosphatase and tensin homolog (PTEN) and protein phosphatase 2A (PP2A). PP2A is inhibited via overexpression of PME‐1. Such cancers are particularly aggressive and often relapse from standard therapy, indicating PME‐1 as a potential clinically applicable biomarker for PCa. Mechanistically, PME‐1 expression protects cancer cells from anoikis, promoting their survival outside the primary tumour.