158 Background: A subset of mCRPC patients (pts) that develop resistance to next-gen androgen signaling inhibitors are subsequently found to harbor t-SCNC. We have undertaken a longitudinal prospective biopsy (bx) study to clinically and molecularly characterize these pts. Methods: Eligible pts underwent an image-guided mCRPC bx at one of 5 WCDT centers. Tissue was both frozen and formalin fixed/paraffin embedded (FFPE). FFPE tissue was used for targeted next generation sequencing (NGS) and independent pathologic review by 3 pathologists. Frozen specimens underwent laser capture micro-dissection prior to RNA sequencing (seq). Machine learning was used to derive histology-specific expression signatures. Linear Discriminant Analysis (LDA) was applied to the RNA seq data from the first 131 bx using 3 observed histologic subtypes as labels to test for an intermediate subtype. Results: Of 391 mCRPC metastasis (53% bone, 26% node, 12% liver, 9% other soft tissue), 295(75%) yielded cancer. Overall, 89% of the bx contained a single histologic subtype: pure adeno in 156(53%); pure t-SCNC in 35(12%). A novel morphologically distinct subtype, IAC, with features of both tSCNC and adeno was seen in 72(24%). Samples comprised of two subtypes made up 32(11%) of all bx. Overall, 50(17%) of bx had a t-SCNC component. TP53 and/or RB1 loss of function variants were significantly more frequent in t-SCNC. NGS revealed no difference between adeno and IAC. LDA classified IAC as intermediate between adeno and t-SCNC 93% of the time, across 100 bootstrap replicates, significantly better than the 33% expected by chance (p <10⁻¹⁷). Conclusions: Nearly half of mCRPC bx exhibit non-adeno features with t-SCNC found in 17%. IAC is a reproducible mCRPC histologic subtype found in 24% of bx, with a gene expression signature that is intermediate to adeno and t-SCNC, and targeted NGS results similar to adeno. Understanding the role of IAC in disease evolution and resistance is critical for improving outcomes in mCRPC. Clinical trial information: NCT02432001.