Aggarwal R, Rydzewski NR, Zhang L, et al. - This cohort study offers the largest integrated clinical, transcriptomic, and genomic analysis of metastatic castration-resistant prostate cancer (mCRPC) samples to date, and findings indicate that mCRPC can be categorized as luminal and basal tumors. Analogous to primary prostate cancer, results revealed a more pronounced advantage of androgen-signaling inhibitor (ASI) treatment in luminal tumors, and employment of ASIs in this population is supported. In the basal tumors, consideration may be given to a chemotherapeutic approach in some patients given the similarity to small cell/neuroendocrine prostate cancer (SCNC) and the diminished benefit of ASI treatment.

• A retrospective analysis of 4 cohorts with mCRPC (N = 634) was performed; 288 (45%) had tumors categorized as luminal, and 346 (55%) had tumors classified as basal; however, 53 of 59 (90%) SCNC tumors were basal.

• AR pathway genes were overexpressed in luminal tumors, and there was a significantly higher rate of RB1 loss (23% basal vs 4% luminal), FOXA1 alterations (36% basal vs 27% luminal) and MYC alterations (73% basal vs 56% luminal) in basal tumors.

• Worse overall survival was observed in patients with basal tumors vs those with luminal tumors only in patients treated with an ASI postbiopsy (East Coast Dream Team: hazard ratio [HR], 0.39; West Coast Dream Team: HR, 0.57).

• Significantly better survival was conferred by ASI treatment in patients with luminal tumors (HR, 0.27), whereas not in patients with basal tumors (HR, 0.62).

• Statistically significant interaction term between subtype and ASI treatment was evident (HR, 0.42).