Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1−/−; Trp53−/−; cMyc+ or Pten−/−; Trp53−/−; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Here, MYC is linked to adenocarcinoma.