Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e.g., <i>Rb1</i><sup>-<i>/</i>-</sup>; <i>Trp53</i><sup>-<i>/</i>-</sup>; <i>cMyc</i><sup>+</sup> or <i>Pten</i><sup>-<i>/</i>-</sup>; <i>Trp53</i><sup>-<i>/</i>-</sup>; <i>cMyc</i><sup>+</sup>), but only those with <i>Rb1</i> deletion progress to ASCL1+ neuroendocrine prostate cancer (NEPC), a highly aggressive, androgen receptor signaling inhibitor (ARSI)-resistant tumor. The gene discussed is ASCL1; the disease is neoplasm.