Using multiplexed editing and lentiviral oncogene delivery, we established organoids with six combinations of cancer drivers selected based on their co-occurrence in human prostate cancer (Fig. 1a, Extended Data Fig. 1a–c and Supplementary Table 1; hereafter: Pten−/−; Trp53−/− = PtP, Rb1−/−; Trp53−/− = RP, Pten−/−; Rb1−/− = PtR, Pten−/−; Trp53−/−; cMyc+ = PtPM, Rb1−/−; Trp53−/−; cMyc+ = RPM, Pten−/−; Rb1−/−; cMyc+ = PtRM). Here, PTCHD3 is linked to prostate carcinoma.