Advanced prostate cancer is often treated sequentially with monotherapies until tumours inevitably develop resistance. This has created new clinical challenges, including the emergence of aggressive androgen receptor (AR)-null subtypes of prostate cancer. Nevertheless, recent clinical trials demonstrate that combining different treatments for prostate cancer can improve patient outcomes. Consistent with this, we are using the Melbourne Urological Research Alliance (MURAL) collection of patient-derived models to identify novel combination therapies that target diverse phenotypes of prostate cancer.
One of the most promising combinations so far is the small molecule CX-5461, an RNA Polymerase I (Pol I) I transcription inhibitor that induces nucleolar localised DNA damage, combined with talazoparib, a PARP inhibitor (PARPi) that prevents DNA damage repair. Together, these compounds synergistically decreased in vitro growth of patient-derived organoids and androgen-responsive and -independent cell lines. This was associated with increased DNA damage compared to either agent alone, with upregulation of yH2AX and Rad51 foci formation and increased phosphorylation of checkpoint kinases 1 and 2 (CHK1 and CHK2). Furthermore, oral administration of talazoparib and CX-5461 significantly attenuated the in vivo growth of four different patient-derived xenografts (PDXs). Notably, the decrease in tumour growth was maintained for up to two weeks after treatment, resulting in a significant increase in survival. Importantly, these responses occurred in PDXs from diverse, castration-resistant tumours, including AR-null and neuroendocrine disease from patients who failed currently available treatments in the clinic. All tumours were proficient in homologous recombination, demonstrating that the efficacy of the combination treatment does not require genomic defects in DNA damage repair. Together these studies provide strong preclinical evidence that CX-5461 and PARPi combination therapy may represent a new treatment strategy for aggressive subtypes of advanced prostate cancer. This work provides promise for further clinical development of novel therapies targeting DNA damage in prostate cancer.