Drug and molecular radiotherapy combinations for metastatic castration resistant prostate cancer

Metastatic castration resistant prostate cancer (mCRPC) is a highly lethal disease. Several novel therapies have been assessed in the past years. Targeting DNA damage response (DDR) pathways in prostate cancer became a promising treatment strategy and olaparib and rucaparib, Poly(ADP-ribose) polymerase (PARP) inhibitors, have been approved for patients carrying mutations in homologous recombination (HR) repair pathways. Other DDR inhibitor targets, such as ATM, ATR, CHK1, CHK2, and WEE1 are under extensive investigation. Additionally, molecular radiotherapy (MRT) including [177Lu]Lu-PSMA, [225Ac]Ac-PSMA, [223Ra]Ra-dichloride, [153Sm]-EDTMP, [188Re]Re-HDMP and GRPR-targeted MRT treat cancer through internal ionizing radiation causing DNA damage and demonstrate promising efficacy in clinical trials. In the field of immunotherapy, checkpoint inhibition as well as sipuleucel-T and PROSTVAC demonstrated only limited efficacy in mCRPC when used as monotherapy. This review discusses recent therapeutic strategies for mCRPC highlighting the need for rational combination of treatment options.