Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies

Background Androgen-targeted therapy and chemotherapy are currently the mainstay of treatment in metastatic castration resistant prostate cancer (mCRPC). When progression occurs despite these therapeutic strategies, additional FDA-approved treatment options are lacking. However, there is a vast amount of emerging data surrounding novel investigational therapies in this space. Methods We reviewed and summarized the body of literature surrounding the current treatment options for mCRPC. Medline and Pubmed as well as abstracts from international congresses were utilized to gather relevant literature surrounding investigational treatment of mCRPC. We highlight the results of recent trials investigating the use of novel strategies to treat mCRPC. Results Androgen-targeted therapy and chemotherapy will remain foundational in the treatment of mCRPC. However, heavily pretreated patients who have developed resistance may benefit from novel therapeutic strategies. The use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) has now gained FDA approval for patients with homologous recombination repair (HRR) gene mutations. Novel androgen receptor (AR) degraders and the use of radioligand therapy (RLT) with Lu-PSMA-617 (Lu-PSMA) are under investigation. Immune-directed therapies, including programmed death (PD-1) inhibition, bi-specific T-cell engager (BiTE) technology, and chimeric antigen receptor (CAR) T-cell therapy, have shown promise in early phase trials. Further understanding of resistance mechanisms has led to additional therapeutic targets, including targeting the PI3K-Akt-mTOR pathway and enhancer of zester homolog 2 (EZH2). Conclusions Based on our review of the literature, exciting new therapeutic strategies exist for the treatment of mCRPC. In particular, PARPi, AR degraders, PSMA-targeted therapies, immune-directed therapies, and agents targeting resistance mechanisms as monotherapy or in combination could improve patient outcomes. Additional data from randomized trials are necessary to understand the efficacy and tolerability of these treatment strategies.