PARP Inhibitors and Radiometabolic Approaches in Metastatic Castration-Resistant Prostate Cancer: What’s Now, What’s New, and What’s Coming?

Abstract

In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by PARP inhibitors and radiometabolic approaches. The result is that DNA repair genes need to be altered in a high percentage of patients with metastatic prostate cancer, making these patients optimal candidates for PARP inhibitors. These compounds have already been proved to be active in pretreated patients and are currently being investigated in other settings. Radiometabolic approaches combine specific prostate cancer cell ligands to radioactive particles, thus allowing to deliver cytotoxic radiations in cancer cells. Among these, radium-223 and lutetium-177 have shown promising activity in metastatic pretreated prostate cancer patients and further studies are ongoing to expand the applications of this therapeutic approach. In addition, nuclear medicine techniques also have an important diagnostic role in prostate cancer. Herein, we report the state of the art on the knowledge on PARP inhibitors and radiometabolic approaches in advanced prostate cancer and present ongoing clinical trials that will hopefully expand these two treatment fields.

PARP Inhibitors: A New Horizon for Patients with Prostate Cancer

“…Some trials are studying the combination of 177Lu-PSMA radioligands with PARPi [ 96 ]. Ongoing trials with this and other combination of drugs are shown in Table 4 .…”

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations

“…Furthermore, those with BRCA1/2 alterations were particularly responsive to Olaparib when compared to other HRR gene mutations (52% vs 5% achieving a radiological response to Olaparib respectively). 46 , 47 Finally, in the randomized phase III PROfound clinical trial, the effectiveness of Olaparib was compared to being treated with enzalutamide or abiraterone in patients with mCRPC with alterations in 15 prespecified HRR genes (the mutations analyzed can be seen in Table 2 . Other than those listed, mutations in the PPP2R2A gene were examined as well).…”

“…These results led to approvals by both the FDA and EMA for mCRPC with HRR mutations, although the EMA was more conservative in the scope of Olaparib’s approval. 37 , 46 , 47 …”

“…Currently, two other PARP inhibitors have completed and/or are undergoing testing for their effect on mCRPC. 46 One of them, niraparib, differs from rucaparib in a number of ways. These differences include its metabolism — as niraparib is not metabolized by hepatic cytochrome enzymes, there is less risk of adverse drug–drug interactions, as previously mentioned with rucaparib and Olaparib.…”

“… 56 Based on these results, niraparib received a Breakthrough Therapy Designation from the FDA to accelerate the approval process. 46 …”