PARP Inhibitors in Metastatic Castration-resistant Prostate Cancer: Rationale, Mechanisms, and Clinical Applications

Abstract

Background and introduction: Over the past 15 yr, significant progress has been made in the management of prostate cancer (PC), including the development of chemotherapy, androgen receptor pathway inhibitors (ARPIs), and, more recently, radium-223 radioligand therapy. However, metastatic PC is still the third leading cancer-related cause of death among men in Europe, with a 5-yr survival rate of ∼30% and median overall survival (OS) of <3 yr for castration-resistant PC (CRPC). Current strategies are moving towards personalised treatment, with the emergence of PARP inhibitors (PARPi) that exploit a vulnerability in the DNA repair system in patients with alterations in genes involved in homologous recombination.

Methods: We reviewed the literature on PARPi treatment for CRPC and provide a narrative synthesis of the evidence for the rapidly evolving treatment landscape in this setting.

Key findings and limitations: Phase 3 studies evaluating the efficacy of PARPi agents available (olaparib, niraparib, rucaparib, and talazoparib) for the treatment of metastatic CRPC have confirmed their ability to prolong OS, especially in patients carrying BRCA1/2 mutations. Studies on PARPi + ARPI combinations have shown longer radiological progression-free survival, and better OS with talazoparib + enzalutamide, regardless of mutational status for DNA repair genes, with synergistic activity identified. However, response to PARPi seems to vary depending on the genes altered, with a greater benefit for patients with mutations in genes encoding the repair effector proteins BRCA1/2, CDK12, and PALB2.

Conclusions and clinical implications: Promising results have led to the approval of several PARPi agents as monotherapy or in combination with ARPIs in selected or unselected patients when chemotherapy is not clinically indicated. However, some questions remain regarding patient selection and treatment sequencing.

Keywords: Androgen receptor pathway inhibitor; BRCA gene; DNA repair; PARP inhibitors; Prostate cancer.