Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease with a median survival of 36 months. With the advent of genetic sequencing to identify individual genomic profiles and acquired tumor-specific pathways, targeted therapies have revolutionized cancer treatment, including the treatment strategy in mCRPC. Poly(adenosine 5ʹdiphosphate) ribose polymerase inhibitors (PARPi) are oral drugs that target mutations in the homologous recombination repair (HRR) pathway, which are found in approximately 27% of prostate cancer patients. In May 2020, the first PARP inhibitor, olaparib, was approved by the US Food and Drug Administration for men with mCRPC with HHR gene mutations based on the findings of the Phase III PROfound trial that showed improved overall survival in men with mCRPC who received olaparib and whose disease had progressed on a novel hormonal agent. This review summarizes the current evidence and clinical utility of olaparib as treatment in men with mCRPC. We describe the mechanism of action of PARPi, key clinical trials of olaparib in men with mCRPC, and ongoing Phase II and III clinical trials investigating olaparib in combination therapy and as front-line therapy in mCRPC.

Clinical implications of homologous recombination repair mutations in prostate cancer

“…When PARP is not functional, for example, by using PARPi, SSB progress to DSBs, and cells depend on their HRR system to repair these efficiently; upon PARPi, cells that cannot repair by homologous recombination are pushed towards cell death programs. 45 Beyond the synthetic lethal concept and PARP1 catalytic inhibition, PARPi are also cytotoxic by creating more DNA damage and replicative stress:…”

“…PARP enzymes participate in the early stages of single‐strand break (SSB)‐DDR. When PARP is not functional, for example, by using PARPi, SSB progress to DSBs, and cells depend on their HRR system to repair these efficiently; upon PARPi, cells that cannot repair by homologous recombination are pushed towards cell death programs 45 . Beyond the synthetic lethal concept and PARP1 catalytic inhibition, PARPi are also cytotoxic by creating more DNA damage and replicative stress: PARP1 located at SSB cannot detach from DNA in the presence of PARPi, an effect known as “PARP trapping,” creating a physical obstacle for the replication machinery.…”

“…There are several PARPi in clinical use for various indications, such as olaparib, talazoparib, rucaparib, and niraparib; they all have slightly different profiles in terms of catalytic PARP1 inhibition and PARP1 trapping potency. 45,46 The main clinical trials testing these agents in prostate cancer are summarized in (Table 1). The TOPARP trial represented the first proof-of-concept for PARP inhibitors in prostate cancer, showing responses to olaparib among patients with mCRPC, particularly among those with mutations in BRCA2 and other HRR genes.…”

“…Beyond the synthetic lethal concept and PARP1 catalytic inhibition, PARPi are also cytotoxic by creating more DNA damage and replicative stress: PARP1 located at SSB cannot detach from DNA in the presence of PARPi, an effect known as “PARP trapping,” creating a physical obstacle for the replication machinery. There are several PARPi in clinical use for various indications, such as olaparib, talazoparib, rucaparib, and niraparib; they all have slightly different profiles in terms of catalytic PARP1 inhibition and PARP1 trapping potency 45,46 . The main clinical trials testing these agents in prostate cancer are summarized in (Table 1).…”

Targeted Approaches in Metastatic Castration-Resistant Prostate Cancer: Which Data?

“…The somatic mutations analysis, through next-generation sequencing (NGS)-based approaches, can be performed on tumor sample sources such as biopsies, surgical material, circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). The NGS testing success rates depend on tumor sample characteristics, with better accuracy for newly collected metastatic samples or archival tissue aged < 1 year [ 18 , 19 ]. However, somatic mutations observed in tumor tissue may change over time due to genetic instability and selective pressure from therapy.…”