Is It Time to Anticipate the Use of PARP Inhibition in Prostate Cancer Patients?

Abstract

The increasing diffusion of genetic analysis regarding the pathogenetic variants (PVs) of genes involved in DNA Damage Repair (DDR) mechanisms and the development of Poly ADP ribose polymerase (PARP) inhibitors (PARPis) led to the first valid precision medicine option tailored toward metastatic prostate cancer (mPC). The concept of anticipation in the systemic treatment of mPC was initially adopted for androgen receptor signaling inhibitors (ARSIs) to describe the expansion of their indications, from the setting of the late-stage second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) to first-line therapy in selected cases. There is already mounting evidence in favor of the anticipation of PARPis in the first line of mCRPC therapy, and further evidence in favor of mHSPC is emerging. Many studies have demonstrated the synergism between ARSIs and PARP inhibitors. Recent discoveries regarding the crosstalk between the androgen receptor (AR) and DNA repair mechanisms are disconnecting the use of PARPis from genetic analysis. The new message emerging is that the combination of PARPis with ARSIs may work independently of DDR mutational status. As a matter of fact, most of the recent trials analyzing the combination of PARPis with abiraterone or enzalutamide as a first-line therapy enrolled mCRPC patients irrespective of their mutational status. The PROPEL trial concluded that the advantage of the combination was independent of PV status, despite a higher advantage being reported in the BRCA1/2 mutated subgroup. The MAGNITUDE trial, however, showed a significant advantage only in the DDR mutated subgroup, and the DDR non-mutated cohort was closed for further enrollment. The combination of PARPis with ARSIs represents a significant strategy with a view to the anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR genes.

Keywords: CRPC; DDR gene; PARP inhibitors; prostate cancer.

Figure 1

The concepts of the anticipation and intensification of care in the systemic therapy of metastatic PC and the ways in which PARP inhibitors and HRR genetic analysis are involved (mCRPC = metastatic castration-resistant prostate cancer; mHSPC = metastatic hormone-sensitive prostate cancer; nmCRPC = non-metastatic castration-resistant prostate cancer; PFS = progression-free survival; HR = hazard ratio; HRR = homologous recombinant repair; ABI = abiraterone; ENZA = enzalutamide; PARPi = Poly ADP ribose polymerase inhibitor).