PARPing up the right tree; an overview of PARP inhibitors for metastatic castration-resistant prostate cancer.

PARP inhibitors (PARPi) are transforming the current treatment landscape of metastatic castration-resistant prostate cancer. By reanalysing published data on olaparib, talazoparib, rucaparib and niraparib, we provide a concise overview of responses by molecular subgroup. As monotherapy, all PARPi showed comparable efficacy and the same hierarchy in responsiveness: patients with tumours harbouring aberrations in BRCA1 or BRCA2 (BRCAm) evidently demonstrate superior responses when compared to aberrations in other homologous recombination repair (HRR) related genes. Niraparib seems to cause more grade ≥3 adverse events in comparison to other PARPi. PARPi have also been combined with androgen-receptor signalling inhibitors (ARSI) for both patients with tumours harbouring aberrations in HRR genes (HRRm), and molecularly unselected patients. Compared to wildtype, BRCAm patients responded best, followed by HRRm. Olaparib-abiraterone, niraparib-abiraterone, and talazoparib-enzalutamide all prolonged progression-free survival compared to an ARSI alone in HRRm patients. In the non-HRRm subgroup, only olaparib-abiraterone and talazoparib-enzalutamide were effective. Results for the combination of rucaparib with enzalutamide are yet to be reported. The rate of grade ≥3 adverse events for the combination regimens is 10-30% higher when compared to an ARSI alone. Given the limited efficacy in unselected patients, these PARPi-ARSI combinations may be best reserved for selected patients.