Twelve mutations, three trials, and five different labels: PARP inhibitors regulatory inconsistencies in prostate cancers.

Abstract

Three different PARP (Poly (ADP-ribose) Polymerase)-inhibitors have been approved in combination with androgen receptor pathway inhibitors (ARPIs) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Regulatory authorities, however, have divergent opinions. Although the US Food and Drug Administration (FDA) has limited approval of two PARP-inhibitors to patients with <i>BRCA</i> mutations or other alterations in homologous recombination repair (HRR) genes, the European Medicines Agency (EMA) has approved the indication for the overall mCRPC population, irrespective of HRR status. Of all trials, only MAGNITUDE, evaluating niraparib and abiraterone, led to aligned conclusions from both the EMA and FDA, as its design effectively identified the subgroup most likely to benefit. The discrepancies observed in the assessment of the other two trials stem from limitations in their designs. A key issue with PROpel is the lack of patient stratification based on known biomarkers, and the subgroup analysis is underpowered. In TALAPRO-2, although an enriched cohort is included, combining these data with the all-comers cohort results in a potentially misleading conclusion. Currently, there is a need for harmonisation in biomarker-driven trial designs and the definition of homologous recombination repair deficiency (HRD). Access to biomarker and clinical data from all PARP-inhibitor trials would allow researchers to clarify the impact of different HRR mutations on outcomes.