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

## TL;DR

Regulatory agencies differ in approving PARP inhibitors for prostate cancer, with FDA focusing on specific gene mutations while EMA approves for broader use.

## Contribution

Highlights inconsistencies in regulatory approvals of PARP inhibitors and identifies trial design flaws affecting biomarker-driven decisions.

## Key findings

- FDA approves PARP inhibitors only for patients with BRCA or HRR gene mutations, while EMA approves for all mCRPC patients.
- MAGNITUDE trial design successfully identified a beneficial subgroup, aligning FDA and EMA conclusions.
- PROpel and TALAPRO-2 trials suffer from design limitations, leading to conflicting regulatory decisions.

## 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 BRCA 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.