Poly(ADP-ribose) Polymerase Inhibitor Combinations in First-Line Metastatic Castration-Resistant Prostate Cancer: Increasing Toxicity With Unclear Benefits

Cet article examine les controverses concernant l'utilisation des inhibiteurs de PARP dans le traitement de première ligne des cancers métastatiques de la prostate résistants à la castration

Résumé en anglais

Since 2015, it has been clear that a small but meaningful percentage of patients with prostate cancer harbor homologous recombination repair mutations (HRRms) and may benefit from treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor.1,2 Multiple clinical trials have demonstrated the efficacy of PARP inhibitor monotherapy in patients with HRRms in metastatic castration-resistant prostate cancer (mCRPC) in the second-line setting after androgen receptor pathway inhibitors (ARPIs).3,4 Over the past year, emerging data from several trials have reported that ARPIs (either enzalutamide or abiraterone) combined with a PARP inhibitor have a progression-free survival (PFS) advantage relative to enzalutamide or abiraterone alone.5-7 The scientific rationale for these studies comes from limited investigations suggesting potential synergy when cotargeting the androgen receptor and DNA repair mechanisms, which to date have not been fully validated in the clinic to our knowledge.8,9 The clinical trials have culminated with the approvals by the US Food and Drug Administration (FDA) of abiraterone with olaparib (in BRCA1/2m prostate cancer) and enzalutamide with talazoparib (in HRRm prostate cancer) as first-line therapeutic options for mCRPC on the basis of data from the PROpel and TALAPRO-2 trials, respectively, without any postapproval requirements.10,11 Despite the regulatory greenlight, there remain significant gaps in data and clarity regarding the optimal timing of PARP inhibitor treatment for patients with prostate cancer whose tumors have HRRms.