Abstract
Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status. Methods: On August 2020, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical studies on PARP inhibitors in mCRPC patients. Data were extracted independently by two investigators and analyzed using Review Manager software version 5.3. Primary endpoints included overall response rate (ORR) and progression-free survival (PFS). Results: Nine clinical trials were identified and analyzed for the clinical benefit of PARP inhibitors in mCRPC patients (n = 1,219). Pooled analyses demonstrated that PARP inhibitors could provide a significant improvement of ORR and PFS in patients with homologous recombination deficiency (HRD) when compared with non-HRD patients. Within the HRD subgroup, BRCA mutation patients achieved significantly higher ORR [odds ratio (OR): 9.97, 95% confidence interval (CI): 6.08–16.35] and PFS rates at 12 months (OR: 3.23, 95% CI: 1.71–6.10) when compared with BRCA wild-type patients. Furthermore, patients harboring HRD without BRCA mutations have a higher objective response after PARP inhibitor treatment compared with non-HRD patients. Conclusion: PARP inhibitor is an effective treatment option for mCRPC patients with mutations in genes related to the HR DNA repair pathway when compared with non-HRD patients. In addition to BRCA mutations, other HRD-related gene aberrations may also be used as novel biomarkers to predict the efficacy of PARP inhibitors.
Highlights
Metastatic prostate cancer is an incurable disease and has a poor survival, with a 5-year survival rate of 29.8% (Siegel et al, 2019)
poly(ADP-ribose) polymerase (PARP) inhibitor is an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients with mutations in genes related to the homologous recombination (HR) DNA repair pathway when compared with non-HR deficiency (HRD) patients
Our findings showed that mCRPC patients with HRD positive are more likely to benefit from PARP inhibitor treatments when compared with patients with HRD-negative tumors
Summary
Metastatic prostate cancer is an incurable disease and has a poor survival, with a 5-year survival rate of 29.8% (Siegel et al, 2019). Modern systemic treatments, including abiraterone, enzalutamide, docetaxel, and novel androgen receptor (AR)signaling inhibitors, only provide a median survival of 2.8 years for mCRPC patients. These approved agents show different efficacy profiles and only modestly improve survival (Francini et al, 2019). In cancer cells with tumor-specific HR deficiency (HRD), unrepaired double-strand DNA breaks after PARP inhibition treatment will persistently accumulate and eventually lead to tumor cell death. We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status
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