Background: Poly (ADP-ribose) polymerase-inhibitors (PARPis) showed antitumour activity in BRCA1/2-mutated cancers, with more heterogeneous outcomes in tumours harbouring mutations that impair other genes involved in the DNA homologous recombination repair (HRR) or wild-type (wt). Methods: We conducted a systematic review and meta-analysis to better assess the role of PARPis in the treatment of metastatic solid tumours, with and without BRCA1/2 mutations. The primary end-point was progression-free survival (PFS). The secondary end-points were overall response rate (ORR) and overall survival (OS). A random-effects model was applied. Results: Twenty-nine studies (8,839 patients) were included. PFS was significantly improved (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.51–0.68, p < 0.001), without being affected by BRCA mutational status (p = 0.65). Significant subgroup differences were observed with regard to the tumour site (p = 0.001), line of therapy (p = 0.002), control arm (p < 0.001), type of PARPi (p < 0.001) and trials' phase (p = 0.006). PARPis were associated with ORR (relative risk: 1.35, 95% CI: 1.16–1.56, p < 0.001), with significant subgroup differences observed with regard to treatment line (p = 0.03), control arm (p = 0.04) and PARPis (p < 0.001) and independent of mutational status (p = 0.44), tumour site (p = 0.86) and trials' phase (p = 0.09). OS was significantly improved by PARPis (HR: 0.86, 95% CI: 0.80–0.92, p < 0.001), regardless of mutational status (p = 0.57), tumour site (p = 0.82), treatment line (p = 0.22), control arm (p = 0.21), PARPis (p = 0.30) and trials' phase (p = 0.26). Finally, an exploratory subgroup analysis showed a significant PFS improvement (HR: 0.51, 95% CI: 0.43–0.60, p < 0.001) with PARPis in BRCA-wt/HRR-deficient tumours. Conclusion: Our results confirm the efficacy of already approved PARPi-based treatments in BRCA1/2-mutant solid tumours, support their role also in BRCA-independent HRR-deficient tumours and suggest a potentially broader efficacy in some wt tumours, perhaps with appropriate therapeutic partners. Prospective studies are warranted.

Poly (ADP-ribose) polymerase inhibitors in solid tumours : Systematic review and meta-analysis / F. Schettini, F. Giudici, O. Bernocchi, M. Sirico, S.P. Corona, M. Giuliano, M. Locci, I. Paris, G. Scambia, S. De Placido, P. Rescigno, A. Prat, G. Curigliano, D. Generali. - In: EUROPEAN JOURNAL OF CANCER. - ISSN 0959-8049. - 149(2021 May), pp. 134-152.

Poly (ADP-ribose) polymerase inhibitors in solid tumours : Systematic review and meta-analysis

O. Bernocchi;G. Curigliano
Conceptualization
;
2021

Abstract

Background: Poly (ADP-ribose) polymerase-inhibitors (PARPis) showed antitumour activity in BRCA1/2-mutated cancers, with more heterogeneous outcomes in tumours harbouring mutations that impair other genes involved in the DNA homologous recombination repair (HRR) or wild-type (wt). Methods: We conducted a systematic review and meta-analysis to better assess the role of PARPis in the treatment of metastatic solid tumours, with and without BRCA1/2 mutations. The primary end-point was progression-free survival (PFS). The secondary end-points were overall response rate (ORR) and overall survival (OS). A random-effects model was applied. Results: Twenty-nine studies (8,839 patients) were included. PFS was significantly improved (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.51–0.68, p < 0.001), without being affected by BRCA mutational status (p = 0.65). Significant subgroup differences were observed with regard to the tumour site (p = 0.001), line of therapy (p = 0.002), control arm (p < 0.001), type of PARPi (p < 0.001) and trials' phase (p = 0.006). PARPis were associated with ORR (relative risk: 1.35, 95% CI: 1.16–1.56, p < 0.001), with significant subgroup differences observed with regard to treatment line (p = 0.03), control arm (p = 0.04) and PARPis (p < 0.001) and independent of mutational status (p = 0.44), tumour site (p = 0.86) and trials' phase (p = 0.09). OS was significantly improved by PARPis (HR: 0.86, 95% CI: 0.80–0.92, p < 0.001), regardless of mutational status (p = 0.57), tumour site (p = 0.82), treatment line (p = 0.22), control arm (p = 0.21), PARPis (p = 0.30) and trials' phase (p = 0.26). Finally, an exploratory subgroup analysis showed a significant PFS improvement (HR: 0.51, 95% CI: 0.43–0.60, p < 0.001) with PARPis in BRCA-wt/HRR-deficient tumours. Conclusion: Our results confirm the efficacy of already approved PARPi-based treatments in BRCA1/2-mutant solid tumours, support their role also in BRCA-independent HRR-deficient tumours and suggest a potentially broader efficacy in some wt tumours, perhaps with appropriate therapeutic partners. Prospective studies are warranted.
Breast cancer; Meta-analysis; Niraparib; Olaparib; Ovarian cancer; PARP inhibitor; Prostate cancer; Rucaparib; Talazoparib; Veliparib
Settore MED/06 - Oncologia Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/838384
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