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Meta-Analysis
. 2021 May:149:134-152.
doi: 10.1016/j.ejca.2021.02.035. Epub 2021 Apr 13.

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

Francesco Schettini  1 , Fabiola Giudici  2 , Ottavia Bernocchi  3 , Marianna Sirico  4 , Silvia P Corona  3 , Mario Giuliano  5 , Mariavittoria Locci  6 , Ida Paris  7 , Giovanni Scambia  8 , Sabino De Placido  5 , Pasquale Rescigno  9 , Aleix Prat  10 , Giuseppe Curigliano  11 , Daniele Generali  12
Affiliations
Meta-Analysis

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

Francesco Schettini et al. Eur J Cancer. 2021 May.

Erratum in

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.

Keywords: Breast cancer; Meta-analysis; Niraparib; Olaparib; Ovarian cancer; PARP inhibitor; Prostate cancer; Rucaparib; Talazoparib; Veliparib.

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Conflict of interest statement

Conflict of interest statement M.G. and S.D.P. have declared honoraria from Roche, Pfizer, AstraZeneca, Novartis, Celgene, Eli Lilly, Amgen and Eisai. A.P. has declared an immediate family member being employed by Novartis; personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo; travel, accommodations and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; a consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol Myers Squibb and patent PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY. G.C. is an expert testimony for Pfizer, Novartis and Roche Genentech and a member of the steering committee for randomised clinical trials of Cascadian, Roche Genentech and MacroGenics. D.G. has declared consulting fees from Novartis, Lilly and Pfizer and research funding from LILT, Novartis, AstraZeneca and the University of Trieste. I.P. has declared consulting fees from Roche, Novartis, Lilly, Pfizer, AstraZeneca, Pierre Fabre and Ipsen. G.S. has declared grant/research Support from MSD Italia S.r.l. and a consulting role for TESARO Bio Italy S.r.l., Johnson & Johnson and Clovis Oncology Italy S.r.l. The other authors have nothing to declare.

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