Francesco Schettini1, Fabiola Giudici2, Ottavia Bernocchi3, Marianna Sirico4, Silvia P Corona3, Mario Giuliano5, Mariavittoria Locci6, Ida Paris7, Giovanni Scambia8, Sabino De Placido5, Pasquale Rescigno9, Aleix Prat10, Giuseppe Curigliano11, Daniele Generali12. 1. Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy; Translational Genomics and Targeted Therapies in Solid Tumours, IDIBAPS, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain. Electronic address: schettini@clinic.cat. 2. Unit of Biostatistics, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy. 3. Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy. 4. Breast Cancer Unit, Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy. 5. Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. 6. Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, Naples, Italy. 7. Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy. 8. Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Università Cattolica Del Sacro Cuore, Rome, Italy. 9. Interdisciplinary Group for Translational Research and Clinical Trials (GIRT-Uro), Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy. 10. Translational Genomics and Targeted Therapies in Solid Tumours, IDIBAPS, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Oncology, Hospital Clinic of Barcelona, Barcelona, Spain. 11. Division of Medical Oncology, European Institute of Oncology (IEO), Milano, Italy; University of Milan, Milano, Italy. 12. Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy; Breast Cancer Unit, Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy.
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.
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.
Authors: Giovanna Garufi; Luisa Carbognin; Francesco Schettini; Elia Seguí; Alba Di Leone; Antonio Franco; Ida Paris; Giovanni Scambia; Giampaolo Tortora; Alessandra Fabi Journal: Cancers (Basel) Date: 2022-08-23 Impact factor: 6.575
Authors: Sui Par; Sofia Vaides; Pamela S VanderVere-Carozza; Katherine S Pawelczak; Jason Stewart; John J Turchi Journal: Cancers (Basel) Date: 2021-07-03 Impact factor: 6.639
Authors: Francesco Schettini; Mario Giuliano; Matteo Lambertini; Rupert Bartsch; David James Pinato; Concetta Elisa Onesti; Nadia Harbeck; Diana Lüftner; Sylvie Rottey; Peter A van Dam; Khalil Zaman; Giorgio Mustacchi; Joseph Gligorov; Ahmad Awada; Mario Campone; Hans Wildiers; Alessandra Gennari; Vivianne C G Tjan-Heijnen; Javier Cortes; Mariavittoria Locci; Ida Paris; Lucia Del Mastro; Sabino De Placido; Miguel Martín; Guy Jerusalem; Sergio Venturini; Giuseppe Curigliano; Daniele Generali Journal: Cancers (Basel) Date: 2021-09-01 Impact factor: 6.639