PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Background:Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent.Methods:This was a multicentre, phase 2 trial, planned according to a two-stage Simon’s optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150–200 mg m−2 per day on days 1–5 every 28 days.Results:From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively.Conclusions:Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7–34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95–1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3–18.1) and 12.7 (95%CI: 8.8–17.5) months, respectively (HR= 1.31 (95%CI: 0.89–1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02–2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99–2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed.