Clinical PARP Inhibitors: Where Are We Now?
At this point none of the above-mentioned clinical PARP inhibitors has received approval by any drug approval agency. Also, results concerning ongoing Phase II and III trials are not readily available. However, from clinical studies registered it can be deduced that Olaparib is currently running in five Phase III clinical trials and Niraparib in two, whereas the other three PARP inhibitors have one Phase III trial active each (Table 2). Also, AstraZeneca is taking a broad approach by testing Olaparib at many stages of breast and ovarian cancer treatment. One Phase III trial investigates whether patients with germline BRCA1/2 mutations benefit from additional Olaparib treatment after completed definitive local treatment and neo-adjuvant or adjuvant treatment (NCT02032823). Another trial investigates whether metastatic breast cancer, where Olaparib as mono treatment is administered, has any benefit over the regular physicians choice of treatment in patients with BRCA1/2 germ line mutations (NCT02000622). In the case of ovarian cancer, Olaparib mono treatment is being investigated in newly diagnosed ovarian cancers as well as relapsed BRCA mutated ovarian cancers after prior successful platinum-based chemotherapy (NCT01844986, NCT01874353). The rationale behind this set up is, that successful platinum treatment is suggestive for HR defects in these cancers. The focus of these trials would be to extend progression-free survival and omitting highly toxic platinum-based treatment by replacing it with Olaparib. In addition to these approaches with Olaparib as monotherapy in cancers having a defect in HR, a Phase III trial is currently running, which investigates the combination of Olaparib with Taxane drugs in patients with advanced gastric cancer who progressed following first line treatment (NCT01924533). Remarkably, this trial does not take BRCA mutation or HR status into account, thus this trial focusses on the chemo potentiation capacities of Olaparib.
Compared to AstraZeneca, the other pharmaceutical companies have fewer Phase III trials running for their compounds. However, the approaches within these trials resemble the Olaparib trials. Rucaparib and Niraparib are being investigated in platinum sensitive ovarian cancers as a maintenance therapy (NCT01968213 and NCT01847274). BMN-673, Veliparib and Niraparib are being investigated in locally advanced or metastatic breast cancer patients. (NCT01945775, NCT02032277 and NCT01905592). The BMN-673 and Niraparib trials take germ line BRCA mutations into account. Surprisingly, no Phase I or II trials of BMN-673 and Niraparib have been completed at this stage suggesting that these compounds advanced to Phase III trials based on data from trials with the other PARP inhibitors. On the other hand the Veliparib trial disregards BRCA mutation status. In this trial Veliparib is being tested in combination with standard chemotherapy (NCT02032277) similar to the Olaparib chemo potentiation trial. Preliminary data concerning these Phase III trials are already being released bit by bit at various cancer network meetings, for example, ASCO 2014.[48–50] Final data remain to be published.
We conclude that currently these PARP inhibitors are running for approval in clinical practice and we can speculate that this approval will account for preselected patients, in other words, having breast or ovarian cancer with germ line BRCA mutations or platinum-sensitive ovarian cancer patients. However, it is very likely that after this milestone achievement other approvals will follow, especially combination therapies. The inhibition of PARP-1 may potentiate cytotoxic effects of radiotherapy and classical chemotherapies such as Temozolamide, Topoisomerase poisons and Taxane drugs. However, for all these potentiating effects and combination strategies no clear data are yet present on the gain in therapeutic window of these strategies. Furthermore, completed and ongoing Phase II trials (Table 1) of PARP inhibitors in combination with novel anticancer agents such as antivascular therapies are promising. Finally, the use of PARP inhibitors in other tumors than breast and ovarian cancer is under investigation in various settings. Trials are being conducted in prostate, lung, intestinal and head and neck cancers and look promising, however, actual antitumor effects have yet to be reported. Emerging experimental evidence even proposes PARP inhibitor treatment in case of brain tumors.[51,52]
Personalized Medicine. 2015;12(2):139-154. © 2015 Future Medicine Ltd.