Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer

Abstract

Background:Olaparib (AZD2281), a PARP-1/2 inhibitor, has been extensively investigated in clinical trials. However, limited clinical data are available about its long-term safety and anti-tumour activity.Methods:Patients had first participated in a phase I study of olaparib combined with carboplatin and/or paclitaxel. They continued with olaparib monotherapy in their best interest if they failed to tolerate the combination due to the treatment-related adverse events (TRAEs). Safety data were collected by physical examination and regular laboratory evaluations. Disease evaluations were performed by CT scan.Results:At data cutoff, 21 patients were included; 10 with breast, 9 with ovarian and 2 with fallopian tube cancer of whom 16 patients had a BRCA mutation (13 BRCA1; 3 BRCA2). TRAEs were mostly haematological and most prominent shortly after switching from combination to monotherapy, probably due to carry-over effects of chemotherapy. Over time, both severity and frequency of TRAEs decreased. Responses to olaparib were durable with a median treatment duration of 52 (range 7–183) weeks. In total, nine (43%) patients were still on study at data cutoff.Conclusion:Continued long-term daily olaparib was found to be safe and tolerable. Encouragingly, patients who showed a favourable response on earlier combination therapy maintained this response on olaparib monotherapy.

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer

“…Hypokalemia was the only TEAE reported in ≥ 10% of patients. During the once-daily niraparib dosing phase (i.e., after the substudy), the grade ≥ 3 TEAE profile (Table 5) was consistent with the safety profile seen in other niraparib studies [15] and other PARP inhibitors [19][20][21]. There were no reports of clinically significant abnormal ECG changes, including QTc interval prolongation, attributed to niraparib.…”

Nanoformulation of Olaparib Amplifies PARP Inhibition and Sensitizes PTEN/TP53-Deficient Prostate Cancer to Radiation

“…Similarly, dose-escalation studies of Olaparib in combination gemcitabine (15), doxorubicin (16), and paclitaxel (17) found that the monotherapy daily dose (400mg b.i.d) could not be reached with an acceptable tolerability profile. In contrast, daily Olaparib maintenance therapy after combination therapy was well tolerated (18). …”

Reduced tumor burden through increased oxidative stress in lung adenocarcinoma cells of PARP-1 and PARP-2 knockout mice

“…Additionally, PARP-1 and PARP-2 also participate in other biological functions such as angiogenesis and transcription [12,13], apoptosis of oxidative-stress related pathologies [14][15][16], and regulation of the immune response [11,12]. On the other hand, an increased activity or overexpression of PARP-1 and -2 may also induce cellular damage by depleting the ATP stores of cells in several conditions [17][18][19][20] or by altering the mechanisms of DNA repair, leading to tumorogenesis of several cancer types [12,[21][22][23][24]. Therefore, the role of PARP-1 and PARP-2 in cells is two-fold: while they play a critical role in DNA repair, they may also favor carcinogenesis and tumor progression [12,[21][22][23][24][25].…”

“…On the other hand, an increased activity or overexpression of PARP-1 and -2 may also induce cellular damage by depleting the ATP stores of cells in several conditions [17][18][19][20] or by altering the mechanisms of DNA repair, leading to tumorogenesis of several cancer types [12,[21][22][23][24]. Therefore, the role of PARP-1 and PARP-2 in cells is two-fold: while they play a critical role in DNA repair, they may also favor carcinogenesis and tumor progression [12,[21][22][23][24][25]. In line with the latter, PARP-1 overexpression was also shown to correlate with poor survival of patients with breast cancer [26].…”

“…Pharmacological inhibitors of PARP-1 and -2 were also demonstrated to be novel therapeutic targets for the treatment of several cancer types including LC [12,[21][22][23][24][27][28][29][30][31].…”