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BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Veliparib has been widely tested in clinical trials as a single agent and in combination with chemotherapy, radiation and chemo-radiation. Its modest hematopoietic toxicity makes it an attractive agent for combination trials. A phase 2 trial in advanced ovarian cancer with BRCA1 or BRCA2 mutations using single agent veliparib showed a response rate of 26% (9%, CI 16–38%), with efficacy in both platinum-sensitive and platinum-refractory patients. It was well tolerated overall, with only one patient having grade 4 toxicity due to thrombocytopenia. Common side effects were nausea, fatigue, vomiting and anemia [25].
Exposure–Response Analysis in Oncology Trials
Published in Satrajit Roychoudhury, Soumi Lahiri, Statistical Approaches in Oncology Clinical Development, 2018
Yi-Lin Chiu, Balakrishna S. Hosmane
The mean ± standard deviation (SD) pharmacokinetic parameters of veliparib after administration of each of the four regimens to subjects with solid tumors are presented in Table 3.4. Period and sequence effects were not statistically significant for any of the tested pharmacokinetic parameters, as all p-values for the test on period and sequence effects were ≥0.544 and 0.450, respectively. Mean veliparib plasma concentration–time profiles following the single oral doses of Regimens A, B, and C are presented in Figure 3.3. The test statistics for the regimen effect for Tmax, Cmax, and β were not statistically significant (P < 0.05). The central values for AUCt and AUCinf for Regimen B (four 10-mg new formulation, fasting) were statistically significantly higher (P = 0.002 and P = 0.003, respectively) than those for the reference Regimen A (four 10-mg current formulation, fasting). The central values for AUCt and AUCinf for Regimen C (one 40-mg strength of veliparib commercial capsule new formulation, fasting) were statistically significantly lower than those for Regimen B (P < 0.001). There was no statistically significant difference (P > 0.05) between Regimen C (40-mg veliparib commercial capsules, fasting) and Regimen A in AUCt and AUCinf.
Personalized Medicine in Hereditary Cancer Syndromes
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
PARP inhibitors also increase sensitivity to conventional chemotherapy by preventing DNA repair, suggesting a role for combination regimen. In a randomized phase 2 trial of high grade, recurrent ovarian cancer patients, BRCA-mutated patients had a significantly improved progression-free survival when receiving olaparib-chemotherapy combination vs chemotherapy alone (HR 0.21 [95% CI 0.08–0.55]; p = 0.0015) [21]. Olaparib has also shown activity in combination with Cediranib (tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3) [22]. Another PARP inhibitor veliparib plus temozolomide has also shown clinical benefit of 45% in 20 BRCA1-or BRCA2-mutated metastatic breast cancer patients [23]. A randomized phase 2 trial is ongoing, which will compare the combination of veliparib, and temozolomide with the combination of carboplatin plus paclitaxel in BRCA1-or BRCA2-mutated breast cancer patients (NCI trial #NCT01506609). Several other clinical trials are investigating PARP inhibitors either alone or in combination setting for BRCA mutated cancers (NCI trial #s NCT02163694, NCT01905592, NCT01989546, NCT02401347, NCT02326844, NCT01945775, NCT02396433, NCT01472783, NCT01844986, NCT02034916, NCT02286687, NCT02000622, NCT01506609, NCT02042378, NCT02262273, NCT01585805, NCT01482715, NCT01434316, NCT02354586, NCT02338622, NCT00989651, NCT01017640).
The effect of PARP inhibitors in homologous recombination proficient ovarian cancer: meta-analysis
Published in Journal of Chemotherapy, 2023
Marko Skelin, David Šarčević, Dina Lešin Gaćina, Iva Mucalo, Ivo Dilber, Eugen Javor
Current treatment options offer response rate to first line chemotherapy for about 80% of patients. However, most of the patients will experience recurrence within 2 years [14]. For platinum sensitive patients, second line treatment is often retreatment with platinum based chemotherapy and its subsequent utilization results in decreased response rate and increased cumulative toxicity [15,16]. Maintenance therapy with PARP inhibitors in patients with platinum sensitive EOC is prolonging progression free survival (PFS) and chemotherapy-free interval (CFI) [15]. Three PARP inhibitors (olaparib, rucaparib and niraparib) have been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of PARP inhibitor naive EOC [17]. Veliparib has proven its efficacy in EOC treatment as well [6]. Although, in contrast to other members of PARP inhibitors, veliparib was administered in combination with chemotherapy.
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers
Published in Expert Opinion on Investigational Drugs, 2022
Pamiparib has been used in phase II trials to treat advanced ovarian cancer and metastatic castration-resistant prostate cancer [62], and a randomized phase III trial (NCT03427814) for maintenance therapy in advanced gastric cancer that responds to platinum-based chemotherapy [63]. Of note, the results from a phase II completed study (NCT03575065) of pamiparib in the treatment of patients with locally advanced or metastatic HER2 negative breast cancer with gBRCA mutations showed that in the TNBC cohort, confirmed objective response rate (ORR) was 38.2% (95% CI: 25.4–52.3) versus 61.9% (95% CI: 38.4–81.9) in the HR+ cohort [64]. The median duration of response (DOR) was 6.97 and 7.49 months in the TNBC and HR+ cohort, respectively. Additionally, mPFS was 5.49 (95% CI: 3.65–7.33) and 9.20 months (95% CI: 7.39–11.93) in these two cohorts [64] (Table 3). These data suggest pamiparib had a favorable response in patients with locally advanced/metastatic HER2 negative breast cancer with gBRCA mutations. Although veliparib has yet to be FDA-approved, promising preclinical data lead to multiple early clinical settings [65]. Of note, iniparib (BSI-201) was a compound developed as PARPi based on the alternative premise of altering PARP1 zinc fingers. After an unsuccessful phase III study in TNBCs (NCT00938652) [66], preclinical work demonstrated that iniparib was not a bona fide PARPi [67].
Risk of fatigue with PARP inhibitors in cancer patients: a systematic review and meta-analysis of 29 phase II/III randomized controlled trials
Published in Journal of Chemotherapy, 2021
Poly ADP-ribose polymerase (PARP) inhibitors are currently one of the most promising treatment options for ovarian cancer and other tumor types. The family of PARP consists of 18 members and play a key role in the complex landscape of DNA repair mechanism.1 PARP are involved in recognizing single-strand DNA breaks (SSB) and their activation triggers DNA repair mechanisms, such as base excision repair.2 PARP inhibitors were used to improve the curative effect of chemotherapy drugs and as a treatment option for cancers that were mainly caused by DNA repair defects. Several PARP inhibitors have since been FDA approved for advanced ovarian cancer or breast cancer, such as olaparib in 2014, rucaparib in 2016, niraparib in 2017, and talazoparib in 2018.3,4 Moreover, some PARP inhibitors are under clinical study. Veliparib is a potent, orally bioavailable, PARP-1/2 inhibitor that showed anticancer effects in clinical trials.5