Parp Inhibitor Olaparib Is Safe and Effective in Patients with BRCA1 and BRCA2 Mutations

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ReseARch highlights targeted therapies parp inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations

omen who harbor BRCA1 olaparib is a novel, orally active ParP were amended to allow patients to receive or BRCA2 mutations have a inhibitor that induces synthetic lethality the higher dose if disease progression Whigh risk of developing breast in homozygous BRCA-mutated cells. a occurred. the orr (primary end point of and ovarian cancer. the BRCA1 and phase i study revealed that olaparib was the trial) was 33% for the high-dose cohort BRCA2 gene products are involved in a safe and well tolerated as a single agent in and 13% for the low-dose cohort. median specialized form of Dna repair, known BRCA mutation carriers. therefore, two progression-free survival was 5.8 months as homologous recombination. if the wild proof-of-concept phase ii studies—one for the high-dose group and 1.9 months for type BRCA allele in a tumor cell is lost, lead by andrew tutt and the other by the low-dose group. the clinical benefit rate the repair mechanism is compromised william audeh—were carried out to test was higher in women receiving the 400 mg and the resulting genetic instability can olaparib safety and efficacy in patients dose. the most frequent adverse effects cause tumor development. Poly (aDP with advanced or recurrent breast or were nausea and fatigue, but in general ribose) polymerase (ParP) is involved in ovarian cancer who had BRCA1 or BRCA2 these were mild in intensity. as audeh repairing single-strand Dna breaks, and mutations. “targeting loss of BrCa1 or observes “these patients were heavily inhibition of ParP results in single-strand BrCa2 function with a ParP inhibitor can pre-treated and some have had prolonged breaks that accumulate to form double- lead to a meaningful anticancer activity in partial and complete responses”. strand breaks. these errors are repaired patients who have had or become resistant the results from both studies show that by components of the homologous to other forms of standard chemotherapy” the underlying pathways that are aberrant recombination repair pathway, which explains tutt. may be more important than the organ of includes BrCa1 and BrCa2. However, in the first phase ii trial by tutt and origin when selecting therapy. “Currently, tumors that cannot repair their Dna coauthors, women with advanced the presence of mutations in BRCA1 or owing to compromised BrCa function are breast cancer and BRCA1 or BRCA2 BRCA2 does not inform systemic therapy highly sensitive to ParP inhibition. this mutations who had received at least one recommendations for women with breast finding provides the concept of synthetic chemotherapy regimen were enrolled in cancer, but the results of this and subsequent lethality, whereby a lethal synergy occurs two sequential cohorts from 16 centers. in studies might change established practice” between two non-lethal events—in this the first cohort, patients received 400 mg concludes tutt. audeh also notes “the case inhibition of ParP induces a genetic olaparib twice daily, and in the second implications of our trial suggest that a lesion that is lethal in patients who lack a cohort they received 100 mg olaparib broader group of patients may benefit from functional Dna repair pathway owing to twice daily. the primary end point was ParP inhibitor therapy”. andrew tutt and loss of BrCa function. objective response rate (orr) and safety his colleagues are now developing ParP Previous research by alan ashworth’s and tolerability were also assessed. the inhibitors to test in clinical trials as single group in cell line models showed that orr was higher in the first cohort than agents and in combination with standard when Dna repair is defective owing to the second (41% versus 22%) and toxic therapies in a wider range of sporadic and loss of BrCa function, this defect was effects—fatigue, nausea and vomiting— BRCA1 BRCA2 associated breast, ovarian lethal when combined with induced were mainly low grade and manageable. and other solid tumors. loss of ParP, but only when cells lacked the median progression-free survival was Lisa Hutchinson functional BrCa. thus, treatment with 5.7 months for the high-dose cohort and ParP inhibitors could be particularly 3.8 months for the low-dose cohort. beneficial in women with BRCA-mutated in the second phase ii trial led by Original articles Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or breast and ovarian cancers. andrew tutt, william audeh, the efficacy and safety BRCA2 mutations and advanced breast cancer: a proof-of- from alan ashworth’s group together with of olaparib was tested at the 100 mg and concept trial. Lancet 376, 235–244 (2010) | Audeh, M. W. other international investigators, set out to 400 mg doses in women with recurrent et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib show whether ParP was selectively lethal ovarian cancer. in both phase ii studies, in patients with BRCA1 or BRCA2 mutations and recurrent for tumors with loss of function of BRCA1 as the frequency of early progression was ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010) and BRCA2. higher in the low-dose group the studies

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