Are there clinical factors that can predict prolonged survival of patients receiving olaparib as maintenance therapy for BRCA-mutated ovarian cancer?
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ABSTRACT:
SUBMITTER: Lieberman H
PROVIDER: S-EPMC8798247 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPatients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review.ResultsOf the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event.ConclusionsAmong patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).
| S-EPMC6810605 | biostudies-literature
Project description:Background: The PARP inhibitor olaparib has been shown to have clinical efficacy in patients with a germline BRCA mutation and ovarian or breast cancer. However, the high treatment cost associated with this drug limits its viability as a clinical treatment option. This work aims to evaluate the cost-effectiveness of olaparib as a maintenance treatment for metastatic pancreatic cancer from the perspective of the United States and China healthcare systems and provides valuable suggestions for clinical decision making. Method: A three-state Markov model (progression-free, progressed disease, death) was constructed using TreeAge Pro 2020 software to evaluate the economic value of olaparib vs. placebo maintenance treatment for metastatic pancreatic cancer based on the clinical data derived from phase III randomized controlled trial (POLO, ClinicalTrials.gov number, NCT02184195). Total costs, quality-adjusted life years and incremental cost-effectiveness ratio were used as economic indicators for this analysis. A 5-years horizon and 5%/year discount rates were used. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were performed to assess the model uncertainty. Results: The incremental cost-effectiveness ratios (ICERs) of the use of olaparib vs. placebo in China and the United States were $6,694/QALY and $13327/QALY, respectively. All ICERs were far below the thresholds of $30829 in China and $50000 in the United States. Sensitivity analysis confirmed a stable economic advantage in the use of olaparib vs. placebo as maintenance therapy in China and the United States. Conclusion: Olaparib was estimated to be more cost effective than placebo for the maintenance therapy of patients with a germline BRCA mutation and pancreatic cancer in China and the United States at thresholds of $30829 and $50000 per QALY, respectively.
| S-EPMC8096350 | biostudies-literature
Project description:BACKGROUND:Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS:Patients were randomized to receive maintenance olaparib (300?mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4?weeks until disease progression, at discontinuation, and 30?days after last dose. Scores ranged from 0 to 100; a ?10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS:Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P?=?0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P?=?0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P?=?0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P?=?0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS:HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER:NCT02184195.
| S-EPMC6938600 | biostudies-literature
Project description:The purpose of this study was to investigate the predictors of the effect of olaparib on platinum-sensitive recurrent ovarian cancer with unknown germline BRCA mutations. We retrospectively examined 20 patients with platinum-sensitive ovarian cancer who were treated at the Nippon Medical School Chiba Hokusoh Hospital, Japan, from 2018 to 2020. We found that the median progression-free survival was 11.4 months (95% Confidence interval (CI): 3.8-Not Available (NA)) in the group with NLPN score [recurrent neutrophil-lymphocyte ratio (rNLR) × number of previous regimens] >7.51, and median progression-free survival was not reached in the group with NLPN score <7.51 (95% CI: 21.8-NA) (p = 0.0185). There was a clear correlation between the degree of dose reduction of olaparib and recurrence (p = 0.00249). Our results show that NLPN scores lower than 7.51 are associated with a favorable outcome of olaparib treatment for platinum-sensitive recurrent ovarian cancer. In cases with a high rNLR, it may be necessary to start olaparib treatment as early as possible to obtain low NLPN scores. Our results imply that the effectiveness of olaparib can be determined after recurrence and before platinum treatment begins. As newer drugs for ovarian cancer are developed, the measurement of biomarker levels at the start of treatment for recurrent ovarian cancer, as shown in our study, may provide strong support for cancer treatment protocols.
| S-EPMC8358390 | biostudies-literature
Project description:ObjectiveTo compare survival outcomes between bevacizumab (BEV) and olaparib (OLA) maintenance therapy in BRCA-mutated, platinum-sensitive relapsed (PSR) high-grade serous ovarian carcinoma (HGSOC).MethodsFrom 10 institutions, we identified HGSOC patients with germline and/or somatic BRCA1/2 mutations, who experienced platinum-sensitive recurrence between 2013 and 2019, and received second-line platinum-based chemotherapy. Patients were divided into BEV (n=29), OLA (n=83), and non-BEV/non-OLA users (n=36). The OLA and non-BEV/non-OLA users were grouped as the OLA intent group. We conducted 1:2 nearest neighbor-matching between the BEV and OLA intent groups, setting the proportion of OLA users in the OLA intent group from 65% to 100% at 5% intervals, and compared survival outcomes among the matched groups.ResultsOverall, OLA users showed significantly better progression-free survival (PFS) than BEV users (median, 23.8 vs. 17.4 months; p=0.004). Before matching, PFS improved in the OLA intent group but marginal statistical significance (p=0.057). After matching, multivariate analyses adjusting confounders identified intention-to-treat OLA as an independent favorable prognostic factor for PFS in the OLA 65P (adjusted hazard ratio [aHR]=0.505; 95% confidence interval [CI]=0.280-0.911; p=0.023) to OLA 100P (aHR=0.348; 95% CI=0.184-0.658; p=0.001) datasets. The aHR of intention-to-treat OLA for recurrence decreased with increasing proportions of OLA users. No differences in overall survival were observed between the BEV and OLA intent groups, and between the BEV and OLA users.ConclusionCompared to BEV, intention-to-treat OLA and actual use of OLA maintenance therapy were significantly associated with decreased disease recurrence risk in patients with BRCA-mutated, PSR HGSOC.
| S-EPMC8550925 | biostudies-literature
Project description:BackgroundThe optimal treatment of BRCA wild-type patients with platinum-sensitive recurrent ovarian cancer remains unknown. Recently, there is an increase in the evidence to support the role of the combination of a poly(adenosine diphosphate-ribose) polymerase inhibitor, anti-angiogenic agents, and immunotherapy as maintenance therapy in BRCA wild-type patients with platinum-sensitive recurrence. We hypothesized that adding pembrolizumab and bevacizumab to olaparib maintenance can increase progression-free survival (PFS) in BRCA wild-type patients with platinum-sensitive recurrent ovarian cancer.MethodsBRCA wild-type patients who received two previous courses of platinum-containing therapy, achieved complete or partial response to last treatment, and the treatment-free interval is >6 months after the penultimate platinum-based chemotherapy offered olaparib maintenance with pembrolizumab and bevacizumab. Forty-four patients will be included from 4 sites across Singapore and Korea. The primary endpoint of the study is 6-month PFS rate.Trial registrationClinicalTrials.gov Identifier: NCT04361370, Clinical Research Information Service Identifier: KCT0005144.
| S-EPMC7930449 | biostudies-literature
Project description:BackgroundWe conducted a Phase 1 study to evaluate safety and activity of olaparib tablets and oral cyclophosphamide.MethodsPatients had metastatic breast cancer (BC) or recurrent high-grade serous ovarian cancer (HGSOC), performance status 0-2, and ≤3 lines of prior therapy. Patients were treated using a dose escalation strategy with cohort expansion once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1): olaparib 300 mg bid, cyclophosphamide 50 mg on days 1, 3, and 5, weekly. DL2: olaparib 300 mg bid, cyclophosphamide 50 mg, days 1-5 weekly.ResultsOf 32 patients, 23 had HGSOC (germline BRCA mutation [gBRCAm] 70%) and 9 had BC (gBRCAm 67%). Four were treated at DL1 and 28 at DL2, the MTD. Haematological adverse events (AEs) were most common: grade 3/4 AEs: lymphopenia 75%, anaemia 31%, neutropenia 37%, thrombocytopenia 47%. Two permanently discontinued treatment due to haematological AEs. In BC, no objective response was reported. Unconfirmed objective response was 48% and 64% for all HGSOC and gBRCAm subset, respectively. CA125 responses were 70% (all HGSOC) and 92% (gBRCAm).ConclusionsIn HGSOC and BC, olaparib 300 mg bid and cyclophosphamide 50 mg on days 1-5 weekly were tolerable and active, particularly in gBRCAm, and is worthy of further investigation.
| S-EPMC6353881 | biostudies-literature
Project description:ObjectiveTo evaluate the cost-effectiveness of olaparib as a maintenance treatment versus routine surveillance (RS) in patients with BRCA mutated (BRCAm) advanced ovarian cancer (OC) following response to first-line platinum-based chemotherapy in Singapore.MethodsA 4-health state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of olaparib versus RS from a healthcare payer perspective. Progression-free survival, time to second disease progression, and overall survival were estimated using SOLO-1 data and extrapolated beyond the trial period using parametric survival models. Any patient who remained progression-free at year 7 was assumed to be no longer at risk of progression. Mortality rates were based on all-cause mortality, adjusted based on BRCA1/2 mutation. Health state utilities and adverse event frequencies were from SOLO-1. Drug costs were from local public healthcare institutions. Healthcare resource usage and costs were from local clinician input and publications. A 3% discount rate was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of results.ResultsThe base-case analysis of olaparib maintenance therapy versus RS resulted in an ICER of Singapore dollar (SGD) 19,822 per quality-adjusted life-year (QALY) gained. The ICER was most sensitive to variations in the discount rate. PSA demonstrated that olaparib had an 87% probability of being cost-effective versus RS at a willingness-to-pay of SGD 60,000 per QALY gained.ConclusionOlaparib has a high potential of being a cost-effective maintenance treatment versus RS for patients with BRCA1/2m advanced OC after response to first-line chemotherapy in Singapore.
| S-EPMC7930440 | biostudies-literature
Project description:BackgroundPlatinum resistance is a major obstacle in the treatment of epithelial ovarian cancer (EOC). Activation of the AKT pathway promotes platinum resistance while inhibition of AKT sensitizes chemoresistant cells. Patients with BRCA mutant EOC, and thus a defect in the homologous recombination (HR) repair pathway, demonstrate greater clinical response to platinum and olaparib therapy than patients with BRCA wild-type EOC. MK-2206, an allosteric inhibitor of AKT phosphorylation, sensitizes a variety of cell types to various anticancer agents and is currently undergoing phase II trials as monotherapy for platinum-resistant ovarian, fallopian tube, and peritoneal cancer. This study examines the differential effects of AKT inhibition with cisplatin and olaparib therapy in BRCA1/2-deficient versus wild-type EOC.MethodsPEO1, a chemosensitive BRCA2-mutant serous ovarian adenocarcinoma, and PEO4, a reverted BRCA2-proficient line from the same patient after the development of chemotherapeutic resistance, were primarily used for the study. In PEO1, MK-2206 demonstrated moderate to strong synergism with cisplatin and olaparib at all doses, while demonstrating antagonism at all doses in PEO4.ResultsBaseline phospho-AKT activity in untreated cells was upregulated in both BRCA1- and 2-deficient cell lines. MK-2206 prevented cisplatin- and olaparib-induced AKT activation in the BRCA2-deficient PEO1 cells. We propose that BRCA-deficient EOC cells upregulate baseline AKT activity to enhance survival in the absence of HR. Higher AKT activity is also required to withstand cytotoxic agent-induced DNA damage, leading to strong synergism between MK-2206 and cisplatin or olaparib therapy in BRCA-deficient cells.ConclusionsMK-2206 shows promise as a chemosensitization agent in BRCA-deficient EOC and merits clinical investigation in this patient population.
| S-EPMC4964088 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells. We exploited the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1), and its physiological tropism toward cell nucleus. TNBC cell lines over-expressing TfR-1 were successfully recognized by H-Ferritin, displaying a fast internalization into the cells. HOla induced remarkable cytotoxic effect in cancer cells, exhibiting 1000-fold higher anticancer activity compared to free olaparib (Ola). Accordingly, HOla treatment enhanced PARP-1 cleavage, DNA double strand breaks and Ola delivery into the nuclear compartment. Our findings suggest that H-Ferritin nanoformulation strongly enhances cytotoxic efficacy of Ola as a stand-alone therapy in both BRCA-mutated and wild type TNBC cells, by promoting targeted nuclear delivery.
| S-EPMC5548799 | biostudies-other