scholarly journals DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment

2020 ◽  
Vol 30 (11) ◽  
pp. 1824-1828
Author(s):  
Michelle McMullen ◽  
Katherine Karakasis ◽  
Bienvenu Loembe ◽  
Emma Dean ◽  
Graem Parr ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Treatment ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Recist 1.1

BackgroundWith the success of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in the first-line and second-line treatment settings, a new patient population is emerging with platinum-sensitive relapsed ovarian cancer, who have previously received a PARP inhibitor in the maintenance setting and for whom no second maintenance standard of care exists. DUETTE (NCT04239014) will evaluate the combination of ceralasertib (a potent, selective inhibitor of the serine/threonine kinase ataxia telangiectasia and Rad3-related protein (ATR) + olaparib, or olaparib monotherapy, compared with placebo, in this patient population of unmet need.Primary ObjectiveThe primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive relapsed ovarian cancer.Study HypothesisThis study will test the hypothesis that ceralasertib + olaparib, or olaparib monotherapy, is tolerable, and effective at prolonging progression-free survival compared with placebo.Trial DesignThis is a phase II, multicenter study where patients will be randomized in a 1:1:1 ratio to receive either (Arm 1) ceralasertib + olaparib, (Arm 2) olaparib monotherapy, or (Arm 3) placebo. The olaparib and placebo arms will be double-blinded, whereas the ceralasertib + olaparib arm will be open label. Patients will be stratified according to BRCA status, and response to platinum-based chemotherapy.Major Inclusion/Exclusion CriteriaEligible patients will have histologically diagnosed high-grade epithelial ovarian cancer, with platinum-sensitive relapse on, or after, completion of at least 6 months of any prior PARP inhibitor maintenance therapy (a minimum of 12 months is required if the patient received PARP inhibitor maintenance following first-line chemotherapy). If the prior PARP inhibitor used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Disease relapse in the second-line or third-line setting is allowed. Patients who have received secondary debulking surgery are potentially eligible if they meet all other inclusion criteria.Primary EndpointsThe primary endpoint is progression-free survival determined by blinded independent central review according to RECIST 1.1, with sensitivity analysis of progression-free survival using investigator assessments according to RECIST 1.1.Sample Size192 patients.Estimated Dates for Completing Accrual and Presenting ResultsDecember 2022.Trial RegistrationNCT04239014.

The safety and efficacy of weekly paclitaxel and cisplatin chemotherapy for patients with ovarian cancer who developed carboplatin hypersensitivity reaction in previous chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6058-6058
Author(s):  
Kyoko Nishikimi ◽  
Shinichi Tate ◽  
Ayumu Matsuoka ◽  
Makio Shozu
Keyword(s):  
Ovarian Cancer ◽  
Sodium Phosphate ◽  
Progression Free Survival ◽  
Weekly Paclitaxel ◽  
First Line ◽  
Peritoneal Carcinoma ◽  
Free Survival ◽  
Safety And Efficacy ◽  
Platinum Sensitive ◽  
Carboplatin Hypersensitivity

6058 Background: Carboplatin (CBDCA) hypersensitivity reactions (HSR) often occur in patients with ovarian cancer. Once CBACA HSR occurs, it is difficult to use platinum even though the patients had platinum-sensitive disease and consequently the survival of the patients cannot be prolonged. We had administered weekly paclitaxel and cisplatin (CDDP) chemotherapy (wTP) for patients with ovarian cancer who developed CBDCA HSR in previous chemotherapy. We investigated the safety and efficacy of wTP. Methods: We investigated 86 patients with ovarian, fallopian tube, and peritoneal carcinoma who developed CBDCA HSR in previous chemotherapy (paclitaxel/CBDCA) at our institution between 2011 and 2019. After premedication was administered, paclitaxel and sequentially CDDP were administered as one hour infusion, respectively (paclitaxel 80 mg/m2, CDDP 25 mg/m2; 1, 8, 15 day/4 weeks). Results: The median cycle of the previous chemotherapy of CBDCA was 8 (interquartile range [IQR], 6–11). The grade of CBDCA HSR was 1 in 57 (66%), 2 in 26 (30%), and, 3 in 1 (1%) patient(s). WTP was administered for the first line in 21 (24%), second line in 35 (41%) and third or more line in 30 patients (34%). The median cycles of wTP administration was 4 (IQR, 3–7). We observed that severe CDDP HSR did not occur in any patients and 15 patients (17.4%, grade 1, 10 patients; grade 2, 5) developed CDDP HSR. All CDDP HSR were successfully managed with infusion interruption and Hydrocortisone Sodium Phosphate administration. There was no relation between the grade of CBDCA HSR in the previous chemotherapy and the rate of CDDP HSR (p = 0.363). Progression-free survival and overall survival after administration of wTP were 10.9 months (95% CI: 7.7–17.7) and 25.9 months (95%Ci: 19.0–50.2), respectively. Conclusions: 71 patients (82%) who developed CBDCA HSR in previous chemotherapy were able to continue administration of wTP without CDDP HSR. WTP was safe and effective for the patients who developed CBDCA HSR. [Table: see text]

Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): A randomized, open-label phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5001-5001 ◽  
Author(s):  
Amit M. Oza ◽  
David Cibula ◽  
Ana Oaknin ◽  
Christopher John Poole ◽  
Ron H.J. Mathijssen ◽  
...  
Keyword(s):  
Maintenance Treatment ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Open Label ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Open Label Phase ◽  
Secondary Endpoints ◽  
Grade 3

5001 Background: The oral PARP inhibitor olaparib has shown antitumor activity in pts with SOC. Our multicenter study compared the efficacy of (Arm A) olaparib capsules plus P/C for 6 cycles then maintenance olaparib monotherapy vs (Arm B) P/C alone for 6 cycles and no further therapy in pts with PSR SOC (NCT01081951). Methods: Pts received 6 x 21-day(d) cycles of olaparib (200 mg bid, d1–10/21) + P (175 mg/m2 iv, d1) + C (AUC4 iv, d1), then olaparib monotherapy as maintenance (400 mg bid, continuous) (Arm A), or 6 x 21d cycles of P (175 mg/m2 iv, d1) + C (AUC6 iv, d1) then no further therapy (Arm B), until progression. Randomization (1:1) was stratified by number of platinum treatments and platinum-free interval. Primary endpoint: progression-free survival (PFS) by central review (RECIST 1.1). Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Archival tissue was collected where available for analysis of biomarker correlation. Results: Of 162 pts randomized (n=81 per arm), 156 received treatment (Arm A, n=81; Arm B, n=75) and 121 began the maintenance/no further therapy phase (Arm A, n=66; Arm B, n=55). Olaparib + P/C (AUC4) followed by maintenance olaparib showed a significant improvement in PFS vs P/C (AUC6) alone (HR = 0.51, 95% CI 0.34, 0.77; P=0.0012; median = 12.2 vs 9.6 months). OS data are immature (total events: 14%). ORR was similar for Arm A and Arm B (64 vs 58%). Most common AEs during the combination phase were alopecia (74 vs 59%), nausea (69 vs 57%) and fatigue (64 vs 57%) for Arm A vs Arm B, respectively. Pts with grade ≥3 AEs (65 vs 57%), serious AEs (SAEs: 15 vs 21%) and AEs leading to treatment discontinuation (19 vs 16%) were similar for Arm A vs Arm B. Most common AEs during maintenance/no further therapy were nausea (50 vs 6%) and vomiting (29 vs 7%). 29 vs 16% of pts had grade ≥3 AEs, 9 vs 7% had SAEs and 8% vs N/A discontinued due to AEs in the olaparib vs no treatment arms, respectively. There were no fatal AEs. Conclusions: In pts with PSR SOC, olaparib plus P/C (AUC4) followed by olaparib 400 mg bid monotherapy maintenance treatment resulted in a significant improvement in PFS vs P/C (AUC6) alone.

scholarly journals Use of PARP Inhibitors for Ovarian Cancer

2021 ◽  
Vol 19 (5.5) ◽  
pp. 636-638
Author(s):  
Deborah K. Armstrong
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Resistant Disease ◽  
Relapsed Disease ◽  
Increased Activity

PARP inhibitors have been used to treat numerous diseases, but these agents have been approved the longest for use in ovarian cancer. All trials of PARP inhibitor maintenance in newly diagnosed ovarian cancer are positive for prolonged progression-free survival (PFS), but patients with BRCA mutations consistently derive the most benefit. Testing for homologous recombination deficiency may provide information regarding the degree of PFS benefit. In individuals without a BRCA mutation, PARP inhibition also prolongs PFS after chemotherapy for platinum-sensitive, PARP-naïve disease. As in the up-front setting, patients with BRCA mutations derive the most benefit in these trials. Finally, PARP inhibitors are active as monotherapy in PARP-naïve, BRCA-mutated relapsed disease, with increased activity observed in platinum-sensitive versus platinum-resistant disease.

scholarly journals The role of subgroup analyses: results from the NOVA trial

2017 ◽  
Vol 5 (1) ◽  
pp. 40-42
Author(s):  
Massimo Di Maio ◽  
Alice Bergamini
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Wild Type ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Subgroup Analyses

The clinical efficacy of poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors in BRCA-mutated ovarian cancer patients has been widely reported. However, novel challenges are currently aimed at broadening the benefit of PARP inhibitors to patients with wild-type BRCA and homologous recombination deficiency (HRD) and identifying a test able to select those patients who might benefit most from this therapy. The recently published ENGOT-OV16/NOVA trial reported an advantage in progression-free survival (PFS) for patients receiving the PARP1/2 inhibitor niraparib, as maintenance treatment for platinum-sensitive ovarian cancer compared to placebo, regardless of their germline BRCA or HRD status. This suggests that niraparib could potentially represent a valuable maintenance option for virtually all patients with platinum-sensitive relapsed ovarian cancer and that the HRD assay used in this trial is not able to reliably identify those patients who benefit the most from niraparib maintenance. These provocative considerations are the result of subgroup analyses that should be interpreted with caution but are useful to show the consistency of the effect of niraparib across the whole population.

ATL

2013 ◽  
Vol 23 (5) ◽  
pp. 846-852 ◽  
Author(s):  
Angeles Alvarez Secord ◽  
Jason Cory Barnett ◽  
Jonathan A. Ledermann ◽  
Bercedis L. Peterson ◽  
Evan R. Myers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Cost Effective ◽  
Mutation Testing ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Free Survival ◽  
Platinum Sensitive

Objectives(1) To determine whether use of a PARP inhibitor or (2) BRCA1/2 mutation testing followed by a PARP inhibitor for test positives is potentially cost-effective for maintenance treatment of platinum-sensitive recurrent high-grade serous ovarian cancer.MethodsA modified Markov decision analysis compared 3 strategies: (1) observe; (2) olaparib to progression; (3) BRCA1/2 mutation testing; treat mutation carriers with olaparib to progression. Progression-free survival and rates of adverse events were derived from a phase 2 randomized trial. Key assumptions are as follows: (1) 14% of patients harbor a BRCA1/2 mutation; (2) progression-free survival of individuals treated with olaparib is improved for BCRA1/2 carriers compared with noncarriers (estimated hazard ratio, approximately 0.4). Costs derived from national data were assigned to treatments, adverse events, and BRCA1/2 test. Monte Carlo probabilistic sensitivity analysis was performed.ResultsGlobal olaparib was the most effective strategy, followed by BRCA1/2 testing and no olaparib. BRCA1/2 testing had an incremental cost-effectiveness ratio (ICER) of $193,442 per progression-free year of life saved (PF-YLS) compared to no olaparib, whereas global olaparib had an ICER of $234,128 per PF-YLS compared to BRCA1/2 testing. At a 52% lower-than-baseline olaparib cost estimate of $3000 per month, BRCA1/2 testing became potentially cost-effective compared with observation, with an ICER of $100,000 per PF-YLS. When strategy (1) was removed from the analysis, BRCA1/2 testing was the preferred strategy.ConclusionsThe use of maintenance olaparib in women with high-grade serous ovarian cancer is not cost-effective regardless of whether BRCA1/2 testing is used to direct treatment. However, BRCA1/2 testing is a preferred strategy compared to global maintenance olaparib alone.

scholarly journals Estimating long-term overall survival with olaparib as maintenance therapy in patients with newly diagnosed advanced ovarian cancer with BRCA mutations

2021 ◽  
Vol 17 (3) ◽  
pp. 97-105
Author(s):  
N. A. Avxentyev ◽  
S. V. Khokhlova ◽  
M. Yu. Frolov ◽  
A. S. Makarov
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
First Line ◽  
Brca Mutations ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Line Chemotherapy

Background. According to randomized clinical trial SOLO1 olaparib statistically significantly improves progression-free survival versus placebo as a maintenance monotherapy in patients aged 18 and over with newly diagnosed advanced ovarian cancer with BRCA mutations, who had response to first-line chemotherapy. As the data on overall survival (OS) in this trial remains interim it is still uncertain whether treatment with olaparib can provide any benefits in terms of OS.Objective: to evaluate a long-term OS for olaparib versus placebo as a maintenance monotherapy in patients with newly diagnosed advanced ovarian cancer with BRCA mutations, who had response to first-line chemotherapy.Materials and methods. A 10-year mathematic model of disease progression and survival on olaparib versus placebo was developed. Modelling was based on data on progression-free survival from SOLO1 trial and data on OS after platinum-sensitive and platinum-resistant relapses from OCEANS and AURELIA trials. Additionally, patients who haven’t been treated with olaparib after first-line therapy in base-case scenario were assumed to get olaparib as a second-line treatment after platinum-sensitive relapse; mortality modelling for these patients was based on data from SOLO2 trial.Results. Median OS for olaparib was 107 months versus 66 months for placebo. 46 % of patients treated with olaparib were alive by the end of 10-year modelling period, but only 28 % patients from the placebo group. Hazard ratio of death for olaparib versus placebo was 0.64 (95 % confidence interval 0.49–0.84). Probabilistic sensitivity analysis showed robustness of these results.Conclusion. Using olaparib as a maintenance therapy in patients with newly diagnosed advanced ovarian cancer with BRCA mutations, who had response on first line chemotherapy, statistically significantly reduces risk of death by 36 %, compared to placebo.

Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5535-5535 ◽  
Author(s):  
Joyce F. Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Free Survival ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

5535 Background: We previously reported that the combination of cediranib (ced) and olaparib (olap) improved progression-free survival (PFS) and overall response rates (ORR) in women with recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related ovarian cancer (OvCa) (NCT 01116648). We conducted an updated PFS and overall survival (OS) analysis. Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. PFS was defined as time from randomization to radiographic progression or death. OS was defined as time from randomization to death. Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). As of Dec 21, 2016, 67 pts had a PFS event, and 52 pts had an OS event. Updated median PFS was 8.2 mos for Olap and 16.5 mos for Ced/Olap (HR 0.50, 95% CI 0.30-0.83, p=0.007). Median OS was 33.3 mos for Olap and 44.2 mos for Ced/Olap (HR 0.64, 95% CI 0.36-1.11, p=0.11). Within known germline BRCA mut carriers, updated PFS was 16.5 vs 16.4 mos (HR 0.75, p=0.42), and OS was 40.1 vs 44.2 mos (HR 0.79, p=0.55) for Olap and Ced/Olap, respectively. In pts without known germline BRCA mut, updated PFS was 5.7 vs 23.7 mos (HR 0.32, p=0.002), and OS was 23.0 vs 37.8 mos (HR 0.48, p=0.074). Conclusions: Updated PFS results consistently demonstrated that Ced/Olap significantly extended PFS compared to Olap in the overall population of women with plat-sens OvCa. In this Phase 2 study not powered to detect OS diferences, there was a trend towards OS improvement with Ced/Olap, particularly in pts without a known germline BRCA mutation. Results from ongoing studies of this oral combination in OvCa are of clinical interest. Clinical trial information: NCT 01116648.

Real world outcomes in platinum sensitive relapsed ovarian, fallopian tube, or peritoneal cancer treated in routine clinical practice in the United Kingdom prior to poly-ADP ribose polymerase inhibitors

2020 ◽  
Vol 30 (7) ◽  
pp. 1026-1033
Author(s):  
Rosemary Lord ◽  
Jyoti Rauniyar ◽  
Tamsin Morris ◽  
Orlaith Condon ◽  
Rachel Jones ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Real World ◽  
Index Date ◽  
Median Overall Survival ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Polymerase Inhibitors

IntroductionThe introduction of poly-ADP ribose polymerase inhibitors in ovarian cancer has demonstrated significantly improved progression free survival in four randomized controlled clinical trials in patients with platinum sensitive relapsed ovarian cancer. While overall survival data remain immature, this real world evidence study sets a baseline for future evaluation of poly-ADP ribose polymerase inhibitors.MethodsA retrospective chart review was undertaken to investigate real world survival outcomes across 13 National Health Service Trusts in England, Wales, and Scotland. Patients were included if they had platinum sensitive relapsed high grade serous ovarian cancer and had responded to secondline platinum based chemotherapy. Clinical data were collected retrospectively from electronic prescribing records and chart notes. The index date for overall survival analysis was defined as the later of (1) day 1 of the final secondline platinum based treatment or (2) date of response to secondline treatment. The primary objective was overall survival from the index date. Secondary objectives included progression free survival and overall survival by subsequent line of treatment. BRCA mutation status was collected where available. Quality of life questionnaires were not assessed within this study.Results233 patients were identified who met the study inclusion criteria. Patient characteristics were consistent with other published data, with a median age of 61 years (range 35–85). Sensitivity analysis of the primary objective demonstrated that the earliest point poly-ADP ribose polymerase inhibitors may be initiated (following completion of secondline chemotherapy) is associated with a median overall survival of 19.8 months. Secondline median overall survival and progression free survival from the index date were 19.3±2.4 months and 7.3±1.2 months, respectively. 144 patients were treated with thirdline chemotherapy with median overall survival and progression free survival from the index date (either date of last cycle of thirdline treatment or date of response to thirdline treatment) of 8.3±2.6 and 4.4±1.8 months, respectively.ConclusionOverall survival was shown to be shorter in this real world study compared with randomized clinical trials, and underlines the differences in clinical outcomes of patients in a real life setting. This baseline real world study has demonstrated poor survival outcomes in this patient group prior to availability of poly-ADP ribose polymerase inhibitors.

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