Platinum-sensitive Recurrent Ovarian Carcinoma Research Articles

Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer

BackgroundIGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. MethodsPatients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1–18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8–89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0–3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8–2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. ConclusionsIGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Efficacy of Niraparib-bevacizumab combination maintenance therapy in Platinum-sensitive recurrent Ovarian Carcinoma.

Abstract To access clinical trials assessing efficacy of Niraparib-bevacizumab combination maintenance therapy in patients with Ovarian Carcinoma.

Cost-effectiveness of fuzuloparib compared to routine surveillance, niraparib and olaparib for maintenance treatment of patients with germline BRCA1/2 mutation and platinum-sensitive recurrent ovarian carcinoma in China.

Background: Maintenance therapy with the poly (ADP-ribose) polymerase inhibitors (PARPis) for platinum-sensitive recurrent ovarian carcinoma (OC) have proven to be effective compared with placebo. We aimed to evaluate the cost-effectiveness (CE) of maintenance fuzuloparib compared to routine surveillance (RS), niraparib and olaparib for platinum-sensitive recurrent OC from the Chinese healthcare systems. Method: A partitioned survival model with three-state (progression-free, progressed, death) was constructed utilizing TreeAge Pro 2011 software to evaluate the economic value of fuzuloparib, niraparib and olaparib maintenance treatment for platinum-sensitive recurrent OC based on the clinical data derived from FZOCUS-2, ENGOT-OV16/NOVA and ENGOT-Ov21/SOLO2. Transition probabilities were estimated from the reported survival probabilities in those trials. Cost and health preference data were derived from the literature. The quality-adjusted life-years (QALYs) and lifetime costs were measured for this analysis. A 5years horizon and 5%/year discount rates were used. One-way analysis, and probabilistic sensitivity analysis (PSA) were performed to explore the model uncertainties. Results: Total cost of fuzuloparib, niraparib and olaparib were $31628.10, $48183.48 and $54605.54, whereas they had an incremental cost-utility ratio of $31992.69, $32216.08 and $23359.26 per additional progression-free survival (PFS) QALYs gained compared with RS, relatively. Model showed that maintenance fuzuloparib achieved at least an 85.5% probability of CE at the threshold of $37654.50/QALY. One-way sensitivity analysis revealed that the results were sensitive to the PFS and the price of medicines. Conclusion: Fuzuloparib was less cost-effective for patients with germline BRCA1/2 mutation and platinum-sensitive recurrent OC compared to olaparib, but was superior to niraparib from the Chinese healthcare systems perspective.

Novel inflammatory markers and prognostic importance of platinum-sensitive ovarian carcinoma relapse

Introduction/Objective. Ovarian carcinomas are the deadliest gynecological tumors. Despite advances in treatment options, survival rates are still not at the desired level. Since clinical signs are not typical in early-stage disease, two-thirds of patients are diagnosed late. Carbohydrate Antigen 125 (CA125) does not have sufficient sensitivity and specificity in early-stage disease and early post-relapse progression. There is a need for a simple and cost-effective marker that correlates with CA125. For this purpose, we aimed to evaluate the potential of systemic inflammatory markers? as diagnostic aids. Methods. Patients with platinum-sensitive recurrent ovarian carcinomas were preferred because the treatment options were more diverse than the resistant group. Using retrospective data collection, 105 patients with platinum-sensitive recurrent ovarian carcinoma, admitted in the last four years were included in the study. Complete blood count data was recorded based on recurrence and progression periods. Results. When the systemic immune inflammatory index (SII) values were evaluated in combination with CA125 in terms of progression during the control visits after platinum-sensitive disease recurrence treatment, progression detection proportions increased to 97.5%, which was 82.9% when only CA125 was used. On the other hand, false positivity, which was 18.5% for CA125 alone, decreased to 2.5% when combined with SII. Furthermore, neutrophil lymphocyte ratio, white blood cells, and neutrophil values showed correlations with high CA125 values. Conclusion. The SII value could be used together with CA125 because it is easy to use, accessible, and has low cost in clinical practice, as well as to increase the accuracy rate and make precise corrections in the false positivity rate.

Post hoc exploratory analysis of rucaparib in patients with platinum-sensitive recurrent ovarian carcinoma from the randomized, placebo-controlled phase III study ARIEL3: Effect of a deleterious germline or no germline BRCA mutation on efficacy

Post hoc exploratory analysis of rucaparib in patients with platinum-sensitive recurrent ovarian carcinoma from the randomized, placebo-controlled phase III study ARIEL3: Effect of a deleterious germline or no germline BRCA mutation on efficacy

Exploratory analysis of the effect of maintenance rucaparib on postprogression outcomes in patients (pts) with platinum-sensitive recurrent ovarian carcinoma (OC) and updated safety data from the phase 3 study ARIEL3.

5522 Background: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-type BRCA/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Exploratory endpoints of time to first subsequent therapy (TFST), time to investigator-assessed PFS on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the predefined cohorts. Results: Exploratory efficacy endpoint data are given in the Table. As of Dec 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs 0.0%). Conclusions: Rucaparib significantly improved the clinically meaningful endpoints TFST, PFS2, and TSST vs placebo in all predefined cohorts of pts with platinum-sensitive, recurrent OC. The updated safety profile was consistent with prior reports. Clinical trial information: NCT01968213. [Table: see text]

SOLO1 versus SOLO2: Cost-effectiveness of olaparib as maintenance therapy for newly diagnosed and platinum-sensitive recurrent ovarian carcinoma among women with germline BRCA mutations (gBRCAmut).

5545 Background: With the December 19, 2018 regulatory approval by the US FDA of olaparib tablets as maintenance therapy for women with deleterious or suspected deleterious germline or somatic BRCAmut advanced ovarian carcinoma, it becomes important to clarify the role of PARP inhibitors in this disease. We evaluated cost-effectiveness of olaparib in the upfront (SOLO1) versus the recurrent maintenance setting (SOLO2). Methods: Data were obtained from SOLO1, the phase 3 placebo-controlled randomized upfront maintenance study among gBRCAmut patients [median PFS greater than 49.8 vs 13.8m: HR 0.30; 95% CI, 0.23-0.41; p < 0.001, NCT01844986] and SOLO2, the phase 3 placebo-controlled randomized maintenance study among gBRCAmut patients with platinum-sensitive recurrence and at least two prior lines of therapy [median PFS 19.1 vs 5.5m: HR 0.30; 95% CI, 0.22-0.41; p < 0.0001, NCT01874353]. Investigator-assessed median PFS and toxicity data from the trials were incorporated in a Markov model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2015, the costs of pre-treatment testing (eg. gBRCAmut), medications, and management of adverse effects were analyzed. Incremental cost-effectiveness ratios (ICERs) per month of life gained and individual PFS-life year saved (PFS-LYS) were also calculated and compared. Results: In SOLO1, cost prior to progression was 1.7x that of SOLO2 ($937,440 vs $564,451). With the extended, estimated median PFS of at least 49.8m for SOLO1 and 19.1m for SOLO2, upfront maintenance therapy was more cost-effective. SOLO 1 was associated with $312,480 PF-LYS per individual patient, while SOLO2 demonstrated $498,045 PF-LYS. Maintenance olaparib was found to be more cost-effective in the 1st-line setting, with an ICER of $12,149 per month of life gained when compared directly to SOLO2. Conclusions: Although the higher cost associated with olaparib in SOLO1 reflects the longer time patients stay on drug due to extended PFS, the ICER supports early use in the disease course as first-line maintenance therapy among women with gBRCAmut advanced ovarian carcinoma.

947P - Subgroup analysis of rucaparib in platinum-sensitive recurrent ovarian carcinoma: Effect of prior chemotherapy regimens in ARIEL3

947P - Subgroup analysis of rucaparib in platinum-sensitive recurrent ovarian carcinoma: Effect of prior chemotherapy regimens in ARIEL3

Evaluation of rucaparib in platinum-sensitive recurrent ovarian carcinoma (rOC) in patients (pts) with or without residual bulky disease at baseline in the ARIEL3 study.

5537Background: In ARIEL3, pts were randomized 2:1 (oral rucaparib 600 mg or placebo). Rucaparib significantly improved progression-free survival (PFS) vs placebo in all primary analysis groups (Co...

Exploratory analysis of percentage of genomic loss of heterozygosity (LOH) in patients with platinum-sensitive recurrent ovarian carcinoma (rOC) in ARIEL3.

5545Background: In ARIEL3, rucaparib significantly improved progression-free survival (PFS) vs placebo in all randomized patients, including patients with BRCA-mutant, BRCA wild-type/high-LOH (pres...

A phase II study of lenalidomide in platinum-sensitive recurrent ovarian carcinoma

Lenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated. Patients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety. Most of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9-56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6-12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4-4.4). Most frequent toxicity was hematologic, notably grade 3-4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity. Lenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents. NCT01111903.

Is the current concept of recurrent ovarian carcinoma as a chronic disease also applicable in platinum resistant patients?

The treatment of recurrent ovarian carcinoma (ROC) has become increasingly oriented according to the therapy principles of a chronic disease. We evaluated whether it is justifiable to also apply this concept to the treatment of platinum resistant patients with their known poor prognosis and short overall survival (OS). We analyzed the overall courses of 85 unselected ROC patients and defined the following groups: A, platinum resistant patients (n=39); subgroup A.1, those who received no or at maximum one line of palliative chemotherapy (n=15, 38.5%); subgroup A.2, those who received>or=two therapy lines (n=24, 61.5%); B, platinum sensitive patients, n=46. Group A had significantly lower OS than group B (median: 16 vs. 25 months; p=0.019). Group A.1 had significantly worse outcome compared to group A.2 (median: 5 vs. 21.5 months; p<0.001). The comparison between study group A.2 and group B showed comparable survival rates (p=0.738). Considering only the patients who had completed treatment courses, the median number of therapy lines administered was higher in group A.2 than in group B (4 vs. 3; p=0.008). There is not only the known dichotomy between platinum sensitive and resistant ROC patients, but rather also within the platinum resistant subgroup itself. There is a considerably large subgroup of platinum resistant patients who will subsequently enter a phase where multiple treatment programs will be considered and administered. These patients have similar survival rates compared to those from the platinum sensitive patient group and the therapy principles of a chronic disease are applicable.

A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma

Objectives To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. Methods Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3–6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. Results Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1–6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia ( n = 1), and non-dose limiting G3 neutropenia ( n = 3). Of the 11 patients who received ≥ 1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. Conclusions This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Español de Investigación en Cáncer de Ovario) study

The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma. Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL). Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis. Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.