Platinum-sensitive Ovarian Carcinoma Research Articles

Analysis of sequential chemotherapy efficacy in ovarian epithelial carcinoma, fallopian tube carcinoma and primary peritoneal carcinoma

Objective: To explore the sequential chemotherapy efficacy of different chemotherapeutic regimens in ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. Methods: A retrospective analysis was conducted on clinical and pathological data of 100 patients with platinum-sensitive ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma treated at Peking University Peopel's Hospital from January 1992 to January 2019. All patients underwent staging surgery or cytoreductive surgery followed by adjuvant chemotherapy. Based on different postoperative adjuvant chemotherapy regimens, patients were divided into the sequential chemotherapy group (70 cases) and the conventional chemotherapy group (30 cases). Clinical and pathological characteristics, chemotherapy efficacy, adverse reactions, and prognosis were compared between the two groups. Results: (1) Clinical and pathological characteristics: the age, tumor types (including ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma), pathological types, International Federation of Gynecology and Obstetrics (FIGO) stage, postoperative residual disease size, presence of neoadjuvant chemotherapy, and total number of chemotherapy cycles were compared between the sequential chemotherapy group and the conventional chemotherapy group. There were no statistically significant differences observed in these characteristics between the two groups (all P>0.05). (2) Chemotherapy efficacy: the median sum of complete response (CR)+partial response (PR) duration in the sequential chemotherapy group was 80.0 months (range: 39 to 369 months), whereas in the conventional chemotherapy group, it was 28.0 months (range: 13 to 52 months). A statistically significant difference was observed between the two groups (Z=-7.82, P<0.001). (3) Chemotherapy adverse reactions: in the sequential chemotherapy group, 55 cases (79%, 55/70) experienced bone marrow suppression and 20 cases (29%, 20/70) had neurological symptoms. In the conventional chemotherapy group, these adverse reactions occurred in 11 cases (37%, 11/30) and 2 cases (7%, 2/30), respectively. Statistically significant differences were observed between the two groups for both bone marrow suppression and neurological symptoms (all P<0.05). For the other chemotherapy adverse reactions compared between the two groups, no statistically significant differences were observed (all P>0.05). (4) Prognosis: during the follow-up period, the recurrence rate in the sequential chemotherapy group was 73% (51/70) and in the conventional chemotherapy group was 100% (30/30). The median sum of recurrence-free interval was 70.5 months (range: 19 to 330 months) in the sequential chemotherapy group and 15.0 months (range: 6 to 40 months) in the conventional chemotherapy group. Statistically significant differences were observed between the two groups for both recurrence rate and median recurrence-free interval (all P<0.01).In the sequential chemotherapy group, the median progression-free survival (PFS) time was 84.0 months (range: 34 to 373 months), and the median overall survival (OS) time was 87.0 months (range: 45 to 377 months). In contrast, in the conventional chemotherapy group, the median PFS time was 30.5 months (range: 14 to 60 months), and the median OS time was 37.5 months (range: 18 to 67 months). Statistically significant differences were observed between the two groups for both PFS and OS (all P<0.001). In the sequential chemotherapy group, the 3-year, 5-year, and 10-year OS rates were 100% (70/70), 93% (65/70), and 21% (15/70), respectively. In contrast, in the conventional chemotherapy group, the OS rates were 50% (15/30) at 3 years, 3% (1/30) at 5 years, and 0 at 10 years, respectively. The two groups were compared respectively, and the differences were statistically significant (all P<0.05). Conclusions: Sequential chemotherapy significantly prolongs PFS and OS in patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. The efficacy is superior to that of the conventional chemotherapy, with manageable adverse reactions. The use of sequential chemotherapy as first-line treatment for patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma is recommended.

Carboplatin plus Paclitaxel in Combination with the Histone Deacetylate Inhibitor, Vorinostat, in Patients with Recurrent Platinum-Sensitive Ovarian Cancer

Background: This phase II study evaluated the efficacy and safety of the histone deacetylase (HDAC) inhibitor, vorinostat, administered in combination with paclitaxel and carboplatin in patients with platinum sensitive recurrent ovarian cancer. Methods: Women with recurrent platinum-sensitive ovarian, peritoneal, or Fallopian tube carcinoma, a performance status of 0–2, and good overall organ function were eligible. Patients received 6 courses of paclitaxel (175 mg/m2) and carboplatin area under the curve (AUC) of 5.0 mg/mL/min administered via intravenous infusion on day 1 of a 3-week schedule. In addition, patients received vorinostat 400 mg orally once daily on days −4 through 10 of Cycle 1 and days 1 through 14 of each subsequent treatment cycle. The primary endpoints were progression-free survival (PFS) and adverse events. The secondary endpoints were the objective response rate and overall survival. Results: Fifty-five patients were included. CR was obtained in 14 patients (26.4%) and PR in 19 patients (35.8%), resulting in an ORR of 62.2%. Twenty patients (37.7%) had SD. The median duration of response (DoR) was 12.6 (range 6–128) months. The median PFS was 11.6 months (95% CI, 10.3–18.0; p &lt; 0.001). Median OS was 40.6 months (95% Cl, 25.1–56.1). The most common treatment-related adverse events (all grades) were fatigue, anemia, thrombocytopenia, neutropenia, anorexia, nausea, pain, sensory neuropathy, myalgia, stomatitis and diarrhea. Conclusions: Vorinostat combined with carboplatin plus paclitaxel was tolerable and generated significant responses including a long median overall survival in recurrent platinum-sensitive ovarian cancer.

Single-cell RNA-sequencing analysis reveals divergent transcriptome events between platinum-sensitive and platinum-resistant high-grade serous ovarian carcinoma.

Tumor resistance is one of the main reasons leading to the failure of ovarian cancer treatment. Overcoming platinum resistance remains the greatest challenge in the management of high-grade serous ovarian carcinoma (HGSC). Small conditional RNA-sequencing is a powerful method for exploring the complexity of the cellular components and their interactions in the tumor microenvironment. We profiled the transcriptomes of 35,042 cells from two platinum-sensitive and three platinum resistance HGSC clinical cases downloaded from Gene Expression Omnibus (GSE154600) and annotated tumor cells as platinum-resistant or sensitive based on the clinical trait. The study systematically investigated the inter-tumoral (using differential expression analysis, CellChat, and SCENIC) and intra-tumoral heterogeneity (using enrichment analysis such as gene set enrichment analysis, as well as gene set variation analysis, weighted gene correlation network analysis, and Pseudo-time analysis) of HGSC. A cellular map of HGSC generated by profiling 30,780 cells was revisualized using Uniform Manifold Approximation and Projection. The inter-tumoral heterogeneity was demonstrated with intercellular ligand-receptor interactions of major cell types and regulons networks. FN1, SPP1, and COLLAGEN play important roles in the cross-talk between tumor cells and the tumor microenvironment. HOXA7, HOXA9_extended, TBL1XR1_extended, KLF5, SOX17, and CTCFL regulons consistent with the distribution of platinum-resistant HGSC cells were the high activity regions. The intra-tumoral heterogeneity of HGSC was presented with corresponding functional pathway characteristics, tumor stemness features, and the cellular lineage transition from platinum-sensitive to resistant condition. Epithelial-mesenchymal transition played an important role in platinum resistance, whereas oxidative phosphorylation was the opposite. There was a small subset of cells in platinum-sensitive samples that had transcriptomic characteristics similar to platinum-resistant cells, suggesting that the progression of platinum resistance in ovarian cancer is inevitable. The present study describes a view of HGSC at single-cell resolution that reveals the characteristics of the HGSC heterogeneity and provides a useful framework for future investigation of platinum-resistant.

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.

The value of PET/CT for cytoreductive surgery selection in recurrent ovarian carcinoma.

To evaluate the value of positron emission tomography/computed tomography (PET/CT) in predicting no residual disease (NRD) after secondary cytoreductive surgery (SCS) compared with MSK criteria, the iMODEL, and the AGO score. We analyzed 112 patients with platinum-sensitive ovarian carcinoma who underwent SCS. We excluded patients for whom PET/CT was not performed, those without sufficient data, and who received chemotherapy before SCS. Ultimately, 69 patients were included. Variables that correlated with NRD were peritoneal carcinomatosis index (odds ratio [OR]=0.91; 95% confidence interval [CI]=0.83-0.99; p=0.044), European Cooperative Oncology Group Performance Status (ECOG) 0 (OR=8.0; 95% CI=1.34-47.5; p=0.022), and ≤2 lesions by PET/CT (OR=4.36; 95% CI=1.07-17.7; p=0.039). Of the patients with ≤2 lesions by PET/CT, 48 (92.3%) underwent complete SCS. The sensitivity, positive predictive value, negative predictive value, and accuracy of PET/CT for NRD were 85.7%, 92.3%, 33.3%, and 81.2%, respectively. NRD was achieved after fulfilling the MSK criteria, iMODEL and AGO Score in 89.1%, 88.1% and 85.9%, respectively. The accuracy of the MSK criteria, iMODEL, and AGO score in predicting NRD was 87%, 83.3%, and 77.3%, respectively. The PET/CT findings agreed well with the AGO score and iMODEL. The addition of PET/CT to these models increased the NRD rates (92.2%, 91.8%, and 89.4% for MSK+PET/CT, iMODEL+PET/CT, and AGO+PET/CT, respectively), but lowered their accuracy. We observed NRD in 92.3% of patients with ≤2 lesions by PET/CT, with an accuracy of 81.2%. PET/CT did not increase the accuracy of the MSK criteria, iMODEL, or AGO score models.

Impact of bevacizumab and secondary cytoreductive surgery on survival outcomes in platinum-sensitive relapsed ovarian clear cell carcinoma: A multicenter study in Korea

ObjectiveThis study investigated survival outcomes for platinum-sensitive relapsed ovarian clear cell carcinoma (OCCC) by treatment method. MethodsOCCC patients with platinum-sensitive recurrence that received secondary treatment at five institutions between July 2007 and June 2021 were included. Patient characteristics and survival outcomes were compared according to the use of bevacizumab (BEV) during second-line chemotherapy and secondary cytoreductive surgery (CRS). Results138 patients were included. The BEV (n = 36) and non-BEV (n = 102) groups had similar initial FIGO stages and proportions of secondary CRS. The BEV group showed improved progression-free survival (PFS; median, 15.4 vs. 7.5 months; P = 0.042) and overall survival (OS; P = 0.043) compared to the non-BEV group. In multivariate analyses, BEV was identified as an independent prognostic factor for PFS (adjusted hazard ratio [aHR], 0.571; 95% confidence interval [CI], 0.354–0.921; P = 0.022) and OS (aHR, 0.435; 95%CI, 0.195–0.970; P = 0.042). The secondary CRS group (n = 42) had early-stage disease at diagnosis more frequently (P = 0.009) and multi-site metastasis (P < 0.001) at recurrence less frequently than the no surgery group (n = 96). The secondary CRS group showed significantly better PFS (median, 33.7 vs. 7.2 months; P < 0.001) and OS (P < 0.001). Secondary CRS was associated with a significantly improved PFS (aHR, 0.297; 95% CI, 0.183–0.481; P < 0.001) and OS (aHR, 0.276; 95% CI, 0.133–0.576; P = 0.001). The BEV and non-BEV groups showed similar PFS and OS among the patients who underwent secondary CRS. In contrast, the BEV group showed improved PFS and OS among patients who did not undergo surgery. ConclusionsThe use of BEV during second-line chemotherapy and secondary CRS may improve PFS and OS in patients with platinum-sensitive relapsed OCCC. Further prospective studies are warranted.

731P Multi-maintenance olaparib in relapsed, platinum-sensitive BRCA-mutant high-grade serous ovarian carcinoma (MOLTO): A phase II feasibility study

Relapsed, platinum-sensitive high-grade serous ovarian carcinoma (RPS-HGSOC) is treated with platinum re-challenge. One course of olaparib maintenance monotherapy (OLAP1) improves PFS in RPS-HGSOC. It is unclear whether a second olaparib maintenance monotherapy course (OLAP2) in RPS-HGSOC following platinum re-challenge (PLAT2) is feasible.

Abstract B22: Development of the first ovarian carcinosarcoma patient-derived xenograft and tissue organoid model to predict clinical response to chemotherapy

Abstract Objectives: Ovarian carcinosarcoma is an unusual and aggressive form of ovarian cancer. Due to the rarity of the disease, little empirical evidence exists about the efficacy of different chemotherapeutic regimens. Thus, the objective of this research is to establish and validate patient-derived carcinosarcoma xenograft and organoid models and assess the ability these models to predict response to chemotherapy. Methods: A patient-derived xenograft (PDX) was established during an optimal (R=0cm) upfront debulking surgery. Fresh tumor tissue was implanted subcutaneously in an 8-week-old NOD.Cg-Prkdcscid (NSG) mouse. Tumor growth was closely monitored until volume exceeded 2.0 cm3. The mouse was sacrificed and tumor tissue was harvested. A portion of the tissue was digested with highly purified collagenase I and collagenase II for establishment of in vitro monolayer and tissue organoid cell lines. IHC and flow cytometry were performed to validate the harvested PDX tumor and the in vitro cell line using FLEX monoclonal anti-human cytokeratin, high molecular weight, clone 34E12. Dose response curves were generated to assay the effects of five standard-of-care cytotoxic chemotherapy regimens (paclitaxel, carboplatin, gemcitabine, doxorubicin, and topotecan) and one experimental regimen (artesunate) after 96hours of incubation. Drug sensitivities were compared to other established commercially available platinum-sensitive ovarian carcinoma cells (UWB1.289), a model of acquired platinum-resistance (UWB1.289-CR), and to the patient’s clinical response to chemotherapy. Results: Palpable tumor tissue was harvested 14 weeks after implantation. The harvested tissue reveals strong expression of high molecular weight cytokeratin. Successful propagation of the patient’s malignancy in vitro was confirmed via flow cytometry. Dose response curves of cytotoxic chemotherapy reveals a relatively high resistance to carboplatin (IC50 44.6uM), gemcitabine (IC50 307.1nM), and topotecan (IC50 117.4nM) but sensitivity to paclitaxel (IC50 2.9nM), doxorubicin (IC50 59.7nM), and artesunate (IC50 1.8uM) when compared to established ovarian cancer cell lines. The patient recurred approximately 4 months after optimal debulking surgery despite treatment with adjuvant carboplatin/paclitaxel, thus classifying her disease as clinically platinum refractory. Conclusions: This is the first ovarian carcinosarcoma established in a PDX model and as an organoid cell line. Notably, the model predicted clinical response. The IC50 of the carcinosarcoma in vitro model was 44.6uM compared to 25.9uM in our established acquired platinum-resistant cell line and the patient had platinum-refractory disease. Additional insight into the intrinsic platinum resistance of this tumor may be gleaned from RNA and whole-exome sequencing that is currently in process. Citation Format: Joseph R. McCorkle, Brian T. Burgess, Anthony B. McDowell, Jodi DeJohn, Christopher P. DeSimone, Frederick R. Ueland, Jill M. Kolesar, Justin W. Gorski. Development of the first ovarian carcinosarcoma patient-derived xenograft and tissue organoid model to predict clinical response to chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B22.

Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial

In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Clovis Oncology.

A randomized phase III trial in patients with recurrent platinum sensitive ovarian cancer comparing efficacy and safety of paclitaxel micellar and Cremophor EL-paclitaxel

ObjectivePaclitaxel micellar was developed to avoid Cremophor-EL (Cr-EL) associated dose limiting toxicity and to allow a shorter infusion time. The efficacy and safety of paclitaxel micellar (+carboplatin) was compared to Cr-EL paclitaxel (+carboplatin) in recurrent platinum-sensitive ovarian, fallopian tube or peritoneal carcinoma. MethodsThis was a multicentre, open-label, randomized phase III trial. Adult patients with recurrent disease was assigned to six 3-week cycles of paclitaxel micellar (250 mg/m2) administered as 1-h infusion or Cr-EL paclitaxel (175 mg/m2) as 3-h infusion. Both arms received carboplatin (AUC 5–6). Primary objective was non-inferiority for progression free survival (PFS) using computed tomography scans. Overall survival (OS) was included as secondary endpoint. ResultsBetween 2009 and 2013, 789 patients were randomized to receive experimental (N = 397) or control (N = 392) treatment. PFS for paclitaxel micellar was non-inferior to Cr-EL paclitaxel with a hazard ratio of 0.86 (95% CI: 0.72;1.03) in the per protocol population (PP), favouring paclitaxel micellar (non-inferiority margin was 1.2). Non-inferiority of OS was shown in the PP population with a hazard ratio of 0.95 (95% CI: 0.78; 1.16), favouring paclitaxel micellar (non-inferiority margin was 1.185). The most common adverse event was neutropenia (grade ≥ 3); 245 patients (79%) for paclitaxel micellar vs 213 patients (66%) for Cr-EL paclitaxel. The frequency of peripheral sensory neuropathy (any grade) was similar between the arms; 16% for paclitaxel micellar and 20% for Cr-EL paclitaxel. ConclusionPaclitaxel micellar (+ carboplatin) is non-inferior to Cr-EL paclitaxel (+ carboplatin) in terms of PFS and OS in the studied population. It provides a treatment option of a higher paclitaxel dose with a shorter infusion time without mandatory premedication. Trial registration number2008–002668-32 (EudraCT), NCT00989131 (ClinicalTrials.gov)

109P - PARP inhibitor (PARPi) monotherapy treatment in non-BRCA and/or non-serous gynaecological cancers

Background: The vast majority of PARPi clinical trial experience in gynaecological cancer is for patients with platinum sensitive high grade serous ovarian carcinoma (HGSOC) and deleterious BRCA1/2 mutations. It is known that other homologous recombination deficiency (HRD) associated mutations exist eg RAD51, BRIP1 that can potentially sensitise to PARPi. Extremely limited clinical data exists on the use of PARPi in HGSOC with HRD mutations other than BRCA1/2; or in BRCA-mutated gynaecological cancers excluding HGSOC. We investigated the role of PARPi in a cohort of patients with non-BRCA and/or non-high grade serous (HGS) gynaecological cancer. Methods: Retrospective case series from two tertiary referral centres. Results: Ten cases were identified. Non-HGS cohort included large cell neuroendocrine carcinoma (LCNEC) of the cervix, small cell ovarian cancer, low grade ovarian cancer (LGSOC) and endometrial carcinoma. Non-BRCA patients were affected by alterations of RAD51, ATM and EMSY. Median number of cycles of PARPi received was 2 (range 1-16). CA125 response was seen in 75% (6 of 8 cases with minimum three CA125 results) with a median reduction of 53.3%. Overall radiological response rate 28.6% (2 of 7 cases with minimum one restaging scan). Progression free survival (PFS) was greater for non-HGS BRCA mutant patients (median PFS 10.5m, range 2-15m), than for HGSOC non-BRCA patients (median PFS 1.2m, range 1-2m). Legend: Abbreviations as in text, germline (g), somatic (s). Conclusions: In this series, deleterious BRCA mutation or variant of unknown significance (VUS) remains the single strongest predictor for response to PARPi irrespective of histology. It may be difficult to classify a BRCA mutation as deleterious or VUS in rarer gynaecological cancer populations. Non-BRCA mutations in HRD related genes eg RAD51/ATM may also sensitise to treatment with PARPi. Four patients remain on treatment and updated results will be presented. Legal entity responsible for the study: Dr R Kristeleit. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Table: 109PSiteBRCA 1/2Other mutsNumber cyclesCA125 ResponseRadiological ResponsePFSEndometrialBRCA1 mut (g)16yesyes15.5LCNEC cervixBRCA2 VUS (s)8yesN10.7LGSOCBRCA2 VUS (g)13yes (<50%)yes (on treatment)7.9Small cell ovarianBRCA2 VUS (g)2no dataN2.2HGSOCWTEMSY (s)4yes (<50%)N2.7HGSOCWTATM (s)2NN1.2HGSOCWTRAD51L3 (s)2NN1.0HGSOCWTRAD51C (g)2Nno data (on treatment)NAPP (as HGSOC)WTRAD51D (g)1yes (<50%)no data (on treatment)NAHGSOCWTRAD51C (g)2yesno data (on treatment)NA Open table in a new tab

Nanoparticle micellar formulation of paclitaxel in combination with carboplatin for women with recurrent platinum sensitive ovarian cancer (OAS07-OVA): Overall survival results of a phase 3 randomized trial.

5560 Background: The primary objective in the pivotal trial OAS-07OVA was reached and it was demonstrated that Paclical, a nanoparticle micellar formulation of paclitaxel (Oasmia Pharmaceutical AB) is non-inferior to Cremophor-EL Paclitaxel in terms of progression free survival (PFS) in the treatment of recurrent platinum-sensitive ovarian, fallopian tube or peritoneal carcinoma. Paclical is given as 1-h infusion without standard use of premedication. The follow-up analyses presented here includes overall survival (OS) and subgroups of PFS and OS. Methods: In this open 1:1 randomized 2-armed phase 3 study, 789 patients were included 2009 - 2012 in 81 centers. Non-inferiority in terms of OS was included as a secondary objective, anddefined as the time between date of randomization and death. Following the end of study, information of the death of participating patients was collected on a special form until August 2016. The upper non-inferiority limit of the one-sided confidence interval of the hazard ratio of the two treatment arms was set to 1.185. Results: Non-inferiority of OS was showed as the hazard ratio estimated based on a Cox proportional hazards model stratified by CA125 and relapse was 0.95 (95% CI: 0.78; 1.16) in the PP population. The median overall survival time was 25.7 months in the Paclical arm and 24.8 months in the Taxol arm. Non-inferiority of OS was also seen in patients experiencing their first relapse, and patients with serous adenocarcinoma at diagnosis. In addition, sensitivity analyses as well as subgroup analyses showed a consistent tendency of favor for Paclical in terms of PFS. Conclusions: Paclical is non-inferior to Taxol with respect to OS and PFS for patients with recurrent platinum-sensitive ovarian cancer. Even though the pivotal study was not designed to show superiority, subgroup analyses show a consistent tendency of favor for Paclical in terms of OS and PFS indicating a benefit for the Paclical group. Clinical trial information: NCT00989131, Eudra CT: 2008-002668-32 Clinical trial information: 2008-002668-32.

Abstract LB-A12: Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma

Abstract Background: High-grade ovarian carcinomas (HGOC) with a mutation in BRCA1/2 or other core homologous recombination repair (HRR) genes are sensitive to treatment with the PARP inhibitor rucaparib. To study whether HRR gene mutations confer sensitivity to rucaparib in the maintenance setting, we performed next-generation sequencing (NGS) on carcinomas from a double-blind, placebo-controlled, phase 3 study of rucaparib in patients with HGOC following response to platinum-based chemotherapy (ARIEL3, NCT01968213). Materials and Methods: Archival ovarian carcinoma specimens were required for all 564 patients who were randomized in ARIEL3 and were sequenced using Foundation Medicine’s NGS-based assay to identify deleterious mutations in a prespecified list of HRR genes (BRCA1/2 and 28 non-BRCA HRR genes, including ATM, BARD1, BRIP1, CHEK2, RAD51C, RAD51D, RAD54L, and FANC family genes). Patients were randomized 2:1 to receive oral rucaparib 600 mg twice daily or placebo. The randomization was stratified by HRR gene mutation status (BRCA, non-BRCA HRR, no mutation in BRCA or HRR gene), progression-free interval of the penultimate platinum-based regimen, and best response to most recent platinum regimen. The primary endpoint for ARIEL3 was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Exploratory analysis of confirmed response was conducted for the subgroup of patients with measurable disease at study entry. Results: Deleterious mutations in non-BRCA HRR genes were detected in ovarian carcinoma specimens from 7.6% (43/564) of randomized patients. In these patients, PFS was significantly longer with rucaparib than with placebo (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.50; P=0.0005), with a median PFS of 11.1 mo and 5.5 mo, respectively. This HR is similar to that found in women with carcinomas containing a BRCA1/2 mutation (0.23; 95% CI, 0.16-0.34). The most commonly found non-BRCA HRR gene mutations among the 28 patients in the rucaparib arm were RAD51C (n=6) and RAD51D (n=4) and among the 15 patients in the placebo arm were BRIP1 (n=5) and RAD51C (n=2). A diverse set of mutation types were detected, including frameshift insertions/deletions, homozygous deletions, and nonsense and splice site mutations. All 10 RAD51C/D mutations were homozygous within the carcinomas, indicating biallelic loss. Additionally, all RAD51C/D-mutant carcinomas exhibited high genomic loss of heterozygosity, which is a type of genomic scar characteristic of HRR deficiency. At the visit cutoff date (15 April 2017), only 2 of the 10 RAD51C/D cases in the rucaparib arm had disease progression; 7 had a PFS duration of at least 1 y (median PFS, 16.4 mo; range 5.4+ to 30.4+ mo). Three of the RAD51C/D cases were in the subgroup of patients who had measurable disease at baseline, and all achieved a confirmed response (1 complete response and 2 partial responses). In comparison, the 3 RAD51C/D cases in the placebo arm had a median PFS of 5.4 mo (range, 3.9 to 5.5 mo). Conclusions: Patients with recurrent platinum-sensitive HGOC harboring a deleterious mutation in non-BRCA HRR genes (including RAD51C/D) had significantly longer PFS with rucaparib maintenance treatment than with placebo. Citation Format: David M. O'Malley, Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Iain A. McNeish, Elizabeth M. Swisher, Clare L. Scott, Gottfried E. Konecny, Heidi Giordano, Terri Cameron, Lara Maloney, Sandra Goble, James Sun, Thomas C. Harding, Kevin K. Lin, Jonathan A. Ledermann. Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A12.

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9-16·2) versus 5·4 months (5·1-5·6; 0·32 [0·24-0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3-11·4) versus 5·4 months (5·3-5·5; 0·36 [0·30-0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Clovis Oncology.

PARP inhibitors for targeted treatment in ovarian cancer

Poly(ADP-ribose) polymerase (PARP) inhibitors emerged as the first targeted treatment for ovarian cancer, and are selectively active for women with mutations in BRCA1 and BRCA2 (mBRCA). On the basis of data showing activity (measured by the proportion of patients who achieved an objective response), 1 Kim G Ison G McKee AE et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015; 21: 4257-4261 Crossref PubMed Scopus (379) Google Scholar the PARP inhibitor olaparib received US Food and Drug Administration (FDA) approval in 2014 specifically for women with germline mBRCA-associated (gBRCA) recurrent ovarian cancer. 2 US Food and Drug AdministrationFDA approves Lynparza to treat advanced ovarian cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm Google Scholar However, subsequent findings from clinical trials of PARP inhibitors have suggested that the importance of mBRCA as a predictive biomarker has diminished. For instance, among women without a germline mBRCA, predictors of PARP activity include a somatic (tumour) mutation in BRCA (sBRCA) and evidence of homologous recombination deficiency. 3 Swisher EM Lin KK Oza AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017; 18: 75-87 Summary Full Text Full Text PDF PubMed Scopus (785) Google Scholar , 4 Mirza MR Monk BJ Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; 375: 2154-2164 Crossref PubMed Scopus (1490) Google Scholar Indeed, FDA approval of the PARP inhibitor rucaparib in 2016 broadened the eligibility for PARP inhibitor treatment beyond gBRCA and included patients with sBRCA-associated ovarian cancers. 5 US Food and Drug AdministrationFDA grants accelerated approval to new treatment for advanced ovarian cancer. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm533873.htmDate: Dec 19, 2016 Google Scholar Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trialAcross all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Full-Text PDF

BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1

BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1

Rucaparib in patients with relapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic BRCA mutations: Integrated summary of efficacy and safety from the phase II study ARIEL2

Rucaparib in patients with relapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic BRCA mutations: Integrated summary of efficacy and safety from the phase II study ARIEL2

Abstract AP28: BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma

Abstract Germline and somatic mutations in BRCA1 and BRCA2 (BRCA) confer PARP inhibitor sensitivity. Promoter hypermethylation is an alternate mechanism of gene down-regulation, and BRCA1 promoter methylation is relatively common in sporadic ovarian cancer. The clinical significance of BRCA1 methylation is less clear than for mutations, as the Cancer Genome Atlas (TCGA) and others have failed to show improved survival in ovarian carcinomas with BRCA1 methylation. No one has previously tested whether BRCA1 methylation confers in vivo sensitivity to PARP inhibitors in patients with ovarian cancer. ARIEL2 is a phase 2 study of the PARP inhibitor rucaparib in patients with recurrent platinum sensitive high-grade ovarian, peritoneal or fallopian tube carcinoma. At enrollment, ARIEL2 required pre-treatment tumor biopsies with the goal of developing tissue predictors of PARP inhibitor sensitivity other than BRCA mutations. The number of women with known germline mutations was capped at 15 patients in order to predominantly enroll BRCA wildtype cases. As presented at ASCO 2016, in cases with no BRCA mutations, a high fraction of genomic loss of heterozygosity (LOH) significantly predicted a better progression-free survival (the primary endpoint), longer duration of response, and a higher fraction of responders compared to cases with low LOH. We assessed BRCA1 and RAD51C promoter hypermethylation using methylation-sensitive polymerase chain reaction in paired archival and pre-treatment biopsies from patients on ARIEL2. Of 165 cases for which methylation analyses were completed, 21 (12.7%) were methylated at the BRCA1 promoter and four (2.4%) at the RAD51C promoter. Methylation of BRCA1 and RAD51C was mutually exclusive with mutation in BRCA or other homologous recombination genes. All four cases with RAD51C methylation and 15/19 (78.9%) with BRCA1 methylation were associated with high LOH. In 90 paired samples archival and pre-treatment tissues, RAD51C methylation was 100% concordant and BRCA1 methylation was highly concordant (p&amp;lt;0·001). For 13 cases with BRCA1 methylation in the archival specimen, 4 (30·8%) were unmethylated in the paired pretreatment tumor, but for 77 unmethylated archival specimens, gain of methylation in the pretreatment biopsy was observed just once. Confirmed RECIST responses were seen in 52.4% (11/21) BRCA1 methylated and 75.0% (3/4) RAD51C methylated cases. In conclusion, BRCA1 and RAD51C methylation in ovarian carcinomas correlates with a high response rate to PARP inhibitors. If methylation was to be used as a predictor of PARP inhibitor sensitivity, it would need to be assessed in a pre-treatment (not archival) specimen. The loss of BRCA1 methylation in recurrent ovarian carcinoma, which was common even in these platinum sensitive cases, could explain why BRCA1 methylation is associated with similar survival to methylated cases, despite initial improved therapeutic sensitivity. Citation Format: Elizabeth Swisher, Maria Harrell, Kevin K. Lin, Clare Scott, Sandra Goble, Amit Oza, Robert L. Coleman, Gottfried Konecny, Anna V. Tinker, David M. O'Malley, Rebecca Kristeleit, Ling Ma, James Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Mitch Rapon, Iain McNeish, Scott H. Kaufmann. BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP28.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.

Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive ovarian carcinoma cell lines.

Although epithelial ovarian cancers (EOCs) are initially treated with platinum-based chemotherapy, EOCs vary in platinum responsiveness. Cataloging antineoplastic agents according to their effectiveness against platinum-resistant and platinum-sensitive EOC cell lines is valuable for development of therapeutic strategies to avoid platinum inefficacy and to exploit platinum sensitivity. TOV-21G devoid of FANCF expression, OV-90 and SKOV-3 were employed as examples of platinum-sensitive, platinum-intermediate and platinum-resistant cell lines, respectively. Antineoplastic agents examined included mitomycin C, doxorubicin, etoposide, gemcitabine, chlorambucil, paclitaxel, triapine and X-rays. Their effectiveness against cell lines was analyzed by clonogenic assays. Cytotoxic profiles of mitomycin C and carboplatin were similar, with mitomycin C exhibiting greater potency and selectivity against TOV-21G than carboplatin. Cytotoxic profiles of doxorubicin, etoposide and X-rays overlapped with that of carboplatin, while OV-90 overexpressing Rad51 was more resistant to chlorambucil than SKOV-3. The efficacy of paclitaxel and triapine was independent of platinum sensitivity or resistance. Consistent with these cytotoxic profiles, cisplatin/mitomycin C, triapine, and paclitaxel differed in the capacity to induce phosphorylation of H2AX, and produced unique inhibitory patterns of DNA/RNA syntheses in HL-60 human leukemia cells. Paclitaxel and triapine in combination produced additive antitumor effects in M109 murine lung carcinoma. In conclusion, mitomycin C is potentially more effective against Fanconi anemia pathway-deficient EOCs than carboplatin. Doxorubicin and etoposide, because of their overlapping cytotoxic properties with carboplatin, are unlikely to be efficacious against platinum-refractory EOCs. Paclitaxel and triapine are effective regardless of platinum sensitivity status, and promising in combination for both platinum-sensitive and platinum-refractory EOCs.