Search

Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.

ObjectiveChemotherapy for high-grade serous ovarian cancers in platinum-sensitive relapse includes carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin. According toin vitrodata,BRCAmutated patients are sensitive to replicative stress agents butBRCAstatus is not yet used for the choice of chemotherapy at relapse. Our aim was to assess these doublets according toBRCAstatus in first platinum-sensitive relapse.MethodsThe ESME ovarian cancer database comprises a multicenter retrospective cohort of patients with ovarian cancer treated in French cancer centers between January 2011 and December 2017. Patients with high-grade serous ovarian cancers at first platinum-sensitive relapse who received one of these doublets were included. The objective was to compare progression-free survival of each chemotherapy doublet according toBRCAstatus.ResultsAmong the 10 263 patients in the database, 1539 patients had a first platinum-sensitive relapse: 825BRCAwild type patients (53.6%) and 304BRCAmutated patients (19.8%) (7 patients had a homologous recombination mutation andBRCAstatus was unkown for 403 patients). Median progression-free survival was longer inBRCAmutated patients than inBRCAwild type patients when receiving carboplatin/pegylated liposomal doxorubicin without maintenance treatment (15.8 vs 11.8 months; pBRCAwild type patients without maintenance, better progression-free survival occurred with carboplatin/paclitaxel (median progression-free survival 14.3 months) than with carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin (9.8 and 11.8 months, respectively; p=0.017). InBRCAmutated patients without maintenance, there was no difference between the three doublets (median progression-free survival of 14.6, 12.0, and 15.8 months with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin, respectively; p=0.40).ConclusionWhile treatment with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin shows comparable efficacy inBRCAmutated patients, treatment with carboplatin/paclitaxel appears to be more effective than carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin inBRCAwild type patients with high-grade serous ovarian cancers at first platinum-sensitive relapse.

International audience; Objective > Despite an increasing number of therapeutic indications, there are no specific recommendations regarding the management of PARP inhibitors other than what is specified in the SmPC of each substance. A Delphi French consensus was conducted to establish practical guidelines to meet the needs identified by healthcare professionals and patients. Method > Following the Delphi method, statements to optimize PARP inhibitor management were drafted by a multidisciplinary Steering Committee made up of 17 experts. These statements were submitted to the independent and anonymous vote of clinicians involved in treating patients on PARP inhibitors. Results > This article presents 52 statements on the following topics: initiation and treatment; management of adverse events (hematological effects, gastrointestinal effects, renal effects, pulmonary effects, cutaneous effects, hypertension, insomnia, fatigue, dizziness); special popu-lations and situations; communication with the patient; adherence. Forty-nine statements obtained voter consensus after 3 voting rounds. A hematologist and a nephrologist supplemented this task by drafting an expert opinion on the risk of occurrence of secondary leukemia and nephrological toxicity. Conclusions > This paper is the first Delphi consensus on the practical management of PARP inhibitors. The pragmatic recommendations resulting from this paper should make it possible to manage the side effects of PARP inhibitors better and thus prevent early treatment discontinua-tion and improve patient adherence by preserving quality of life.

PURPOSE In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986 ), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting. METHODS This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up. RESULTS The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [ P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups. CONCLUSION Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

ObjectiveWe sought to evaluate the impact of chemotherapy response score according to the number of cycles of neoadjuvant chemotherapy, on disease-free survival and overall survival, in patients with advanced epithelial ovarian cancer ineligible for primary debulking surgery.MethodsThis multicenter retrospective study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent 3–4 or 6 cycles of a platinum and taxane-based neoadjuvant chemotherapy, followed by complete cytoreduction surgery (CC-0) or cytoreduction to minimal residual disease (CC-1), between January 2008 and December 2015, in four institutions. Disease-free survival and overall survival were assessed according to the histological response to chemotherapy defined by the validated chemotherapy response score.ResultsA total of 365 patients were included: 219 (60.0%) received 3–4 cycles of neoadjuvant chemotherapy, and 146 (40.0%) had 6 cycles of neoadjuvant chemotherapy before cytoreductive surgery. There were no significant differences in early relapses, disease-free survival, and overall survival according to the number of neoadjuvant chemotherapy cycles. However, regardless of the number cycles of neoadjuvant chemotherapy, persistent extensive histological disease (chemotherapy response score 1–2) was significantly associated with a higher peritoneal cancer index, minimal residual disease (CC-1), and early relapses. Median disease-free survival in patients with complete or near-complete response (score 3) was 28.3 months (95% CI 21.6 to 36.8), whereas it was 16.3 months in patients with chemotherapy response score 1–2 (95% CI 14.7 to 18.0, pConclusionIn our cohort, the number of neoadjuvant chemotherapy cycles was not associated with disease-free survival or overall survival. Chemotherapy response score 3 improved oncological outcome regardless of the number of neoadjuvant chemotherapy cycles.

Older patients with ovarian cancer represent a heterogeneous population. The French National Group of Investigators for the Study of Ovarian and Breast Cancer developed the geriatric vulnerability score (GVS) to identify geriatric parameters predictive of poor outcomes. A prospective validation of the GVS was needed.The EWOC-1 study (NCT02001272) was an international, open-label, phase 2, three-arm trial designed according to a two-step process. Patients aged 70 years or older with newly diagnosed stage III or IV ovarian cancer were identified and the GVS determined. Those with a GVS of 3 or greater were randomly assigned to the EWOC-1 trial, stratified by country and surgical outcome, to receive three different carboplatin with or without paclitaxel regimens; those not included in the EWOC-1 trial were followed up in the EWOC-1 registry. External validation of the GVS was a secondary endpoint of the trial. Three validation cohorts were identified: the total population (validation cohort 1 [V1], n=447), the registry-only population (validation cohort 2 [V2], n=327), and the carboplatin-paclitaxel-treated population (validation cohort 3 [V3], n=320).From Dec 11, 2013, to Nov 16, 2018, 447 patients were included in 48 academic centres in six countries; 120 in the EWOC-1 trial and 327 in the EWOC-1 registry. Median follow-up was 19·7 (95% CI 8·5-29·7) months for the total cohort; missing values were low (2%). According to the maximum likelihood analysis, the hazard ratio (HR) of death in V1 was 1·8 (95% CI 1·1-3·1, p=0·029) for those with a GVS of 1; 2·4 (1·4-4·0, p=0·0009) with a GVS of 2; 4·1 (2·5-7·0, p0·0001) for a GVS of 3; 5·5 (3·3-9·3, p0·0001) for a GVS of 4; and 9·1 (4·7-17·5, p0·0001) for a GVS of 5 compared with a score of 0. Whatever the validation cohort, GVS of 3 or more significantly segregated two groups with different overall survival: V1 (median 13·2 [95% CI: 10·8-18·7] vs 40·8 [32·0-45·6] months; HR 2·8 [95% CI 2·2-3·7]; p0·0001); V2 (11·9 [95% CI 8·8-18·1] vs 40·8 [32·0-45·6] months, HR 3·5 [2·5-4·9]; p0·0001); and V3 (18·1 [95% CI 15·8-31·8] vs 43·0 [40·6-49·7] months, HR 2·6 [1·9 to 3·7]; p0·0001).The GVS has high prognostic performance for overall survival in patients with advanced ovarian cancer, independently of geographic and historic effect (V1), as well as treatment patterns (V3), validated in an international population. Even though the GVS is time consuming it will allow the stratification of populations for clinical research and might permit the orientation of the geriatric intervention to specific domains.French National Cancer Institute.For the French translation of the abstract see Supplementary Materials section.

Key gene alterations in uterine and ovarian CS. Oncoprint of alterations identified in the 50 most altered genes from TCGA cancer pathways and custom lists of CRG. The type of genomic alteration (deletion, amplification, fusion, broken by SV, missense, truncated) is described in the legend. Number and proportions of alteration types are summarized by gene (horizontal bars on right) and by sample (vertical bars on top). The samples are classified into MSI and CN-high according to TCGA endometrial carcinoma classification.

Complete clonal evolution of P12 tumor.

Evolutionary histories of CS. Clonal lineage histories of P02 MSI phenotype tumor (A), P12 BRCAness-phenotype tumor (B), and P15 ovarian bilateral tumor (C). Left, Clonal lineage inference for the whole tumor: subclonal populations (Ci), main cancer gene alterations, genome doubling events, and representative mutational signature proportions are represented. Right, Subclonal population frequencies projection in each tumor sample. Clones colored in gray are found in both derived samples, pink (or green) clones are specific to sarcoma- (or carcinoma-) derived samples, respectively.

Differential expression and methylation analysis (C vs. S). A, Heatmap and pathway overrepresentation analysis of differentially expressed genes between C and S (or undifferentiated) components of the 10 samples derived from the five selected CS tumors. Gene clustering method: Ward's; distance: Spearman. FDR: false discovery rate. B, Heatmaps of EMT and stemness pathways scores (left) and methylation level of EMT-related miRNAs (right). mRNA level: scaled TPM. Pathway scores: scaled ssGSEA scores. Methylation level: scaled beta-values.

Curated list of chromatin remodeling genes.

Genomic landscape of CS. A, Tissue origin and histological subtypes for each tumor (from P01 to P15). B, Main component and detailed percentage content for both samples (a and b) derived from the same tumor. C, CNA analysis: tumor purity (%), ploidy, FGA, and CNA breakpoints number. D, SV number, classified as deletion, duplication, inversion, and interchromosomal translocation. E, SNV and small indel number. F, Proportion of each of four mutational signatures deciphered in the whole cohort. G, MSI phenotype: MSI score (representing the percentage of unstable microsatellite loci), MLH1 promoter methylation (beta-value), and mRNA expression level (TPM – transcripts per million). H, Kataegis number illustrating APOBEC error-prone DNA repair process. I, BRCAness phenotype: number of LST, (white stars highlight samples with LST number ≥20), BRCA1 promoter methylation level (beta-value), BRCA1/2 genes alterations and TDP score, collectively summarized by the HRD status track.

List of differentially methylated gene promoters (paired analysis of 5 selected tumors).

List of differentially expressed genes (paired analysis of 5 selected tumors).

A list of copy number alterations, rearrangements and short variants detected by Foundation Medicine NGS

Supplementary Tables, Figures and Video legends, Tables 2,3,5 and all Supplementary Figures. Supplementary Table 2. Confirmation of cis configuration of BRCA1 primary and secondary mutations in case 4 by colony PCR. Supplementary Table 3. IC50 (mircoM) values of the PARPi and platinum drugs in parental OVCAR8 cell line and OVCAR8 RAD51C KO clone, and the fold change in IC50 values. Supplementary Table 5. Sequences of primers used for site-directed mutagenesis. Supplementary Figure 1. Foundation Medicine NGS analysis of the 12 cases with archival tissue and/or pre-treatment and post-progression biopsies. Supplementary Figure 2. Sanger sequencing trace of the primary and secondary BRCA1 mutations in cis configuration in case 4 post-progression biopsy sample. Supplementary Figure 3. In vitro response to PARP inhibitor therapy and platinum agents in RAD51C deficient cell lines, with primary or secondary mutations in RAD51C. Supplementary Figure 4. RAD51 foci formation in geminin positive cells deficient for RAD51C, complemented with primary or secondary mutations in RAD51C. Supplementary Figure 5. Diagram of HR reporter assay. Supplementary Figure 6. RAD51C expression in MCF10A cells and in yeast. Supplementary Figure 7. Analysis of serial sections by direct PCR sequencing approach of a post-progression biopsy containing multiple secondary mutations in RAD51C. Supplementary Figure 8. Molecular Dynamics Modeling of WT RAD51D protein and RAD51D protein with secondary mutation c.770_776delinsA, p.S257_R259delinsK. Supplementary Figure 9. In vitro response to PARP inhibitor therapy and cisplatin in RAD51D deficient CHO cell line, with primary or secondary mutation in RAD51D. Supplementary Figure 10. Examination of the parental PEO4 cell line, PEO4 cells with the homozygous frameshift RAD51D mutation (c.762_763del, D254E*fs72) in the same exon as the primary mutation and PEO4 cells with the homozygous secondary RAD51D mutation (c.770_776delinsA, S257_R259delinsK). Supplementary Figure 11. Modeling of tumor clonal fractions in the post-progression biopsy sample with germline RAD51C mutation and multiple secondary mutations.

Molecular Dynamics Modeling of WT RAD51D monofilament interaction with dsDNA.

Copy number estimation by SNP array in the archival tumor tissue of the patient identified to have a germline RAD51C mutation (c.577C

Supplementary Data from Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study

Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2–IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups. Clin Cancer Res; 21(11); 2530–7. ©2015 AACR.

supplementary table 4. Multivariate analysis for Complete Clinical Response and Figo stage

Supplementary Figure from Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study

Supplementary Table from Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study

supplementary table 2. Protocol�defined treatment�related Adverse Events

Table. Clinico-morphologic and genomic data.

supplementary table 3. Response evaluation at 2 time points

Purpose:Uterine leiomyosarcoma, which accounts for 7% of all soft-tissue sarcomas and 1%–3% of all uterine malignancies, is an aggressive tumor responsible for a significant proportion of uterine cancer–related deaths. While Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage is the most important prognostic factor, metastatic and relapse rates at stage I exceed 50% so it is currently impossible to predict the clinical outcome of stage I leiomyosarcomas. In 2010, our team published a transcriptomic signature composed of 67 genes related to chromosome biogenesis, mitosis control, and chromosome segregation. It has demonstrated its prognostic value in many cancer types and was recently successfully applied to formalin-fixed, paraffin-embedded sarcomas by NanoCind on NanoString technology, making another step forward toward its use in routine practice.Experimental Design:Sixty uterine leiomyosarcomas at any stage, including 40 localized in the uterus (stage I), were analyzed with the NanoCind (CINSARC with NanoString) signature. Its prognostic value was evaluated for overall survival and relapse-free survival and compared in multivariate analysis with other prognostic markers like FIGO staging and genomic index.Results:The NanoCind signature was able to split the heterogeneous group of uterine leiomyosarcomas of any stage including stage I into two distinct groups with different relapse-free survival and overall survival. These results were validated on an independent cohort of uterine leiomyosarcomas in The Cancer Genome Atlas consortium.Conclusions:The NanoCind signature is a powerful prognosticator that outperforms FIGO staging and the genomic index. The CINSARC signature is platform independent and “ready to use” and should now be used for randomization in future therapeutic trials.

supplementary table 1. Radiotherapy and Chemotherapy Treatment dose and Surgery

Purpose:Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models.Patients and Methods:TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses.Results:A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1–2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2–33.9], and the 6-month PFR was 28.6% (95% CI, 8.4–58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7–50.8), and the 6-month PFR was 42.9% (95% CI, 17.7–71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma.Conclusions:Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma.See related commentary by Digklia et al., p. 1745

OBJECTIVES: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status. METHODS: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status. RESULTS: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates). CONCLUSIONS: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone. ispartof: GYNECOLOGIC ONCOLOGY vol:164 issue:2 pages:254-264 ispartof: location:United States status: published

Olaparib; Ovarian cancer; Tolerability Olaparib; Cáncer de ovarios; Tolerabilidad Olaparib; Càncer d'ovaris; Tolerabilitat Objectives In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. Methods Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). Results Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was

Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.