Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR11/ICON-7.

With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.

AGO-OVAR 28/ENGOT-ov57. Niraparib alone versus niraparib in combination with bevacizumab in patients with carboplatin-taxane-based chemotherapy in advanced ovarian cancer: a multicenter randomized phase III trial.

BACKGROUND: Phase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian cancers; and, a significant benefit of the combination of olaparib and bevacizumab compared with bevacizumab monotherapy in HRD positive patients. However, it is unclear whether a PARP inhibitor monotherapy is sufficient, or if the addition of bevacizumab is needed. PRIMARY OBJECTIVES: This trial will investigate if the treatment strategy of carboplatin/paclitaxel/bevacizumab/niraparib is superior to the treatment of carboplatin/paclitaxel/niraparib in an all-comer population. STUDY HYPOTHESIS: Adding bevacizumab to chemotherapy followed by niraparib maintenance improves progression-free survival in patients with newly diagnosed advanced ovarian cancer. TRIAL DESIGN: AGO-OVAR 28/ENGOT-ov57 is an international, multicenter, randomized, prospective phase III trial within the the European Network for Gynecological Oncological Trial (ENGOT), led by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study group. All patients should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of the Study Run-In-Period. Prior to day 1 of cycle 2, patients with a valid central tumor BRCA (tBRCA) test result were randomized in a 1:1 ratio into either: Arm 1, to receive five additional cycles of carboplatin and paclitaxel q21d, followed by niraparib for up to 3 years; or Arm 2, to receive five additional cycles of carboplatin and paclitaxel plus bevacizumab q21d, followed by bevacizumab q21d (for up to 1 year), and niraparib for up to 3 years. MAJOR INCLUSION/EXCLUSION CRITERIA: The trial population is composed of adult patients with newly diagnosed, advanced high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also eligible for the trial. PRIMARY ENDPOINT: The primary endpoint is progression-free survival. SAMPLE SIZE: The study plans to recruit 970 patients (485 patients in each arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The Last-Patient-In is expected to be enrolled in September 2024, with presentation of the primary endpoint in 2028. TRIAL REGISTRATION: NCT05009082; EudraCT Number: 2021-001271-16.

Optimal Treatment Duration of Bevacizumab as Front-Line Therapy for Advanced Ovarian Cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized Phase III Trial.

PURPOSE: To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS: In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS: Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION: Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

Endometrial Cancer Lymphadenectomy Trial (ECLAT) (pelvic and para-aortic lymphadenectomy in patients with stage I or II endometrial cancer with high risk of recurrence; AGO-OP.6).

BACKGROUND: The impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side effects of this procedure, including lymphedema and lymph cysts, are evident. PRIMARY OBJECTIVE: Evaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence. STUDY HYPOTHESIS: Comprehensive pelvic and para-aortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65. TRIAL DESIGN: Open label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingo-oophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended. MAJOR INCLUSION CRITERIA: Patients with histologically confirmed endometrial cancer stages pT1b-pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible. EXCLUSION CRITERIA: Patients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease. PRIMARY ENDPOINT: Overall survival calculated from the date of randomization until death. SAMPLE SIZE: 640 patients will be enrolled in the study. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: At present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031. TRIAL REGISTRATION: NCT03438474.

LION-PAW (lymphadenectomy in ovarian neoplasm) sexual function assessment: a prospective sub-study of the LION trial.

BACKGROUND: There is limited information about the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer. OBJECTIVE: To evaluate the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer as a sub-protocol of the prospectively randomized LION trial. METHODS: The Sexual Activity Questionnaire was applied to assess sexual function according to its sub-scales activity, pleasure, and discomfort. The 'orgasm' sub-scale from the Female Sexual Function Index was also added. The questionnaire was administered in combination with the EORTC QLQ-C30 questionnaire at baseline prior surgery, after 6, 12, and 24 months. The primary endpoint was changes in sexual function. RESULTS: Overall, 495 patients received the questionnaires. 254 (51%) responded at baseline. Of these, 55 (22%) patients were sexually active, 182 (72%) were sexually inactive, and for 17 (7%) patients' data were not available. There was a total of 55/495 (11%) patients at 6 months, 139 (28%) patients at 12 months, and 81 (16%) patients at 24 months. Median age was 60.5 years (range 21.4-75.8). At baseline, sexually active responders were significantly younger (median age 51.5 years,) than sexually inactive responders (median age 61.8 years) and tended to have a better performance status. Discomfort evaluated as dryness of the vagina and pain during sexual intercourse was significantly worse at 12 months than at baseline (p<0.001); however, the surgical variable, lymphadenectomy, did not have any impact on this. The orgasm sub-scale showed diverging results with a deterioration from baseline to 12 months in the lymphadenectomy group compared with the no-lymphadenectomy group (p=0.02). CONCLUSION: The majority of patients were sexually inactive; however, in those who were sexually active, pain during intercourse was worse at 12 months. In addition, the orgasm sub-scale demonstrated worse results in patients who underwent complete lymphadenectomy. The study suggests that surgery in the retroperitoneal space may influence sexual function.

Prognostic role of thrombocytosis in recurrent ovarian cancer: a pooled analysis of the AGO Study Group.

PURPOSE: Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer. METHODS: In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅109/L. RESULTS: Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84-1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00-2.14, P = 0.047). CONCLUSIONS: The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.

Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

Phase II Study Evaluating PegLiposomal Doxorubicin and Carboplatin Combination Chemotherapy in Gynecologic Sarcomas and Mixed Epithelial-Mesenchymal Tumors A Phase II Protocol of the Arbeitsgemeinschaft Gynaekologische Onkologie Study Group (AGO-GYN 7).

BACKGROUND: Gynecologic sarcomas are rare diseases with still undefined optimal treatment. Platinum and anthracyclines were reported as active agents in gynecologic sarcoma and carcinosarcoma. So far, data regarding the combination of carboplatin and pegylated liposomal doxorubicin for this patient population are missing. METHODS: This prospective single-arm multicenter phase II trial evaluated the efficacy of carboplatin AUC 6 in combination with pegylated liposomal doxorubicin 40 mg/m q28 in 40 patients with newly diagnosed or recurrent gynecologic sarcoma or carcinosarcoma. RESULTS: Twenty patients with carcinosarcoma and 20 patients with leiomyosarcoma or endometrial stromal sarcoma were included. The percentage of patients with grade 3/4 neutropenia was 50%, but we did not observe any febrile neutropenia. The rates of grade 1 and 2 palmo-plantar erythema were moderate with 25% and 10%, respectively. Response rate was 33.3%. The 12-month progression-free and overall survival times were 32.5% and 77.0%, respectively. CONCLUSIONS: The combination of carboplatin and pegylated liposomal doxorubicin is feasible and has activity within the investigated study cohort.

Increased number of regulatory T cells (T-regs) in the peripheral blood of patients with Her-2/neu-positive early breast cancer.

BACKGROUND: Although progress has been made in establishing prognostic factors in breast cancer, there remains an urgent need for better prognostic and predictive scores for patients with early breast cancer. The important role of the immune system in controlling cancer progression is widely accepted. Regulatory T cells (T-regs) constitute a specialized T cell subset, which play an essential role in sustaining self-tolerance by negatively regulating immune responses. Increased frequencies of T-regs have been reported in the micromilieu of a variety of malignancies including breast cancer. However, little is known about the role of T-regs in the peripheral blood of cancer patients. METHODS: We analyzed T-reg numbers in the peripheral blood of 292 patients with newly diagnosed early breast cancer by flow cytometry (CD4(+)CD25(+)CD127(low) cells) prior to planned breast surgery. RESULTS: Absolute T-reg numbers/µl varied from 4 to 212/µl. No difference could be detected in T-reg numbers between nodal negative and nodal positive, well and poorly differentiated or small and locally advanced cancers. However, T-reg numbers of Her-2/neu-positive patients were higher than in samples from patients with hormone receptor positive, Her-2/neu-negative cancers. In contrast, numbers of T-regs were not increased in triple negative patients. In addition, T-reg numbers were higher in patients with invasive ductal carcinomas as compared to invasive lobular cancers. CONCLUSIONS: Increased numbers of circulating T-regs may contribute to the higher metastatic potential of Her-2/neu-positive cells. A potential role as a prognostic or predictive parameter is currently being analyzed in a larger cohort of patients with sufficient follow-up.

Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV.

OBJECTIVES: This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS). PATIENTS AND METHODS: We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy. RESULTS: 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)). CONCLUSION: The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.