e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com Anti-angiogenic therapy for ovarian cancer Yolanda Garcı́a Garcı́a*, Maria Marı́n Alcala  1, Clara Martı́nez Vila 2 Medical Oncology Department, Parc Taulı́ Hospital Universitari. Institut d’Investigacio i Innovacio Parc Taulı́, I3PT. Universitat Aut onoma de Barcelona, Parc Taulı́ 1, Sabadell, 08208, Barcelona, Spain article info abstract Article history: Angiogenesis is a known hallmark in cancer and plays a crucial role in ovarian cancer Received 12 June 2019 carcinogenesis and invasion. Anti- angiogenic agents are active in ovarian cancer treat- Received in revised form ment either as monotherapy or combined with chemotherapy, immunotherapy or poly 18 February 2020 ADP ribose polymerase (PARP) inhibitors. We review the mechanism of action, clinical Accepted 29 February 2020 activity and safety profile of the most important drugs either in the actual treatment or in current evaluation in the ovarian cancer treatment scenario (neoadjuvant, first line and Keywords: relapse). ovarian cancer © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC antiangiogenic therapy BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). bevacizumab aflibercept trebananib pazopanib nintedanib cediranib fibroblast growth factor (bFGF) and angiopoietin 1 and 2. These 1. Anti-angiogenic therapy for ovarian factors bind to different receptors, each one transmitting its cancer intracellular signals through a different set of tyrosine kinases [3] (see Tables 1 and 2). Angiogenesis plays a key role in ovarian cancer progression Several drugs have been developed to target all these sig- allowing tumour invasion and metastasis and is known to be nalling pathways involved in the angiogenesis process. These essential for tumour growth beyond 1e2 mm[1]. Vascular are known as anti-angiogenic (AAs) drugs, among them, we endothelial growth factor (VEGF) is the main factor of angio- include humanised anti-VEGF monoclonal antibodies, such as genesis in solid tumours, with its binding to VEFGR-1/2 re- bevacizumab, soluble VEGFR, such as aflibercept; peptide/ ceptors in target cells, that initiates a signalling cascade by antibody fusion proteins, such as trebananib, and small intracellular tyrosine kinases. It promotes the recruitment of molecule tyrosine kinase inhibitors (TKI), such as cediranib, endothelial cell progenitors of the bone marrow, their survival pazopanib, sunitinib and nintedanib [1]. We present a thor- and differentiation[2]. In addition, other growth factors are ough review of these drugs. involved, such as platelet-derived growth factor (PDGF), basic This paper is part of a supplement supported by Pharma Mar S.A. * Corresponding author:  ), cmvila89@gmail.com (C. Martı́nez E-mail addresses: ygarcia@tauli.cat (Y. Garcı́a Garcı́a), mariluchi82@hotmail.com (M. Marı́n Alcala Vila). 1 M. Marı́n Alcala (Marı́a Marı́n Alcala  ), Medical Oncology Department, Hospital Universitari de Vic, Vic, Barcelona, Spain. 2 C. Martı́nez Vila (Clara Martı́nez Vila), Medical Oncology Department, Hospital Clı́nic, Barcelona, Spain. https://doi.org/10.1016/j.ejcsup.2020.02.003 1359-6349/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 78 e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 analysis of mature OS data showed no difference between 2. Bevacizumab arms (HR 0.99; p ¼ 0.89; 58.6 versus 58.0 m)[7]. Interestingly, the beneficial effects of bevacizumab in the subset of patients Bevacizumab is a humanised monoclonal IgG antibody that at high risk for progression continued (HR ¼ 0.78, p ¼ 0.01; 30-2 targets vascular epithelial growth factor (VEGF A) and is the versus 39-7 m). A subset of patients who might not benefit most studied anti-angiogenic agent in ovarian cancer. It has from bevacizumab was also identified: women with early- proven its effectiveness as a single agent in platinum- stage and/or with optimally debulked (<1 cm) stage III. resistant ovarian cancer and in combination with chemo- These finding are relevant since, in practice, bevacizumab is therapy in the adjuvant setting and recurrent disease and has used based on the risk and disease burden. The adverse events recently been tested in the neoadjuvant setting. observed in this study were comparable to those seen in GOG- 0218 (toxicity table). 2.1. Front-line therapy A prospective, observational, phase IV study, OTILIA[8] completed recruitment in September 2019, and final results To date, two randomized double-blind phase III trials have are pending. The aim of this trial is to assess the safety and given the approval for bevacizumab in the adjuvant setting. effectiveness of front-line bevacizumab-containing therapy in In GOG-0218 [4], 1873 women with stage III (74%) and IV the real-world setting. Preliminary results suggest that the (26%) ovarian cancer (OC) were treated in a three-arm, pla- activity and tolerability observed in randomized trials appear cebo-controlled study. Forty per cent of the patients had to be reproducible in daily practice. The average time of bev- macroscopic residual disease. They were randomised to acizumab therapy was 14.0 m (95%CI 13-4-14-3 m). The rea- receive standard chemotherapy (CT) with 3-weekly sons for discontinuation were disease progression (31%), side- carboplatin-paclitaxel with either placebo or bevacizumab effects (15%) and patient’s request (8%). Median PFS was (15 mg/kg/3w) concurrently and also as maintenance treat- 21.7 m (95% CI 20.7e22 m). Elderly patients >70 years benefited ment for up to 16 doses in a three-arm trial with placebo as much as younger patients. In terms of safety, there was no during CT and in maintenance, CT with bevacizumab (15 mg/ difference between patients aged <70 versus 70 years kg/3w) and placebo maintenance (bevacizumab-initiation) regarding median PFS; 27% of patients presented grade 3 and CT þ bev and bev maintenance for up to 16 doses (bev- adverse events, and this led to bevacizumab discontinuation acizumab throughout), chemotherapy; 19% completed the in 5% of the sample. The incidence of all-grade hypertension, planned treatment. The primary end-point was progression- proteinuria and gastrointestinal perforation was 11%, 2% and free survival (PFS) that was longer in the bevacizumab initia- 0.8%, respectively, and there was similar tolerability in sub- tion arm (HR 0.908; p ¼ 0.16; median 11.2 versus 10.3 months) groups stratified by age. and significantly longer in the bevacizumab throughout arm Moving forward to important questions about bev- (HR 0.717; p < 0.001; median 14.1 versus 10.3 months). This acizumab use in daily practice, The MITO16/MANGO2b trial difference in terms of efficacy was consistent across all pa- assessed the treatment beyond progression issue. In this trial, tients subgroups stratified. No significant differences in 405 patients with recurrent ovarian cancer >6 months after overall survival (OS) among the three arms were identified. completion of first-line chemotherapy and in which bev- Hypertension grade2 was higher in the bevacizumab arm: acizumab was already used in first-line treatment, were 16.5% in bevacizumab initiation, 22.9% in bevacizumab included and randomized to platinum doublet chemotherapy throughout and 7-2% in the control arm. There was no dif- with or without bevacizumab. Sixty-four percent of the pa- ference between groups regarding proteinuria, neutropenia, tients had a >12-month recurrence and 72% completed the wound disruption or gastrointestinal perforation. A final OS full-length bevacizumab treatment in first line. The results analysis has been published. With a median follow up-of favoured the experimental arm in the primary objective, PFS, 102.9 months, the previous data reported showing no benefit with 11.1 versus 8.8 months (HR 0.51, 95%CI: 0.41e0.64, in PFS, DFS or OS was confirmed as was the benefit in OS in the p < 0.001) and no different safety profile was detected[9,10]. high-risk stage IV subgroup for the bevacizumab mainte- Another important question still unanswered is the nance, 42.8 versus 32.6 months for stage IV control (HR, 0.75; optimal duration of bevacizumab in front-line treatment. 95% CI, 0.59 to 0.95) [5]. Bevacizumab treatment with 15 versus 30 months length is ICON7[6] was the second phase III trial that evaluated this being explored n the BOOST trial (NCT01462890). aspect. It was a two-armed randomized phase III trial comparing CT (carboplatin þ paclitaxel) against CT and 2.2. Recurrent disease maintenance with bevacizumab (7.5 mg/kg/3w). A total of 1528 women with high-risk disease: stages I-IIa disease (grade Bevacizumab has also shown efficacy in the recurrent setting 3 or clear cell histology) (9%) or more advanced disease stages as monotherapy in the initial phase II trials and in platinum- IIb-IV (91%) after debulking surgery, were enrolled. There was sensitive and platinum-resistant disease. The OCEANS[11,12] significant improvement in PFS, which was the primary end- study is a blinded, placebo-controlled phase III trial, that point of the study, in the bevacizumab arm (HR 0.81; p ¼ 0,004; randomizes a total of 484 women with platinum-sensitive median 19 versus 17.3 months). In the subgroup of patients at recurrent ovarian cancer to receive CT high risk of recurrence (stage IV and stage III with residual (carboplatin þ gemcitabine) plus placebo or CT plus bev- disease >1 cm), the benefit of bevacizumab was more pro- acizumab (15 mg/kg) until progression. Patients were stratified nounced, with a 5.4 -month improvement in PFS, and it was in platinum-free interval (PFI) (6e12 versus >12 m) and cyto- similar to that found in the high-risk GOG218 group. The final reductive surgery for recurrent disease (yes versus no). Table 1 e Phase III studies with anti-angiogenic drugs in ovarian cancer. Study N Setting Eligibility Regimen Median PFS (months) OS (m) RR a GOG-0218 1873 Adjuvant OC, stages III-IV, macroscopic 6 cycles CP or CP þ bevacizumab 10.3 versus 11.2 36.3 versus 38.7 X residual disease after debulking 15 mg/kg with or without HR 0.908 HR 1.036 surgery maintenance with bevacizumab P ¼ 0.16Maintenance P ¼ 0.76Maintenance with bevacizumab with 10.3 versus 14.1 bevacizumab HR 0.717 39.3 versus 39.7 P < 0.001 HR0.915 P ¼ 0.45 a ICON 7 1528 Adjuvant OC, stages I-IIa with high risk 6 cycles CP or CP þþ bevacizumab 17.3 versus 19 58 versus 58.6 48% versus 67% disease and stages IIb-IV after 7.5 mg/kg and maintenance with HR 0.8 HR ¼ 0.99 p < 0.001 debulking surgery bevacizumab p ¼ 0.004 p ¼ 0.89 a OCEANS 484 Recurrent platinum Relapsed platinum-sensitive OC, CG þ placebo versus CG þþ 8.4 versus 12.4 32.9 versus 33.6 57.4% versus 78.5% sensitive up to platinum-based bevacizumab 15 mg/kg and HR ¼ 0.484 HR ¼ 0.95 p < 0.0001 chemotherapy maintenance with bevacizumab p < 0.0001 p ¼ 0.65 a GOG-0213 674 Recurrent platinum Relapsed platinum sensitive OC, up CP or CP þ bevacizumab 15 mg/kg 10.4 versus 13.8 37.3 versus 42.2 59% versus 32% e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 sensitive to platinum-based chemotherapy with maintenance with HR ¼ 0.628 HR ¼ 0.829 p < 0.0001 bevacizumab p < 0.0001 p ¼ 0.056 a AURELIA 361 Recurrent platinum Relapse platinum- resistant OC, up Standard chemotherapy (PDL, Top, 3.4 versus 6.7 13.3 versus 16.6 12.6 versus 30.9 resistant to platinum-based chemotherapy weekly P) þ or standard HR ¼ 0.4 HR ¼ 0.85 p ¼ 0.001 chemotherapy þ bevacizumab p < 0.001 p ¼ 0.174 15 mg/kg a AGO-OVAR-16 940 Maintenance OC, stages II-IV, with no pazopanib 800 mg daily or placebo, 17.9 versus 12.3 HR 0.77; X NR therapy progression after primary surgery 24 m p ¼ 0.0021 and at least 5 cycles of platinum- taxane a AGO-OVAR-12 1366 Adjuvant OC, stages IIB-IV, chemotherapy- 6 cycles of CP þþ 200 mg of 17.2 versus 16.6 HR 0.84; NR NR naive and upfront debulking nintedanib or placebo twice daily p ¼ 0.024 surgery up, days 2e21 of every 3-week cycle up to 120 weeks a ICON 6 456 Recurrent platinum Relapsed platinum-sensitive OC, Placebo þ CT and placebo 11.0 versus 8.7 HR 0.56 X NR sensitive and up to 6 cycles of platinum-based maintenance (arm A), cediranib p < 0.0001 (arm C versus A) maintenance chemotherapy then entered a 20 mg once-daily þ CT and placebo 9.9 (arm B) maintenance phase maintenance (arm B), or cediranib 20 mg once-daily þ CT then cediranib maintenance (arm C) a TRINOVA-1 919 Metastatic 3 regimens, and a platinum-free weekly intravenous paclitaxel (80 7,2 versus 5,4 HR 0.66, X 29.8% versus 38.4% interval of <12 m mg/m2) þ either weekly placebo or p < 0.0001 p ¼ 0.03 trebananib (15 mg/kg) TRINOVA-2 223 Recurrent Recurrent OC (platinum-free PLD 50 mg/m2 4 weeks þ weekly X X 46% versus. Platinum sensitive interval 12 m) intravenous trebananib 15 mg/kg 21%; p < 0.001 or placebo C ¼ carboplatin, P ¼ paclitaxel, G ¼ gemcitabine, PLD ¼ pegylated liposomal doxorubicin, Top ¼ topotecan. a Primary end-point. 79 80 Table 2 e angiogenic drugs adverse events among FIII studies. Drug HTA Thrombo- Intestinal Proteinu-ria Fatigue Neutropenia Anaemia Thrombocytopenia Diarrhoea Oedema Palmoplantar embolic Perforation erythrodysesthesia events A/V Bevacizu-mab4-13 Any grade: Any grade: 11% G3/4: 0e2.2% Any grade: 14% NR Any grade: 29% NR Any grade: 12% NR NR NR 26% G3/4: 0.7e6.7% G3/4: 0.7e9.7% G3/4: 17e63.3% G3-4: 3e12% e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 G3/4: 6e17.8% Pazopanib17,18 Any grade: NR NR Any grade: 8.4% Any grade Any grade: NR Any grade: 15.8% Any grade: NR Any grade:13.4% 5.77% G3/4:1.3% 41.5% 31.7% G3/4:2.5% 53% G3/4: 1.9% G3/4: G3/4:2.7% G3/4: G3/4: 8.2% 30.8% 9.9% Nintedanib14.15 Any grade Any grade: 8% Any grade 4% NR Any grade: Any grade: 33% Any grade: Any grade: 38% Any grade: NR NR 15% G3/4: 5% G3/4: 2% 59% G3/4: 20% 43% G3/4: 18% 77% G3/4: 5% G3/4: 7% G3/4: 13% G3/3: 22% Cediranib20,22 Any grade: 35 Any grade: 5% G3/4: <1% Any grade: 18% Any grade: Any grade: NR Any grade: Any grade: NR NR e45% G3/4: 3% G3/4: 1% 77e79% 29e69% 27e47% 86e92% G3/4: 5e12% G3/4: 6e16% G3/4: 6e26% G3/4: 2e8% G3/4 : 1e11% Trebananib16,19 Any grade: <2% <2% <2% Any grade: Any grade: 16% Any grade: NR Any grade: Any grade: Any grade: 11% 24e57% G3/4: 5% 9e10% 27% 61e71% 69% G3/4 1% G3/4: 3% G3/4: 1% G3/4: 2% G3/4: G3/4: 22% 19e21% NR ¼ not reported. e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 81 Interestingly, the addition of bevacizumab conferred a sig- total of 95 women were randomized (2:1) to receive chemo- nificant improvement in PFS (HR ¼ 0.48, p ¼ 0.001; 12.4 versus therapy for 4 cycles with or without bevacizumab (15 mg/kg) 8.4 months) and was also associated with a higher objective concomitantly for 3 cycles, and adjuvant treatment with response rate (ORR) (78.5% versus 57.4%; p < 0.001) and pro- chemotherapy plus bevacizumab for 4 cycles and mainte- longed the duration of response (HR ¼ 0.534, 10.4 versus nance with bevacizumab up to 26 cycles. The complete 7.4 m). The final analysis of mature OS data showed no dif- resection rate was higher R0 resection in the experimental ference between arms (HR 0.95; p ¼ 0.65; 33.6 versus 32.9 m). arm (58.6% versus 51.4%). Surprisingly, non-significant dif- Regarding toxicity, grade 3 or higher hypertension and pro- ferences were found in grade 3 adverse events between teinuria occurred more frequently in the bevacizumab arm. groups, with 62% of patients presenting AEs in the control No cases of gastrointestinal perforation occurred during the arm versus 63% in the bevacizumab arm. Furthermore, study or within the 30-day reporting period. The rates of postoperative complications (mainly wound, infectious and neutropenia and febrile neutropenia were similar in both gastrointestinal complications) occurred in 28% versus 36%, arms. respectively[16]. The GOG-0213 trial[13] is another recent phase III study The NOVA-GEICO 1205 trial was a phase II open-label study that was performed in recurrent platinum-sensitive disease. that evaluated NA bevacizumab in 68 patients in a 1:1 The primary objective of this study was twofold: bevacizumab randomization. No differences in complete macroscopic rate efficacy in the recurrent scenario and the role of secondary (primary objective) or PFS were found. Although surgical cytoreduction surgery before the initiation of chemotherapy feasibility was improved in the NA arm (67 versus 89%; (surgical objective is accruing). A total of 674 women were p ¼ 0.029), there were no differences in R0 resections. Safety randomized to standard chemotherapy or chemotherapy plus favoured the bevacizumab arm with less  grade 3 events, bevacizumab (15 mg/kg). It showed a non-statistically signif- during the whole treatment period (79 versus 54%, p ¼ 0.033) icant OS advantage of 42.3% versus 37.2% against bev- and in the NA period (61 versus 29%, p ¼ 0.008). These results acizumab (HR ¼ 0.829, p ¼ 0.056), but a post-hoc sensitivity suggest that bevacizumab may be safely added to a preoper- analysis adjusted HR ¼ 0.823, p ¼ 0.0447. Bevacizumab also ative programme in patients with initially unresectable dis- showed an improved in PFS of 13.8 versus 10.4 months (HR ease, without increasing the incidence of postoperative 0.628, p < 0.0001). OR was also higher in the bevacizumab arm, complications. However, the role of bevacizumab in this 78% and 59% (p < 0.0001), with higher CR including a greater setting must be further investigated[17]. number of patients who achieved a complete response: 32% versus 18%. The adverse events were consistent with the known safety profile of the agents under study. 3. Pazopanib The AURELIA trial[14,15] is the main study performed in the platinum-resistant setting. This is a randomized open- Pazopanib is an oral TKI which inhibits VEGFR, PDGFR and cKit label phase III clinical trial that evaluates the addition of signalling. Based on the promising results of a phase II study bevacizumab to standard chemotherapy (topotecan, PDL or [18], a double-blind, placebo-controlled, randomized, phase III weekly paclitaxel) in patients with disease progression <6 m study, AGO-OVAR16, evaluated the benefit of maintenance after completion of front-line platinum-based chemotherapy). treatment with pazopanib in patients with advanced OC Overall, 361 women were included, and crossover was treated with front-line chemotherapy after debulking surgery permitted. Median PFS was longer in the bevacizumab arm [19]. Patients with persistent bulky disease after surgery were (HR ¼ 0.48, p < 0.001, 16.6 versus 13.3 m) and was significantly excluded from this study. A total of 940 patients with histo- longer in patients who received paclitaxel þ bevacizumab logically confirmed OC, stages II-IV, with no evidence of pro- (HR ¼ 0.65, 22.4 versus 13.2 m). The study was not powered to gression after primary surgery and at least five cycles of detect statistically significant differences in OS. The authors platinum-taxane-based chemotherapy, were randomized 1:1 of the trial described higher rates of grade 3 hypertension to receive pazopanib 800 mg once per day or placebo for up to (7% versus 1%) and proteinuria (8.5% versus 0.9%) in the 24 months. Patients were stratified by first-line treatment experimental arm. It is worth mentioning that gastrointes- outcome and geographic region. Maintenance pazopanib tinal perforation occurred in 2.2% of bevacizumab-treated showed an increase in PFS compared with placebo, HR 0.77; patients. p ¼ 0.0021; median 17.9 versus 12.3 m, respectively, but the study was closed due to futility after a third interim analysis in 2.3. Neoadjuvant setting 86% of OS events with no significant differences. One impor- tant point to mention about this study is that more than half Finally, the neoadjuvant setting has been explored through of the patients included had no residual disease after surgery two phase II randomized trials: the ANTHALYA and the (58%) and most patients (88%) were free of disease at study NOVA-GEICO 1205 trials[16,17]. entry. Grade 3 or 4 adverse events of hypertension (30.8%), The primary objective of the ANTHALYA trial was to neutropenia (9.9%), liver-related toxicity (9.4%), diarrhoea assess whether adding bevacizumab to CT would improve (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar- the complete resection rate at interval debulking surgery. On plantar erythrodysesthesia (1.9%) were significantly higher the one hand, the ANTHALYA trial is an open-label, non- in the pazopanib arm. Finally, in Asian patients, the dose of comparative, phase II study, whose primary objective is to pazopanib was reduced from 800 mg to 600 mg daily due improve optimal debulking measured as resection rate. The to side-effects and a trend to better OS in placebo-treated study included 95 women in a 2:1 randomization and found a patients was noticed. 82 e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 effect did not seem to be affected by the number of previous 4. Nintedanib regimens or by PFI. Objective responses (ORs) were signifi- cantly more frequent with trebananib than with placebo, 30% Nintedanib is an oral triple inhibitor of VEGF receptor, PDGF versus 38%, respectively. The interim OS analysis did not receptor and basic fibroblast growth factor (bFGF). In a phase II show any significant difference between groups. study[20], nintedanib showed a PFS advantage of 16.3% versus This is the only randomized trial, together with AURELIA, 5% against placebo, when administered to patients with that showed a significant improvement in PFS in platinum- ovarian cancer as a maintenance treatment after their last resistant patients. chemotherapy. AGO-OVAR 12 [21,22], a double-blind, placebo- The double-blind, placebo-controlled, phase III study controlled, phase III study, evaluated the benefit of adding ENGOT-OV-6/TRINOVA-2 [24] evaluated whether trebananib nintedanib to standard front-line treatment, carboplatin and plus pegylated liposomal doxorubicin (PLD) improved pro- paclitaxel, after debulking surgery in patients with OC, gression-free survival (PFS) in patients with recurrent de Fe ration Internationale de Gyne cologie et d’Obste  trique epithelial ovarian cancer (EOC). Eligible patients had received (FIGO) stages IIBeIV. The primary end-point was PFS, which one prior platinum-based chemotherapeutic regimen with a was significantly longer in the nintedanib group than in the platinum-free interval (PFI) of 12 m and could have received 2 placebo group, 17.2 m versus 16.6 m, HR 0.84; p ¼ 0.024. additional cytotoxic regimens for recurrent/persistent dis- Although in a preplanned subgroup analysis, PFS was initially ease. Patients were randomized to intravenous PLD 50 mg/m2 reported to be improved in the nintedanib group compared once every 4 weeks plus weekly intravenous trebananib with the placebo group for patients with stages IIBeIII disease, 15 mg/kg or placebo. Median PFS was not significantly those differences were not confirmed in the final report, and improved, 7.6 m in the trebananib group and 7.2 m in the no significant differences were noted in subgroups according placebo group. Conversely, ORR was significantly higher in the to the presence of macroscopic residual tumour. trebananib group against placebo, 46% versus 21%. In a post-hoc analysis, the non-high-risk subgroup defined In both trials, trebananib was associated with an increased as the International Federation of Gynecology and Obstetrics rate of localised oedema in comparison with placebo, (FIGO) stage III and postoperative residual disease of 1 cm or including ascites and pleural effusions. Conversely, there was smaller, or FIGO stage II, showed a PFS advantage of 27.1 m in a non-significant difference in class-specific adverse events patients in the nintedanib group versus 20.8 m in those in the associated with anti-VEGF therapy. placebo group (HR 0.74). No significant differences in PFS were In favour of this study, we could argue that the use of non- observed between the nintedanib and placebo groups for platinum chemotherapy might be a valuable treatment option high-risk subgroup (HR 0.99). for patients with partially platinum-sensitive disease. These findings seem to differ from the outcome of trials Response to platinum-containing recurrence therapy varies with bevacizumab, which show an evidence of both PFS and among this patient subgroup. Additionally, some patients OS benefit, but only for patients with high-risk features or a might not be eligible to receive a platinum doublet as recur- high postsurgical tumour burden. Inclusion criteria were rence treatment for various reasons. similar between AGO-OVAR 12 and ICON7. In contrast, the Unfortunately, enrolment was temporarily halted for results of AGO-OVAR 12 are in line with the findings for 14 months in the TRINOVA-2 trial, due to pegylated liposomal pazopanib in the AGO-OVAR 16 phase 2 study. doxorubicin shortage in certain regions. This may have The most common adverse events described in this study affected the final results of the study, although another phase were gastrointestinal with 21% of patients in the nintedanib III study, TRINOVA-3 (NCT01493505), that evaluated the effi- group presenting diarrhoea grade 3 against 2% in the placebo cacy of combining trebananib with first-line carboplatin and group and 22% haematological; with 20% of patients pre- paclitaxel in patients with EOC, stages III-IV, was prematurely senting grade 4 neutropenia in the nintedanib group against terminated by decision of founder given the disappointing 16% in the placebo group. results of prior trials and toxicity profile. 5. Trebananib 6. Cediranib Trebananib, also called AMG 386, is a peptide-Fc fusion pro- Cediranib is a potent oral inhibitor of all 3 VEGFR tyrosine ki- tein that prevents the activation of the TIE2 receptor by nases (VEGFR1, 2, 3), with 800e5000 fold selectivity for the angiopoietin 1 and 2. Angiopoietin 1 is involved in the stabi- VEGFR2 and c-Kit inhibitor. A Phase II study evaluated cedir- lisation of endothelial junctions, while angiopoietin 2 pro- anib (30 mg daily) as a single agent for recurrent EOC, with 30% motes endothelial sprouting; these ligands increase blood of patients presenting clinical benefit, 17% partial responses vessel density. The double-blind, placebo-controlled, phase (PRs) and 13% stable disease (SD)[25]. On the basis of the phase III, TRINOVA-1 study[23], evaluated the addition of trebananib 2 activity in ovarian cancer, a phase III, three-arm, double- to single-agent weekly paclitaxel in patients with recurrent blind, ICON-6 study [26] assessed efficacy and safety of EOC. Patients were stratified by platinum-free interval (PFI) cediranib in combination with platinum-based chemotherapy (0 and 6 m versus >6 and  12 m), measurable disease, and and as a maintenance treatment in patients who had radio- region. Median PFS was significantly longer in the trebananib logical evidence of recurrence more than 6 months after group than in the placebo group: 7.2 m versus 5.4 m, respec- completion of first-line chemotherapy. This trial was prema- tively, HR 0.66, p < 0.0001). In subgroup analysis, treatment turely terminated due to a decision by AstraZeneca to e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 83 discontinue cediranib development in October 2011, after benefit of 85% with 16/25 PR and 16/35 SD for more than disappointing outcomes from pivotal trials in other tumour 4 months[30]. types. The primary end-point was subsequently changed to Aflibercept is a recombinant fusion protein consisting of PFS and the trial consequently was underpowered for OS. A vascular endothelial growth factor (VEGF)-binding portions total of 456 women were randomized 2:3:3, with five stratifi- from the extracellular domains of human VEGF receptors 1 cation factors and in alternating blocks, to receive placebo and 2, that are fused to the Fc portion of the human IgG1 alongside chemotherapy followed by placebo-only mainte- immunoglobulin. To date, its activity in ovarian cancer has nance (arm A; reference), cediranib 20 mg once daily alongside been evaluated in several phase II trials. One phase II study chemotherapy then placebo-only maintenance (arm B; con- combined aflibercept at 6 mg/kg with docetaxel 75mg/m2 current), or cediranib 20 mg once daily alongside chemo- every 3 weeks showed an RR of 54% with 11 CR and 14 PR[31]. therapy then cediranib 20 mg once daily maintenance (arm C; In another phase II trial, aflibercept was given at 4 mg/kg every maintenance). Median PFS was 11.0min arm C, and 8.7 m in 2 weeks to patients with recurrent epithelial ovarian cancer arm A (HR 0.56; p < 0.0001). Median PFS in arm B was 9.9 m. with symptomatic ascites that required 3 or more para- The preliminary OS results with 52% of the events at cut- centesis[32]. The primary objective was to double the time to off showed no statistically significant differences in median next paracentesis compared to the basal interval. A response OS between arm C and A (26.3 m versus 21 m (HR 0.77; was seen in 62.5% of patients with an average time to next p ¼ 0.11). Updated OS results were presented at the American paracentesis of 76 days compared to 16.8 days before starting Society of Clinical Oncology (ASCO) 2017, after a median aflibercept. follow-up of 25.6 m with 86% of the events at cut-off, the median OS was 19.9 m for patients in arm A and 27.3 m for those in arm C (HR 0.85; p ¼ 0.21) this translates into a median 8. angiogenic treatment in combination with difference of 7.4 m. PARP inhibitors Diarrhoea, neutropenia, hypertension and voice changes were significantly more common during chemotherapy with PARP inhibitors have gained recent approval in ovarian can- cediranib, and diarrhoea, hypothyroidism and voice changes cer. They have different mechanisms of action such as were more common during maintenance. Poor compliance blocking the functions of repair of PARP. It seems that hypoxia with cediranib was noted during maintenance treatment with enhances PARP inhibition and simultaneously PARP inhibition toxic effects being the most common cause for reduces the pathway of angiogenesis driven by VEGF and in- discontinuation. creases the phosphorylation of VEFGR2. This has increased the interest in combining AA treatment, especially VEFGR2 inhibitors such as cediranib and PARP inhibitors. The combi- 7. Other anti-angiogenic agents nation of different chemotherapy-free regimens was tested, and results freed. Cediranib and olaparib have already been The efficacy of other AA in OC has been also evaluated: tested in a phase II study in patients with high-grade plat- Sunitinib is a multi-targeted TKI, which was evaluated in a inum-sensitive recurrent serous ovarian cancer[33]. The pri- phase II study as monotherapy in patients with recurrent OC mary end-point was that PFS. 52% of patients were BRCA- treated with one or two previous lines[27]. A total of 73 pa- mutated and 20% had received three or more treatment tients were given sunitinib to 50 mg intermittently (4 weeks on lines. Median PFS with olaparib alone versus cediranib plus and 2 weeks rest) or 37.5 mg continuously. An RR of 5.4% was olaparib was 17.7 and 9 m, respectively (HR 0.42; p ¼ 0.005). observed with PFS of 2.9 and OS of 13.7 m. Moreover, another ORR of 47.8% for olaparib and 76.6% olaparib plus cediranib phase II study evaluating this setting was performed. Thirty- were documented. Furthermore, a post-hoc analysis showed five patients with recurrent OC were given sunitinib with that OR and PFS increased with the combination in BRCA wild- monotherapy in a daily dose of 37.5 mg in a 28-day-cycle. An type patients or in a population with unknown BReast CAncer RR of 8.3% was obtained, with PFS of 9.9 weeks. No OS analysis gene (BRCA) with an average PFS of 5.7 m. An update of the was reported. results was presented at ASCO 2017 and recently published. Sorafenib is also a small molecule TKI of several tyrosine An OS benefit in the BRCAwt subgroup, with 37.8 versus protein kinases, such as VEGFR, PDGFR. In a phase II study, it 23.7 months (HR: 0.44, 95%CI 0.19e1.01, p ¼ 0.047) favouring has been tested in the neoadjuvant setting in combination the combination armEAs were more frequent with the com- with carboplatin-paclitaxel in a daily dose of 400 mg, in pa- bination (70% versus olaparib 7%): fatigue (27 versus 7%), tients with advanced stages and large ascites volume[28]. diarrhoea (23 versus 0%), hypertension (39 versus 0%), Unfortunately, the study was closed after enrolling only 4 respectively[34]. ICON 9 is a placebo-controlled phase III study patients due to life-threatening toxicities. In another in which patients in remission to 4e6 cycles of platinum- placebo-controlled phase II study, its efficacy was evaluated based chemotherapy are being randomized to maintenance in monotherapy as a maintenance treatment after complete with cediranib plus olaparib versus maintenance with cedir- remission with first-line treatment[29]. No differences in PFS anib plus placebo NCT03278717). Primary end-points are PFS were found against placebo (12.7 versus 15.7 months). More and OS. Another phase III trial evaluating this strategy is the G3 toxicities were observed with sorafenib than with pla- NRG GY004 trial which has completed accrual but results are cebo. Finally, its combination with bevacizumab was evalu- pending (NCT02446600). ated in another phase II study, in patients who had not been The AVANOVA2 study, a phase II randomized trial in treated with the monoclonal antibody. It showed a clinical BReast CAncer gene platinum-sensitive relapsed ovarian 84 e j c s u p p l e m e n t s 1 5 ( 2 0 2 0 ) 7 7 e8 6 cancer patients, tested niraparib in combination with bev- followed by bevacizumab and either atezo or placebo main- acizumab versus niraparib monotherapy. In this study, the tenance. The recruitment is completed and results are ex- combination arm showed a benefit in PFS for the combi- pected in late 2020. nation in the intent-to-treat (ITT) population with 11.9 months (95% CI 8.5e16.7) in the niraparib plus bev- acizumab group versus 5.5 months (3.8e6.3) with niraparib, 10. Conclusions HR: 0.35 [95% CI 0.21e0.57], p < 0.0001). All HRD subgroups benefited and bevacizumab in previous lines was allowed Antiangiogenic treatment has demonstrated activity in and 21% in experimental and 27% control all the patients different settings of OC. To date, eight phase 3 randomized had received it previously[35]. This strategy is being eval- controlled trials incorporating AA therapy in the treatment of uated in two important phase III trials, the FIRST study newly diagnosed and recurrent ovarian carcinoma have met (NCT03602859), a phase III randomized trial in first line and their primary end-points, most of them in terms of PFS. Four the ANITA trial in platinum sensitive relapse of these trials included bevacizumab and the other four (NCT03602859). Both trials incorporate bevacizumab in studies were communicated, each studying one of the combination with chemotherapy and maintenance and following novel anti-angiogenetic agents: pazopanib, cedir- evaluate the association with niraparib and an immune anib, trebananib and nintedanib. Several other phase II trials checkpoint inhibitor, dostarlimab in the FIRST trial and have shown a certain activity of other AA drugs in terms of atezolizumab in the ANITA trial. median PFS and RR. PAOLA1 is a phase III trial that included 806 patients in Combinations with PARP inhibitors and immune- first line and allowed inclusion of newly diagnosed checkpoints due to synergic mechanism are presently being epithelial high-grade stage III-IV patients after surgery, explored and seem to also have a potential role in recurrent either primary or interval, and chemotherapy (plati- and first line OC. numetaxane) with bevacizumab. Patients were randomized Nonetheless, the patterns of efficacy may differ between to either olaparib or placebo. BRCA status was determined AA TKIs (nintedanib and pazopanib) and antibodies (bev- but all comers were included. Preliminary results reported acizumab) between high-risk and non-high-risk groups, given in ESMO 2019 showed benefit for olaparib treated patients the outcomes of some phase III studies. However, this aspect with 22.1 month in the olaparib arm versus 16.6 in the must be further evaluated. control arm, HR: 0.59 (0.49e0.72) p < 0.0001. As expected, the results were better in BRCA mutated and HRD positive patients for the olaparib arm. Interestingly, the proficient/ Conflict of interest statement not determined HRD group did not show any difference in terms of PFS in a post-hoc analysis. PFS2 and OS results are All the listed authors declare their conflict of interest: still immature[36].  , MD: none. Marı́a Marı́n Alcala Important ongoing phase III trials in first line setting such Clara Martı́nez Vila, MD: none. as DUO-O (NCT03737643) and ENGOT 43 (NCT03740165) eval- Yolanda Garcia Garcia, MD: uate different combinations with PARP inhibitors and immu- Travel expenses: Roche, Lilly, Boehringer, BMS. nocheckpoint inhibitors and bevacizumab is allowed as Advisory role: Roche, Tesaro, Clovis, BMS, Pharmamar, standard treatment and will add data about the benefit of Astra-Zeneca, Boehringer. combining different strategies. 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