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Abstract

Epithelial ovarian cancer is the leading cause of death in the developed world for women with gynecologic carcinomas. Despite the effectiveness of platinum salts and taxanes as primary treatments, approximately 80% of women will recur and for them prognosis with available treatments is poor. Of the novel mechanisms under active investigation, there is ample evidence to indicate that angiogenesis is important to the development, progression and poor prognosis of ovarian cancer. Novel treatments are therefore required. A number of agents are undergoing evaluation, including vascular disrupting agents, angiogenesis inhibitors, tyrosine kinase inhibitors and agents targeting the folate receptor. At present, Phase III data are only available for the VEGF-targeted monoclonal antibody, bevacizumab, and that has demonstrated a progression-free survival benefit when used in combination with first-line paclitaxel/carboplatin and continued as maintenance therapy. The strategy of inhibiting angiogenesis in ovarian cancer remains promising. However, other agents in development may point to other important targets in ovarian cancer.

Keywords

bevacizumab poly(ADP-ribose) polymerase inhibitors tyrosine kinase inhibitor VEGF

Ovarian cancer is the second most common gynecologic malignancy, but is the leading cause of gynecologic cancer-related mortality, with over 22,000 new cases and 15,500 deaths annually in the USA alone [1]. With the rare exception of localized early-stage disease, systemic chemotherapy is recommended in an effort to reduce the risk of recurrence and mortality from ovarian cancer [101]. Following surgery, standard treatment consists of taxane/carboplatin chemotherapy, which can be delivered intravenously (iv.) or in combination with intraperitoneal treatment (iv./ip.) [101]. The first-line taxane/platinum combination will often prove successful in producing an objective response; however, durable remissions are rare with approximately 80% of women experiencing a relapse after treatment [2]. For women who relapse, the optimal treatment is not well defined, but platinum-based combinations are indicated in those who relapse after 6 months (i.e., platinum-sensitive recurrent ovarian cancer) [3]. For women who relapse, multiple options for cytotoxic treatment exist. However, responses are generally short and women ultimately die from chemorefractory disease. Thus, novel treatments are required for women with ovarian cancer.

Recently, the genomic characterization of serous ovarian cancers demonstrated four distinct subtypes: immunoreactive, differentiated, proliferative and mesenchymal [4]. The serous ovarian tumors were found to be unique in that numerous genes were duplicated or deleted rather than mutated, suggesting that all cancers do not arise from the same kind of genomic changes. A better understanding of the molecular characterization and DNA changes of ovarian cancers may help to better define novel therapeutic strategies that may lead to individualized treatment paradigms.

A number of agents are in Phase II or later clinical trials for ovarian cancer. In this review we will highlight several more promising agents.

Angiogenesis inhibitors

Angiogenesis promotes tumor growth and disease progression in the form of ascites and metastatic spread [5,6]. High levels of VEGF expression have been seen in malignant ascites and peritoneal carcinomatosis, with VEGF-induced vascular permeability implicated in the development of ascites [6]. In addition to VEGF and VEGF receptors (VEGFRs), ovarian cancers are associated with high levels of other neovascularization-related growth factors, including FGF and PDGF [1,5 –10,101]. Current Phase III trials involving antiangiogenic trials are described in Table 1.

Table 1.

Ongoing Phase III trials of investigational antiangiogenic therapy in ovarian cancer.

Agent	Setting (target accrual)	Randomization	Primary outcome(s)
Bevacizumab	First-line stage I–IIA (high risk) or IIB–IV EOC, PPC or FTC having undergone surgery in the prior 6 weeks (exception for stage IV if criteria were met; n = 1520)	Paclitaxel/carboplatin iv. Paclitaxel/carboplatin iv. plus bevacizumab → bevacizumab maintenance	PFS
	Newly diagnosed EOC, PPC or FTC (patients with recurrent disease are eligible if only treated with prior debulking surgery; n = 1000)	Paclitaxel iv./carboplatin iv. plus bevacizumab	Safety
	Newly diagnosed stage II/III/IV or recurrent stage I EOC or FTC (n = 332)	Carboplatin/paclitaxel with or without bevacizumab vs oxaliplatin/capecitabine with or without bevacizumab	OS
	Newly diagnosed stage III/IV EOC, PPC or FTC (n = 625)	Carboplatin/paclitaxel with or without bevacizumab	PFS
	Recurrent platinum-sensitive EOC, PPC or FTC with CR for ≥6 months with first-line chemotherapy (n = 660)	Taxane (paclitaxel or docetaxel)/carboplatin iv. Taxane/carboplatin iv. plus bevacizumab	OS
	Recurrent platinum-resistant EOC, PPC or FTC (n = 300)	Paclitaxel/topotecan/liposomal doxorubicin iv. Paclitaxel/topotecan/liposomal doxorubicin iv. plus bevacizumab	PFS
	Newly diagnosed stage IIB–IV EOC, FTC or PPC after primary debulking surgery	Carboplatin/paclitaxel/bevacizumab iv. → bevacizumab maintenance up to cycle 22 Carboplatin/paclitaxel/bevacizumab iv. → bevacizumab maintenance up to cycle 44	PFS
AMG 386	Recurrent partially platinum-sensitive/-resistant EOC, FTC or PPC (n = 900)	Paclitaxel iv. with/without AMG 386	PFS
	Recurrent partially platinum-sensitive/-resistant EOC, FTC or PPC (n = 380)	Pegylated liposomal doxorubicin with/without AMG 386	Efficacy
BIBF-1120	First-line stage IIB–IV EOC, PPC or FTC after prior debulking surgery (stage IV included even if not candidate for debulking; n = 1300)	Paclitaxel/carboplatin iv. plus BIBF-1120 Paclitaxel/carboplatin iv. plus placebo	PFS
Cediranib	Recurrent platinum-sensitive EOC, PPC or FTC with recurrence ≥6 months after first-line chemotherapy (n = 2000)	Paclitaxel/carboplatin iv. plus placebo → placebo maintenance	Safety
		Paclitaxel/carboplatin iv. plus cediranib → placebo maintenance	PFS
		Paclitaxel/carboplatin iv. plus cediranib → cediranib maintenance	OS
Pazopanib	Maintenance stage II–IV EOC, PPC or FTC treated with surgical debulking and at least five taxane/platinum cycles with CR, PR or SD(n = 900)	Pazopanib maintenance Placebo maintenance	PFS

→: Transition from the adjuvant treatment to the maintenance treatment; CR: Complete response; EOC: Epithelial ovarian cancer; FTC: Fallopian tube cancer; iv.: Intravenous; OS: Overall survival; PFS: Progression-free survival; PPC: Primary peritoneal cancer; PR: Partial response; SD: Stable disease. Data taken from [103].

Bevacizumab

Interest in bevacizumab was based on the Gynecologic Oncology Group (GOG) 170D, which enrolled 62 women with recurrent ovarian cancer (with up to two prior regimens) and treated them with bevacizumab (15 mg/kg every 3 weeks). This study was originally designed to explore bevacizumab as a cytostatic agent with the primary objective defined as a 6-month progression-free survival (PFS). However, unanticipated and encouraging responses also led to a formal evaluation of the response rate. In GOG 170D, the objective response rate (ORR) was 21% (including two complete responses [CRs]) and the PFS at 6 months was 40%. However, a subsequent Phase II trial in recurrent ovarian cancer that allowed up to three prior regimens was terminated owing to safety concerns [11]. In this study, the incidence of gastrointestinal perforation (GIP) was 11%. Still, a consistent ORR of 16% was reported and the median PFS and overall survival (OS) were 4.4 and 10.7 months, respectively.

Other trials have explored combined treatment of chemotherapy plus bevacizumab. Garcia et al. reported the results of a bevacizumab plus metronomic oral cyclophosphamide in a multi-institutional study involving 70 patients [12]. Similar to the results of GOG 170D, the ORR was 24% and the 6-month PFS was 56%, raising questions on the importance of combination treatment [12]. Three treatment-related deaths were reported and a total of four patients developed GIP.

There are limited data for combining bevacizumab with other biologics. Erlotinib was combined with bevacizumab in the recurrent setting without evidence of significant activity [13]. Sorafenib and bevacizumab were noted to have activity in a Phase I trial (43% achieving a partial response [PR]), however toxicity was significant [14].

These promising results in Phase II studies led to the Phase III evaluations of this agent as part of a first-line strategy. GOG 218 and the International Collaboration on Ovarian Neoplasms Trial 7 (ICON 7) have most recently shown a benefit with the use of bevacizumab in the maintenance setting as first-line therapy. In GOG 218, patients were randomly assigned treatment to one of three arms: paclitaxel/carboplatin (arm A) and bevacizumab/paclitaxel/carboplatin with (arm B) and without maintenance bevacizumab (arm C) [15,102]. Results showed that compared with arm A, a significant improvement in PFS was seen in arm C (hazard ratio [HR] for progression or death: 0.717; 95% CI: 0.625–0.824), but not in arm B (HR: 0.908; 95% CI: 0.795–1.040). As in the Garcia study, it has led to questions on the importance of combined chemotherapy with bevacizumab. Unfortunately, that specific regimen (chemotherapy followed by bevacizumab maintenance) was not an arm in the GOG 218 study. Toxicity consisted mainly of grade >2 hypertension (17% in arm B and 23% in arm C). There was no significant difference in the incidences of GIP, thrombosis, wound disruption, proteinuria or neutropenia between the arms.

In ICON 7, 1528 women were randomly assigned to paclitaxel/carboplatin alone or with bevacizumab (followed by maintenance bevacizumab in the paclitaxel/carboplatin plus bevacizumab arm) as first-line systemic therapy. However, as opposed to GOG 218, half the dose of bevacizumab was utilized (7.5 vs 15 mg/kg in GOG 218). As in GOG 218, PFS was improved in the bevacizumab arm compared with the chemotherapy-alone arm (HR: 0.81; 95% CI: 0.70–0.94) with similar toxicities reported. The PFS and OS benefits were higher in women at high risk of progression with an improvement in PFS of 5 months and OS of 7.8 months [16]. Interestingly, the high-risk population seen in a minority of subjects in ICON7 is comparable to the majority of the subjects in GOG 218 that were considered high risk for progression and did not show an improvement in OS with the addition of bevacizumab. We eagerly await the final OS data in both of these trials in the upcoming few years.

Finally, a recent Phase II trial examined the safety and feasibility of adding bevacizumab to a first-line ip. regimen. Intravenous paclitaxel and bevacizumab were given on day 1, ip. cisplatin on day 2, ip. paclitaxel on day 8 and bevacizumab consolidation for 17 weeks after the initial six cycles were complete. A total of 73% completed iv./ip. treatment; 27% of those who discontinued treatment did so secondary to bevacizumab toxicity. Three grade 3 bowel obstructions and one bowel perforation were noted. The estimated PFS was 28.6 months. While the addition of bevacizumab is noted to be feasible, it may increase the risk of bowel complications [17].

VEGF Trap

VEGF Trap differs from bevacizumab in its mechanism of action. While bevacizumab binds to VEGF to prevent interaction with the receptor, VEGF Trap acts as a decoy and binds circulating VEGF-A and -B to inhibit angiogenesis. In an international Phase II trial of VEGF Trap, 162 patients with platinum-resistant epithelial ovarian cancer (EOC) received single-agent treatment. The reported ORR was 11% with no complete responders reported [18]. Recently, the combination of aflibercept with docetaxel was also reported. In a Phase I/II trial in the recurrent setting, 46 evaluable patients in the Phase II setting were noted to have an ORR of 54% (11 CR, 14 PR). When stratified based on platinum sensitivity, a 77% response rate was noted for platinum-sensitive patients and a 45% response rate for the platinum-resistant population. The most common significant toxicities were fatigue, neutropenia, dyspnea and leukopenia. This promising combination of docetaxel and aflibercept was tolerated and showed significant activity [19]. Finally, recent Phase II data of aflibercept use in recurrent ovarian cancer patients with symptomatic ascites showed that mean time to paracentesis was increased by 32 days at the expense of more bowel perforations in the aflibercept group as compared with the control group (three vs one) [20].

Multitargeted tyrosine kinase inhibitors

Cediranib

Cediranib is a tyrosine kinase inhibitor (TKI) against VEGFR-1, −2 and −3 as well as the PDGF receptor (PDGFR) and c-kit. In one Phase II trial, 46 women received single-agent cediranib with a reported clinical benefit rate of 30% (responses plus stable disease) [21]. In a subsequent single-agent trial involving 60 women, the clinical benefit rate was 41% among platinum-sensitive and 30% among platinum-resistant patients [22]. The most common grade 3 or higher toxicities in both trials were hypertension and fatigue [21,22]. Based on these results, cediranib in combination with a carboplarin doublet has now completed enrollment in a Phase III trial in platinum-sensitive relapsed disease (ICON-6).

Sorafenib

Sorafenib shows activity as an anti-VEGFR, -PDGFR, c-kit, -FLT-3 and -RAF TKI. Sorafenib has been evaluated in three Phase II trials in the recurrent setting. A study investigating sorafenib with gemcitabine in 43 patients demonstrated two PRs, ten with stable disease over 6 months, a median time to progression of 5.4 months and an OS of 13 months [23]. GOG 170-F evaluated sorafenib use in 71 patients and demonstrated a PFS of at least 6 months with significant toxicities in the face of only a modest response (two PRs, 20 stable disease and 30 progressive disease). Gastrointestinal, metabolic, pulmonary, cardiac and hand–foot syndrome toxicities were reported [24]. Finally, sorafenib was evaluated in the neoadjuvant setting with carboplatin and paclitaxel. Owing to serious postoperative toxicity including cardiac and gastrointestinal events, this study was terminated prior to completion of enrollment [25].

Imatinib

Imatinib acts as a TKI targeting PDGFRs and c-kit. Unfortunately, single-agent use in the Phase II setting has not shown great activity [26 –28]. Similarly, combining imatinib with weekly docetaxel (ORR: 22%) did not demonstrate greater activity than single-agent cytotoxic therapy in a platinum-resistant cohort [29].

BIBF-1120

BIBF-1120 blocks VEGFR, PDGFR and the FGF receptor. Although limited data are available, results of maintenance BIBF-1120 suggests a potential role of this agent in ovarian cancer. Ledermann et al. reported that compared with placebo, as a maintenance treatment for women in a second or greater remission, BIBF-1120 improved PFS at 9 months (16.3 vs 5%, HR: 0.65; 95% CI: 0.42–1.02) [30]. More patients in the BIBF-1120 group experienced diarrhea, nausea or vomiting, as well as hepato-toxicity. As a result, a Phase III trial of standard chemotherapy (carboplatin and paclitaxel) plus concomitant and maintenance BIBF-1120 versus standard chemotherapy (carboplatin and paclitaxel) plus concomitant and maintenance placebo is in process.

Sunitinib

Sunitinib demonstrates anti-VEGFR, -PDGFR, c-kit, -FLT-3 and -RET activity. A National Cancer Institute Canada Clinical Trials Group two-stage Phase II trial of single-agent sunitinib on an intermittent schedule (second-stage continuous dosing) in recurrent EOC, primary peritoneal cancer or fallopian tube cancer showed modest activity in platinum-sensitive disease, but only at the 50 mg intermittent-dosing regimen [31]. Of 30 eligible patients, one PR and three cancer antigen 125 responses were noted. Sixteen patients had stable disease and the overall median PFS was 4.1 months. There were 21 serious adverse events reported in 14 patients; no bowel perforation was reported.

Angiopoietins

Angiopoietins represent a novel target of angiogenesis. Angiopoietins are protein growth factors that promote angiogenesis. Anti-angiopoietins block the interaction between angiopoietins and their Tie2 receptors by binding and sequestering Ang1 and Ang2. AMG 386 was evaluated in a three-arm, placebo-controlled, Phase II trial of two different doses of AMG 386 (plus weekly paclitaxel in 161 patients with recurrent advanced EOC, primary peritoneal cancer or fallopian tube cancer) [32]. Compared with weekly paclitaxel, AMG-386 (10 mg/kg) in combination with weekly paclitaxel showed a higher ORR (37 vs 27%) with improvement in median PFS (HR: 0.76; 95% CI: 0.57–1.02). Results of a Phase IB study demonstrated tolerability of AMG 386 used in combination with pegylated liposomal doxorubicin and topotecan in heavily pretreated patients [33].

Vascular disrupting agents

Vascular disrupting agents inhibit existing vasculature on tumors, as opposed to preventing the formation of new blood vessels, which is the mechanism of action of VEGFR inhibitors. Of the agents in development, data have been published using fosbretabulin. In a Phase II trial, the combination of paclitaxel/carboplatin plus fosbretabulin was evaluated in 44 patients with platinum-resistant ovarian cancer. It demonstrated an ORR of 29%. While hypertension was reported, it appeared earlier than would be expected with bevacizumab, though it was managed easily with calcium-channel blockers [34]. Currently, fosbretabulin plus bevacizumab is being compared with bevacizumab alone in a randomized Phase II trial of the GOG 186G.

EGF receptor inhibitors

Erlotinib is an anti-EGF receptor TKI that has been investigated in recurrent ovarian cancer in combination with carboplatin. A Phase II study found 14 PRs in 30 evaluable patients in the platinum-sensitive arm and one PR in 14 evaluable patients in the platinum-resistant arm [35]. Erlotinib has also been studied in frontline treatment for ovarian cancer. Blank et al. treated 56 patients with erlotinib in addition to paclitaxel and carboplatin [36]. Pathological CR was noted in eight out of 28 patients who had an optimal debulking and in three out of 23 patients with suboptimal debulking. Unfortunately, these results did not compare with historical responses with carboplatin and taxol alone [36].

Poly(ADP-ribose) polymerase inhibitors

Poly(ADP-ribose) polymerase (PARP) plays a vital role in the repair of ssDNA breaks via the base excision pathway, and PARP inhibitors are potentially new and important targets in ovarian cancer therapy. PARP inhibitors may be more effective in BRCA1/2 mutation carriers due to synthetic lethality. As ssDNA breaks accumulate, double-strand breaks occur and in BRCA1/2-mutated cells these double-strand breaks cannot be repaired, leading to cell death. Olaparib (AZD2281) is an oral PARP inhibitor that has shown activity in Phase I and II studies in BRCA1 or BRCA2 mutation carriers with objective responses of 33% [37,38]. Gelman et dl., in a Phase II study of olaparib in recurrent ovarian cancer, showed objective responses in 24% of non-BRCA mutation carriers and in 41% of BRCA mutation carriers [39]. Toxicity was tolerable with reports of fatigue, nausea and vomiting. Maintenance olaparib was studied in a Phase II trial in platinum-sensitive disease and results showed improved PFS in the maintenance group as compared with placebo [40].

Iniparib

Iniparib, an iv. PARP inhibitor, has been combined with gemcitabine and carboplatin in two nonrandomized Phase II trials. Overall response rates were 70.6 and 31.6% in platinum-sensitive and platinum-resistant cohorts, respectively [41,42]. The GOG is currently investigating PARP inhibition in conjunction with front-line therapy with platinum and taxanes and these results are eagerly awaited.

Agents targeting the folate receptor

The folate-binding receptor is a protein overexpressed in 72% of primary and 82% of recurrent ovarian cancer patients that can be used as a novel target for therapy [43]. MORAb-003 is a humanized monoclonal antibody for folate receptor-α. A Phase II study in recurrent platinum-sensitive ovarian cancer showed a promising increase in overall response rate when given with platinum and taxane as compared with historical control of platinum/taxane therapy alone [44]. Unfortunately, in the platinum-resistant population, MORAb-003 was not proven efficacious and the National Cancer Institute trial was closed early owing to futility at interim analysis.

Conclusion & future perspective

Numerous agents are in development for ovarian cancer that target molecular pathways. Bevacizumab was the first to show that this strategy is associated with efficacy, though with risks of toxicity not seen with conventional chemotherapy. Beyond bevacizumab, there are other agents that may potentially be of benefit in this disease. This presents questions of how best to incorporate these agents into clinical practice:

Is it best to utilize them as part of first-line treatment?

Should they be used in combination with chemotherapy?

How should these agents be sequenced?

Is there a role for combined biologic therapy?

We await results of ongoing studies to help delineate the role of bevacizumab and other agents in ovarian cancer.

Executive summary

Angiogenesis use in ovarian cancer

Angiogenesis plays an important role in ovarian cancer by promoting tumor progression.

Epithelial ovarian cancer overexpresses VEGF and its receptor.

Clinical trial results with antiangiogenic agents

Bevacizumab has shown promising activity in Phase II and III trials in both the primary and recurrent settings.

Imatinib, sorafenib, cediranib, BIBF-1120 and erlotinib have shown activity in Phase II studies.

Aflibercept, fosbretabulin and AMG 386 continue to be investigated.

Poly(ADP-ribose) polymerase inhibitors are an important new target in ovarian cancer therapy and are being investigated in primary and recurrent ovarian cancer.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Novel Antiangiogenic Therapies in Ovarian Cancer

Abstract

Keywords

Angiogenesis inhibitors

Bevacizumab

VEGF Trap

Multitargeted tyrosine kinase inhibitors

Cediranib

Sorafenib

Imatinib

BIBF-1120

Sunitinib

Angiopoietins

Vascular disrupting agents

EGF receptor inhibitors

Poly(ADP-ribose) polymerase inhibitors

Iniparib

Agents targeting the folate receptor

Conclusion & future perspective

Footnotes

References