Agustin A. Garcia, MD
Professor of Medicine and Section Chief
Louisiana State University
New Orleans, LA
The evaluation of noncytotoxic agents for the treatment of epithelial ovarian cancer has produced encouraging findings in recent months. This has led to the approval of new agents with novel mechanisms of action and continuing studies into many more potential therapies.
These are welcome developments for the treatment of patients with this malignancy. This includes approximately 22,000 women who are diagnosed annually with ovarian cancer in the United States alone.1
Although epithelial ovarian cancer is a highly chemoresponsive tumor initially, the development of resistance is a common event. In fact, the majority of women with stage III-IV ovarian cancer, the most common stage at presentation, will relapse and eventually succumb to their disease.
The Cytotoxic Therapy Landscape
This review will focus on recent clinically relevant findings of noncytotoxic agents for the treatment of ovarian cancer, including an expanded indication for bevacizumab (Avastin) and a new drug approval for olaparib (Lynparza).The initial management of ovarian cancer typically includes a staging and debulking surgical intervention and a platinum plus taxane—based chemotherapy regimen. At the completion of this therapy, most patients will have no evidence of disease. However, up to 75% of women with advanced disease will relapse at a median time of approximately 10 months.2
After recurrence, the duration of the platinum- free interval remains as the most important prognostic factor.3,4 Patients who relapse within 6 months of completing a platinum- based regimen are classified as platinum resistant, while those who relapse more than 6 months after treatment are classified as platinum sensitive.
Standard cytotoxic treatment for the latter group of patients includes a platinum-based regimen most frequently combined with paclitaxel,5 pegylated liposomal doxorubicin,6 or gemcitabine. 7 However, the duration of response to each subsequent platinum-based regimen tends to become progressively shorter and eventually patients become platinum resistant.
Many cytotoxic agents have been evaluated in phase II clinical trials in the platinum-resistant setting. Response rates are typically 20% or lower and durations of response are short. Docetaxel,8 weekly paclitaxel,9 pegylated liposomal doxorubicin,10 topotecan,11 gemcitabine,12 pemetrexed,13 and nab-paclitaxel14 are probably the most active and best-studied agents.
Only a few of these agents have been evaluated in phase III randomized trials.15-20 It can be concluded from these studies that topotecan, paclitaxel, weekly paclitaxel, pegylated liposomal doxorubicin, and gemcitabine have comparable activity.
Many other agents were studied before the use of modern chemotherapy regimens and, therefore, their true activity in today’s environment is unknown.21
Recently, etirinotecan pegol, an investigational topoisomerase I inhibitor, was reported to have encouraging activity in patients with heavily pretreated chemotherapy-resistant ovarian cancer.22 However, no further studies have been reported.
Several investigational cytotoxic agents were reported to have encouraging activity in phase II trials. However, phase III trials failed to demonstrate superiority over conventional agents.23-27 Indeed, no cytotoxic chemotherapy agent has been approved for the treatment of recurrent ovarian cancer since 2006.Nearly 20 years ago, it was reported that VEGF was overexpressed in human ovarian tumors and that it conferred a poor prognosis.28, 29 Similarly, it was observed that VEGF was directly associated with the development of ascites and carcinomatosis in animal models and that antibodies against VEGF inhibited tumor growth and ascites formation.30,31 These and other findings prompted researchers to evaluate the potential role of angiogenesis inhibitors in clinical trials in ovarian cancer.Bevacizumab is, by far, the most extensively studied agent in ovarian cancer. Single-arm phase II studies have demonstrated significant activity of bevacizumab as a single agent32,33 or in combination with low-dose metronomic chemotherapy.34
Despite the limitation of cross-comparison studies, the addition of low-dose oral cyclophosphamide appears to confer increased activity, as manifested by an impressive 6-month progression- free survival (PFS) with no significant increase in toxicity or cost. Several tyrosine kinase inhibitors have also been reported to have activity in recurrent ovarian cancer. However, they do not appear to have significant advantages over bevacizumab.35-39
Based on these results, several inhibitors of angiogenesis were evaluated in phase III randomized trials in combination with chemotherapy. Studies have been conducted in combination with chemotherapy in frontline therapy for the treatment of patients with platinum-sensitive and platinum-resistant disease, as well as in maintenance treatment.2,40-45
These studies have universally shown that the addition of bevacizumab to conventional chemotherapy improves response rate and PFS. However, improvements in overall survival have generally not been observed.
In November 2014, the FDA approved the use of bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
The approval was based on an international two-arm trial that compared bevacizumab plus chemotherapy of physician’s choice versus chemotherapy alone. The trial included 361 patients with platinum-resistant disease that had progressed less than 6 months after the most recent therapy. The participants had received ≤2 prior chemotherapy regimens.46
Overall, the bevacizumab-containing regimens registered an improvement in median PFS of 6.8 months compared with 3.4 months for chemotherapy alone (HR, 0.38; P <.0001).46 Patients who received bevacizumab plus paclitaxel demonstrated the largest improvement, with a median PFS of 9.6 months versus 3.9 months for chemotherapy alone (HR, 0.47).
Although there was no statistically significant improvement in overall survival for the bevacizumab- containing arms, the findings suggested that patients who have received paclitaxel in an earlier round of therapy may benefit from bevacizumab plus weekly paclitaxel.46The angiopoietin (Ang)—Tie axis is composed of two cytokines, Ang 1 and Ang 2, which regulate angiogenic pathways in late stages of neovascularization. These interact with the Tie2 receptor to mediate vascular remodeling. Ang 1 predominantly stabilizes endothelial junctions and increases pericyte coverage while Ang2 promotes endothelial sprouting and increases blood vessel density.47-49
Trebananib (AMG 386) is an investigational recombinant peptide-Fc fusion protein that binds and neutralizes Ang 1 and Ang 2.50 Responses were observed in patients with ovarian cancer in a phase I study.51 A dose-dependent prolongation in PFS was observed when combined with paclitaxel in a randomized phase II study.52
However, only modest activity was observed when trebananib was evaluated as a single agent.53 Overall, the agent is well tolerated, with fluid retention as its most common dose-limiting toxicity. These findings led to the development of randomized phase III trials for trebananib as frontline therapy and in the setting of platinumsensitive and -resistant disease.
Patients with recurrent ovarian cancer and a platinum-free interval of less than 12 months were enrolled in a phase III trial using the addition of trebananib to weekly paclitaxel. This treatment resulted in a significant improvement in response rate and PFS (primary endpoint). Although no differences were observed in overall survival, a subset analysis suggested a benefit in those patients with ascites present at baseline. 54,55 Results from additional phase III trials are expected.Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key mechanism in the repair of DNA single-strand breaks.56 BRCA-deficient cells appear to be particularly susceptible to the effects of these drugs.57Olaparib is the PARP inhibitor that has been Strategic Alliance Partnership Program studied most extensively.58 It inhibits several isoforms of PARP. Olaparib inhibits tumor growth of various cell lines and decreases tumor growth in xenograft models. Increased efficacy was documented in BRCA-deficient cell lines.
Several clinical trials of PARP inhibitors, predominantly evaluating patients with BRCA germline mutations, have been reported.59-63 Significant activity was reported in all of these studies, including early phase I trials.
In December 2014, the FDA approved olaparib for the treatment of recurrent ovarian cancer. This was approved for use in patients with a deleterious or suspected deleterious germline BRCA mutation who have been previously treated with three or more prior lines of therapy. This approval was based on an international, multicenter, single-arm trial that enrolled 298 patients with a deleterious or suspected deleterious BRCA mutation. This included 193 women with ovarian cancer, 137 of whom had measurable disease.62
Olaparib was administered at a dose of 400 mg orally until disease progression or toxicity. The median number of prior chemotherapy regimens was five. The overall response rate was 34%, with a median duration of response of 7.9 months and a median PFS of 7 months.
The most commonly observed adverse events were fatigue (66%), nausea (64%), vomiting (43%), diarrhea (31%), and anemia (34%). However, toxicities of grade 3-4 severity were uncommon and were observed for the most frequently observed adverse events in 8%, 3%, 4%, 1%, and 18% of patients, respectively.
The activity of olaparib according to platinum resistance has only been evaluated in one small study that enrolled 37 women. A response rate of 46% was observed among 13 women with platinum-sensitive disease while the response among 24 women with platinum-resistant ovarian cancer was 33%.
Another small study included women with and without a BRCA mutation. The response rates were 41% and 24%, respectively.The efficacy of veliparib was reported in a phase II trial of 50 women with a known BRCA germline mutation.64 Patients had received up to three prior chemotherapy regimens. Veliparib was administered orally at a dose of 400 mg twice a day. The overall response rate was 26%. The response among 20 patients with platinum-sensitive disease was 35%, while among 30 women with resistant disease, the response was 20%. Overall PFS was 8.1 months.Rucaparib was evaluated among 35 women with a germline BRCA mutation and platinum sensitive ovarian cancer.65 The number of prior chemotherapy regimens was two. Overall response rate was 66%.
As a group, these studies show that PARP inhibitors have significant activity in recurrent ovarian cancer. Activity is well documented in patients with a BRCA germline mutation, and early findings suggest that this activity persists in high-grade serous ovarian tumors. Preliminary studies suggest a role when used as maintenance therapy, and confirmatory studies are ongoing.66
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