Over the past year, data regarding 2 specific ovarian cancer management strategies have generated considerable interest within the clinical gynecologic cancer community among patients, clinicians, and re - searchers. One strategy involves the use of bevacizumab (Avastin), and the other approach centers on poly(ADPribose) polymerase (PARP) inhibitors.
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Preliminary results from 2 eagerly awaited phase 3 randomized studies examining a potential role for the antiangiogenic agent bevacizumab in the primary management of advanced ovarian cancer were presented at separate international cancer meetings (Table).1,2 The first study was presented at the 2010 annual meeting of the American Society of Clinical Oncology. Investigators with the Gynecologic Oncology Group (GOG) sought to assess the utility of this drug combined with standard cytotoxic agents as an initial therapeutic strategy or as part of an initial strategy and then continued as maintenance therapy. Patients were randomized to 1 of 3 arms: standard chemotherapy with carboplatin and paclitaxel (the control arm); initial therapy with bevacizumab, carboplatin, and paclitaxel but no maintenance therapy; and initial therapy with bevacizumab plus the same 2 chemotherapy agents followed by 16 cycles of bevacizumab alone as a maintenance strategy.1 The administration of bevacizumab with carboplatin/ paclitaxel followed by bevacizumab monotherapy for 12 months of maintenance therapy following chemotherapy discontinuation resulted in statistically significant improvement in progression-free survival (PFS) compared with chemotherapy alone.
Considering this provocative outcome, it was somewhat surprising to find that patients in this trial randomized to treatment with chemotherapy plus bevacizumab who discontinued the antiangiogenic drug after completing chemotherapy experienced no improvement in PFS compared with patients in the control arm. At the time these data were presented, final information on overall survival (OS) was not available, but preliminary analyses of the median OS and the 1-year OS rate suggested no differences among the 3 study arms.
Data from ICON 7, the second frontline bevacizumab ovarian cancer study, were reported by an international team of investigators from the European Organisation for Research and Treatment of Cancer (EORTC) at the 35th European Society of Medical Oncology Congress in 2010. Patients were randomized to a control arm of carboplatin plus paclitaxel or an investigational regimen of the 2 cytotoxic agents plus bevacizumab.2 In this study, bevacizumab was administered concurrently with chemotherapy and as a single- agent maintenance strategy following discontinuation of chemotherapy. Unlike the study discussed previously, ICON 7 did not include an arm of patients who received only the initial treatment regimen of bevacizumab, carboplatin, and paclitaxel, without any maintenance therapy.
Similar to the data reported from GOG, this study revealed a statistically significant improvement in PFS associated with adding bevacizumab to the cytotoxic regimen. At the time of this preliminary report, no statistically significant difference in OS was observed between the study arms.
It is important to note several major distinctions between the protocols for these 2 studies. The GOG trial was placebo-controlled, whereas the EORTC study made no attempt to conceal from participants or investigators which patients were receiving the antiangiogenic drug. It is reasonable to question, however, whether blinding in the GOG study was effective considering the frequency with which bevacizumab’s wellrecognized adverse effect of significant hypertension was observed.
The GOG trial used a 15-mg/kg dose of bevacizumab in the initial chemotherapy regimen and in the maintenance phase, whereas the EORTC trial used a 7.5-mg/kg dose of bevacizumab throughout the study. It remains to be determined whether this difference in drug dose, associated with differences in treatment cost, will affect the ultimate outcome of therapy.
On the question of OS, it is conceivable that the studies will ultimately reach different conclusions, potentially because of the general—but by no means universal—availability of bevacizumab in the United States as a single- agent treatment for platinum-resistant ovarian cancer. Third parties have provided financial coverage for bevacizumab use in this country based on data reported from several welldesigned and well-conducted phase 2 trials. These studies have demonstrated that the overall clinical activity of single- agent bevacizumab is comparable to the activity seen with a number of other drugs routinely employed as monotherapy in this difficult clinical setting (eg, pegylated liposomal doxorubicin, topotecan, and altretamine).3,4
As a result of far more restrictive payment policies in European countries, it is less likely that a patient from the control arm of the EORTC study, treated with a carboplatin/paclitaxel regimen, will have access to bevacizumab at the time of disease progression compared with a patient in the control arm of the GOG study. How this factor might influence the ability to assess the level of benefit in OS seen with bevacizumab in the 2 studies is not clear.
The second category of agents of particular interest in ovarian cancer is PARP inhibitors. Recently reported data reveal as many as one-third of ovarian cancer patients with either a BRCA1 or a BRCA2 mutation achieve an objective response when treated with a single agent from this novel class of drugs in the second-line setting.5,6 The hypothesis supporting this strategy is that women with BRCA abnormalities have an underlying defect in DNA repair, so using an inhibitor to interfere with PARP—a second relevant DNA repair mechanism—should seriously impair the survival of malignant cells.
As exciting as these data appear to be, germline BRCA mutations are only found in approximately 5% to 10% of all women with ovarian cancer, limiting the potential applicability of this novel approach. Recent data suggest, however, that up to an additional 10% to 20% of patients might possess somatic (nongermline) molecular abnormalities in their tumors that closely resemble the genetic defects observed in women with hereditary cancers.7 If appropriately designed and conducted clinical studies ultimately demonstrate that cancers with this so-called “BRCAness” profile are as sensitive to PARP inhibition as patients with germline mutations appear to be, it could substantially increase the proportion of women who stand to derive clinical benefit from this management strategy. The results of trials exploring the utility of this class of drugs in this specific patient population are keenly anticipated.
Preliminary data from single-arm or randomized phase 2 trials regarding the potential efficacy of quite a number of novel traditional cytotoxic agents and more targeted antineoplastic agents in ovarian cancer were reported at several international meetings during the past year. Additional follow-up data and publication of these results in the peerreviewed literature are needed before we can make a meaningful assessment of the possible role these strategies might play in the future management of ovarian cancer. It is not unreasonable to anticipate, however, that at least 1 of these approaches will someday find a place in the standard treatment of this hard-to-treat neoplasm.
- Burger RA, Brady MF, Bookman MA, et al. Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tumor cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2010;28(185): AbstractLBA1.
- Perren T, Swart AM, Pfisterer J, et al. ICON 7: a phase III Gynecologic Cancer Intergroup (GCIG) trial of adding bevacizumab to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer. Presentation at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy.
- Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JL. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:5165-5171.
- Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25:5180-5186.
- Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinumfree interval. J Clin Oncol. 2010;28:2512-2519.
- Audeh MW, Carmichael J, Person RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376:245-251.
- Hennessy BT, Timms KM, Carey MS, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly(ADP-ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol. 2010;28:3570-3576