Triple negative breast cancer and ovarian cancer featured strongly at this year's 35th European Society of Medical Oncology (ESMO) congress in Milan, with the emerging PARP inhibitor drug class taking centre stage. The role of anti-angiogenic therapy in the treatment of both indications was also an area of significant discussion.
Triple negative breast cancer and ovarian cancer featured strongly at this year's 35th European Society of Medical Oncology (ESMO) congress in Milan, with the emerging PARP inhibitor drug class taking centre stage. Undoubtedly, the most promising data (although not surprising based on releases of interim data) in breast or ovarian cancer presented were the final Phase II efficacy and safety data of Sanofi-Aventis PARP inhibitor iniparib, previously known as BSI-201, in triple negative metastatic breast cancer. In a Phase II study of 123 patients with triple negative metastatic breast cancer the addition of iniparib to carboplatin/gemcitabine improved overall survival by almost five months, from 7.7 months to 12.3 months. More than half of women (55.7%) treated with iniparib experienced clinical benefit (defined as complete or partial response or stable disease for at least 6 months) in comparison to just 33.9% of patients treated with chemotherapy alone. Importantly there was little or no increase in adverse events when iniparib was added to carboplatin/gemcitabine. If the eagerly awaited results of iniparib's Phase III study in combination with carboplatin/paclitaxel in triple negative metastatic breast cancer are true to form, iniparib is likely to become the first agent to gain specific regulatory approval for triple negative breast cancer and could be available to patients in the United States and Europe by the end of next year.
In contrast, the development of PARP inhibition as a therapeutic strategy in ovarian cancer appears to be somewhat behind the game, with plans of a Phase III study in either BRCA1/2 mutated or serous ovarian cancer yet to be announced. AstraZeneca's olaparib is currently the most advanced PARP inhibitor in development for ovarian cancer, with previously presented Phase II data demonstrating its activity as a monotherapy. At this years ESMO congress Phase II results were presented for olaparib (200mg and 400 mg) monotherapy versus pegylated liposomal doxorubicin in patients with platinum resistant/refractory BRCA1/2 mutated ovarian cancer. Although olaparib at a 400mg dose had a numerically higher confirmed response rate and a trend toward better survival, relative to pegylated liposomal doxorubicin (PLD, Doxil) the difference was not statistically significant. Despite these disappointing preliminary results, (in what should be noted was a very small number of patients) the rational behind PARP inhibition in serous ovarian cancer and in particular BRCA1/2 mutated ovarian cancer is intriguing. Consequently, identifying the optimal dosing and chemotherapy combination for olaparib and other PARP inhibitors in ovarian cancer continues to be a high priority among investigators.
In the light of the FDA and European Medicines Agency's decision to revisit bevacizumab's approval in first-line metastatic breast cancer, it's not surprising that anti-angiogenic therapy in breast cancer was an area of significant debate at this years ESMO meeting. Several discussions focused on the identification of biomarkers or imaging methods to predict which patients are most likely to respond to anti-angiogenic therapy. Despite significant effort however none of these methods appear to be close to prime time. In the absence of validated predictive biomarkers for bevacizumab investigators are hopeful that retrospective meta-analyses of bevacizumab's three Phase III studies in CaB (namely E2100, AVADO and RIBBON-1) may identify patient subgroups most likely to benefit for the agent in the hope that some form of approval will be maintained; the consensus being that bevacizumab still has a valuable role to play in the treatment of this disease. For example a meta-analysis presented at ESMO demonstrated that in patients previously treated with taxanes the addition of bevacizumab to taxane therapy in the first-line metastatic setting significantly improved overall survival from 21.3 months to 26.9 months. The investigators noted however that neither of the Phase III trials was powered for overall survival and therefore this subgroup analysis should be interpreted as such.
In ovarian cancer early results from the phase III ICON-7 study evaluating bevacizumab in combination with carboplatin/paclitaxel in patients with high-risk early (FIGO stage I-IIa) or advanced (stage IIb-IV) ovarian cancer were presented. The investigators reported that the addition of bevacizumab (7.5mg/kg) to chemotherapy followed by maintenance bevacizumab (for 12 additional cycles) or until progression resulted in an improvement in median progression free survival from 17.3 months to 19 months. Although a statistically significant (difference), the magnitude of PFS benefit reported in this study, at first glance, appears to be considerably lower then the benefit observed in the first phase III pivotal study (GOG0218) of bevacizumab in ovarian cancer, which was presented at ASCO earlier this year. This study demonstrated that the addition of bevacizumab to carboplatin/paclitaxel followed by maintenance bevacizumab improved PFS by 54% from 10.4 months to 14.1 months. However, a direct comparison of both studies is confounded by several factors; firstly GOG0218 included only patients with newly diagnosed stage III/IV CaO and GOG0218 evaluated a higher dose of Avastin (15mg/kg versus 7.5mg/kg) and a longer maximum bevacizumab treatment duration (22 cycles versus 18 cycles) than ICON-7. Although the data from ICON-7 are not yet mature this early analyses does suggests that the benefit of bevacizumab treatment weakens once treatment is discontinued and that the patients with higher grade large volume tumors are likely to derive more benefit from treatment. Although Phase III data to date of bevacizumab in ovarian cancer are promising, physicians eagerly await mature overall survival data. In addition they are hopeful that translational biomarker or imaging studies with will find a way to successfully identify biological subsets of patients most likely to respond to the agent.