Abstract
Only two new drugs have been licensed for the treatment of epithelial ovarian cancer in the last 5 years (bevacizumab and olaparib). These are also the only two molecularly targeted agents licensed in this disease. As we continue to move into the genomic era of cancer therapy, it is clear that optimal therapy is going to depend on molecular stratification and that the stratification itself is going to need to contend with tumor heterogeneity. In this article, we discuss molecular stratification and tumor heterogeneity in the context of high-grade serous ovarian cancer. The development of bevacizumab and olaparib has provided contrasting examples of stratification in molecularly targeted agents. Bevacizumab is licensed as an unselected agent, currently without molecular (or indeed histological) stratification. However, emerging data may be able to help us refine which patients may benefit the most from this agent (and which may not require it). Any such refinement can be expected to increase the median benefit in the selected population and reinforce the cost:benefit advantage. Conversely, olaparib is licensed as a highly selected agent, currently by genomic or somatic BRCA1/BRCA2 mutation in high-grade serous cancer. However, emerging data may be able to help us expand its role into tumors with other homologous recombination deficits (while also determining if all BRCA1/BRCA2 mutations respond equally). For both agents, however, cancers progress even on continuous therapy and targeting the resistant clones that have emerged from tumor heterogeneity will be key to extending benefit for these patients.
Highlights
Two new drugs have been licensed for the treatment of epithelial ovarian cancer in the last 5 years
As we continue to move into the genomic era of cancer therapy, it is clear that optimal therapy is going to depend on molecular stratification and that the stratification itself is going to need to contend with tumor heterogeneity
While adaptive epigenetic changes have been implicated in platinum resistance [40], a more striking mechanism of resistance may underlie some of the cross-resistance of platinum therapy and poly ADP ribose polymerase (PARP) inhibition that has lead to the focus on platinum sensitive disease in the clinic [28, 41]
Summary
Two new drugs have been licensed for the treatment of epithelial ovarian cancer in the last 5 years (bevacizumab and olaparib). Emerging data may be able to help us expand its role into tumors with other homologous recombination deficits (while determining if all BRCA1/BRCA2 mutations respond ) For both agents, cancers progress even on continuous therapy and targeting the resistant clones that have emerged from tumor heterogeneity will be key to extending benefit for these patients. In the phase 2 single agent studies [19, 20], bevacizumab had a roughly 20% objective response rate (ORR), a figure matched by the additional ORR benefit seen compared to chemotherapy alone in phase 2 and phase 3 combination studies, regardless of setting (Table 1) It is unclear why this clear ORR benefit has not translated into more impressive PFS or OS benefits in the phase 3 first line studies (PFS benefit 3.8m in GOG 218 and 2 months in ICON7, with updated analysis of the latter non-significant and no OS benefit in the ITT population). This was as a result of the subgroup analysis [21] of BRCA1/2 mutant cancers (germline or somatic), in the molecularly unselected
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