February 2015, Vol 4, No 1
PARP Inhibitors in Gynecologic Cancer: More Questions Than Answers
PARP inhibitors are an area of intense interest in gynecologic cancers. At least 8 PARP inhibitors are currently in various stages of development, with olaparib and veliparib the most studied, but to date, there are no FDA approvals of these agents. Ongoing phase 1-3 trials should shed light on best use of these drugs.
Despite the enthusiasm for PARP inhibition in gynecologic cancers, more research is needed to understand the biological mechanisms of action, to identify which patients will be most responsive, to find the best way to administer these drugs, and to identify predictive and prognostic biomarkers, according to a presentation at the recent 2014 Chemotherapy Foundation Symposium.
â€śWe donâ€™t have the answers to these questions yet. PARP inhibitors are an important group of drugs in ovarian cancers, and we await the results from several studies. So far, finding the answers to these questions is a ping-pong game between basic science and clinical studies,â€ť said Tamar Safra, MD, head of the OncoGynecological Unit at Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv, Israel.
It is not clear which of the suggested mechanisms is most important. Suggested mechanisms include synthetic lethality, the nonhomologous end joining DNA repair pathway, PTEN-deficient cells, the presence of specific genes associated with ovarian cancer, and PARP1 trapping.
Studies suggest that the patients who benefit from PARP inhibitors are those with germline or somatic BRCA1/2 mutations and cancers that display other BRCA-like deficiencies.
â€śRegarding biomarkers, we are in a bad position [in ovarian cancer]. We know BRCA1/2 are markers, but we donâ€™t know whether any others can be used as selective or predictive biomarkers. We need further study,â€ť Safra said. â€śWe also need further study on mechanisms of resistance to PARP inhibitors, and once we identify those, we need to find ways to overcome resistance.â€ť
In studies of PARP inhibitors, significant responses are observed in BRCA germline mutation carriers, she continued. Accumulated information suggests a wider application of PARP in serous ovarian cancer. â€śWe await results of many studies of these agents,â€ť she said.
Fifteen percent to 18% of ovarian cancers are related to BRCA1/2 mutations, and 50% of serous ovarian cancers show disruption of homologous repair pathways. These groups of patients may have the best response to PARP inhibition, she said.
Safra reviewed some of the key studies to date. An early phase 2 study of olaparib versus pegylated doxorubicin in patients with BRCA mutations and recurrent ovarian cancer had disappointing results in progression-free survival (PFS) (J Clin Oncol. 2012;30:372-379).
â€śWe thought these drugs would change the life of BRCA carriers,â€ť she said. â€śAn important point here is that olaparib was more effective in BRCA carriers.â€ť
Olaparib as maintenance therapy in platinum-sensitive relapsed serous ovarian cancer (high-risk patients) reduced the risk of disease progression by 65% versus placebo but had no effect on overall survival (OS) (N Engl J Med. 2012;366:1382-1392).
In a subset of patients with BRCA mutations, olaparib maintenance therapy achieved an 82% reduction in risk of progression versus placebo, with a median PFS of 11 months versus 4 months, which was highly sigÂnificant (P?.00001). (J Clin Oncol. 2013;31[suppl]. Abstract 5505).
â€śMaintenance therapy with olaparib seems to be a good option in platinum-sensitive disease,â€ť she said.
Several studies have combined olaparib with chemotherapy. In a phase 2 study of platinum-sensitive serous ovarian cancer, olaparib maintenance therapy after pacÂlitaxel/carboplatin achieved a median PFS of 12.2 months versus 9.6 months with chemotherapy alone (J Clin Oncol. 2012;30[suppl]. Abstract 5001).
â€śIt is still an open question what would have happened if olaparib was given alone,â€ť Safra said.
Two ongoing studies are looking at biologics combined with PARP inhibitors. Interim results of a phase 2 study presented at ASCO 2014 showed improved PFS with olaparib plus cediranib (an antiangiogenic agent) versus olaparib alone: median PFS was 17.7 months with the combination versus 9 months with olaparib alone (P=.005). (J Clin Oncol. 2014;32[suppl]. Abstract LBA5500). BRCA mutation carriers had a small advantage, while noncarriers had a larger benefit in PFS. No OS advantage was observed for olaparib.
A second ongoing phase 1 study is exploring the combination of olaparib plus BKM120, a PI3K inhibitor, she said.
â€śThus far, PARP inhibitors have proven efficacy as maintenance therapy in BRCA mutation carriers and as treatment for active disease. We know there is single-agent activity with a good toxicity profile, and weâ€™ve seen the potential benefit of selected combination therapy with chemotherapy and with cediranib. We await the results of ongoing trials to tell us the best setting for these drugs, whether single or combination therapy is better, and whether PARP inhibitors can be used as prevention in BRCA carriers,â€ť Safra said.
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