New York, NY—Poly (ADP-ribose) polymerase (PARP) inhibitors are an intense area of interest in gynecologic cancers. At least 8 PARP inhibitors are currently in various stages of development, with olaparib (Lynparza) and the investigational drug veliparib the most studied, but to date none has been approved by the FDA for gynecologic cancers.
Despite enthusiasm for PARP inhibition in gynecologic cancers, more research is needed to understand their mechanisms of action, to identify predictive and prognostic biomarkers, as well as the patients who will be most responsive to these agents, said Tamar Safra, MD, Head, Oncogynecological Unit, Tel Aviv Sourasky Medical Center, Sackler Medical School, Israel, at the 2014 Chemotherapy Foundation Symposium.
“We don’t have the answers to these questions yet. PARP inhibitors are an important group of drugs in ovarian cancers, and we await the results of several studies. So far, finding the answers to these questions is a ping pong game between basic science and clinical studies,” said Dr Safra.
It is not clear which of the suggested mechanisms associated with ovarian cancer and PARP 1 trapping is the most important. Studies suggest that the patients who benefit from PARP inhibitors are those with germline or somatic BRCA1 and BRCA2 mutations and cancers that display other BRCA-like deficiencies.
In ovarian cancer, “we are in a bad position. We know BRCA1 and BRCA2 are markers, but we don’t know whether any others can be used as selective or predictive biomarkers. We need further study,” Dr Safra said. “We also need further study on mechanisms of resistance to PARP inhibitors, and once we identify those, we need to find ways to overcome resistance.”
In studies of PARP inhibitors, significant responses are observed in BRCA germline mutation carriers, she continued. The accumulated information suggests a wider application of PARP in serous ovarian cancer. “We await the results of many studies of these agents,” Dr Safra said.
Overall, 15% to 18% of ovarian cancers are related to BRCA1 and BRCA2 mutations, and 50% of serous ovarian cancers show disruption of the homologous repair pathways. These groups of patients may have the best response to PARP inhibition, Dr Safra said.
She reviewed some of the key studies to date. An early phase 2 study of olaparib versus pegylated doxorubicin (Adriamycin) in patients with BRCA mutations and recurrent ovarian cancer had disappointing results in progression-free survival (PFS).1
“We thought these drugs would change the life of BRCA carriers,” Dr Safra said. “An important point here is that olaparib was more effective in BRCA carriers.”
Olaparib as maintenance therapy in platinum-sensitive relapsed serous ovarian cancer (ie, high-risk patients) reduced the risk for disease progression versus placebo by 65%, but had no effect on overall survival (OS).2 In a subset of patients with BRCA mutations, olaparib maintenance therapy achieved an 82% reduction in risk of progression versus placebo, a median PFS of 11 months versus 4 months, which was highly significant (P <.001).3
“Maintenance therapy with olaparib seems to be a good option in platinum-sensitive disease,” Dr Safra said.
Several studies have combined olaparib with chemotherapy. In a phase 2 study of platinum-sensitive serous ovarian cancer, olaparib maintenance therapy after paclitaxel/carboplatin achieved a median PFS of 12.2 months versus 9.6 months with chemotherapy alone.4
“It is still an open question what would have happened if olaparib was given alone,” Dr Safra said.
Two ongoing studies are looking at biologics combined with PARP inhibitors. Interim results of a phase 2 study by Liu and colleagues showed improved PFS with olaparib plus cediranib (an antiangiogenic agent) versus olaparib alone: the median PFS was 17.7 months with the combination versus 9 months with olaparib alone (P = .005).5 BRCA mutation carriers had a small advantage, whereas noncarriers had a larger benefit in PFS. No OS advantage was observed for olaparib.5
A second ongoing phase 1 clinical trial is exploring the combination of olaparib plus BKM 120, a PI3K inhibitor.
“Thus 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 we’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,” Dr Safra said.
- Kaye SB, et al. J Clin Oncol. 2012;30:372-379.
- Ledermann J, et al. N Engl J Med. 2012;366:1382-1392.
- Ledermann JA, et al. J Clin Oncol. 2013;31(15 suppl). Abstract 5505.
- Oza AM, et al. J Clin Oncol. 2012;30(15 suppl). Abstract 5001.
- Liu J, et al. J Clin Oncol. 2014;32(15 suppl). Abstract LBA5500.