A new combination of a poly ADP-ribose polymerase (PARP) inhibitor drug and conventional platinum-based chemotherapy may extend the lives of women with ovarian cancer, according to a new study.
The study, published in Clinical Cancer Research (2013; doi:10.1158/1078-0432.CCR-13-1262), showed that ovarian cancers with acquired resistance to olaparib, a PARP inhibitor drug, often remained sensitive to conventional chemotherapy. Earlier preclinical data had suggested that exposure to PARP inhibitors might reduce any benefit from subsequent platinum-based chemotherapy in women with BRCA mutations, possibly through the acquisition of secondary BRCA mutations.
PARP inhibitors such as olaparib cause fewer, less toxic side-effects than traditional chemotherapy. They are being investigated in clinical trials worldwide as a potential personalized treatment for women with BRCA gene mutations. Some PARP inhibitors have also shown benefit in women with non-BRCA tumors.
A total of 89 women with ovarian cancer and BRCA gene mutations received platinum-based chemotherapy after their tumors developed resistance to olaparib. Almost half (49%) of the women with olaparib-resistant tumors had a significant decrease in the tumor size after treatment with platinum-based chemotherapy. The results show that a significant proportion of women with ovarian cancer could live longer if they received both treatments.
The researchers also used new sequencing techniques to study the genetic mechanisms responsible for drug resistance in ovarian tumors. Previously, tumor resistance to both PARP inhibitors and platinum chemotherapy had been attributed to new, secondary mutations to BRCA genes that turned mutated, nonfunctioning proteins back into working proteins.
However, six women in the study had no sign of secondary BRCA mutations, suggesting that at least in these patients, the cancer developed resistance to PARP inhibitors and platinum-based chemotherapy through a different mechanism.
Study leader Professor Stan Kaye, MD, Cancer Research UK Professor of Medical Oncology at The Institute of Cancer Research in London, the United Kingdom, and Consultant at the Royal Marsden, said: “…for many women with ovarian cancer, it is not a case of either/or chemotherapy or PARP inhibitors—there is a good chance that they may respond to both. Although some scientists were concerned that using PARP inhibitors would prevent chemotherapy from being effective, we’ve resolved that concern by showing that both drug types can work in the same patients. Ovarian cancer is a difficult disease to treat and our research does underline the complexity of cancer, and the many different routes it can use to become resistant to treatment. But it also presents us with an opportunity; by showing us that two different types of drug treatment given in sequence could potentially extend lives.”