Sequencing Treatment with a PARP Inhibitor and Chemotherapy
Name of the Trial
Olaparib in Combination with Carboplatin for Refractory or Recurrent Women’s Cancers (NCI-11-C-0022). See the protocol summary.
Dr. Elise Kohn and Dr. Jung-Min Lee (Associate Investigator), NCI Center for Cancer Research
Why This Trial Is Important
Cancer cells, like normal cells, have a number of mechanisms to repair damaged DNA, a process that is essential for continued cell growth and survival. One mechanism used by cells to repair damaged DNA is the activation of proteins called PARPs, which help repair single-strand breaks in the DNA double helix. Researchers have been interested in determining whether blocking this repair mechanism would hinder the ability of cancer cells to grow and divide. Therefore, they began to develop a group of drugs known as PARP inhibitors to target this repair mechanism.
A PARP inhibitor called olaparib (AZD2281) has already shown promising activity against breast and ovarian cancers in women with BRCA1 or BRCA2 gene mutations. The proteins produced by BRCA1 and BRCA2 are involved in a different DNA repair mechanism than that involving PARPs. It was thought, therefore, that treatment with a PARP inhibitor would further reduce the ability of cancer cells with BRCA gene mutations to repair damaged DNA and increase their rate of cell death, a concept known as synthetic lethality.
Because many chemotherapy drugs work by damaging DNA, another way to use PARP inhibitors would be to combine them with DNA-damaging drugs, such as carboplatin. Increasing the rate of DNA damage while inhibiting DNA repair should also reduce cancer cells’ ability to grow and divide, whether they have BRCA gene mutations or not. In preliminary research, combining carboplatin and the PARP inhibitor olaparib in breast and ovarian cancer patients with BRCA gene mutations was shown to be safe and have anticancer activity.
Since olaparib is expected to increase the effectiveness of chemotherapy, some researchers have suggested that the ideal sequence of administration would be to give olaparib first, followed by carboplatin. However, preclinical research conducted at NCI suggests that administering carboplatin before olaparib may actually result in more DNA damage and cell death.
In this new clinical trial, patients will be treated in 21-day cycles, with the first cycle being either intravenous carboplatin on day 1 followed by 7 days of oral olaparib or oral olaparib for 7 days followed by intravenous carboplatin on day 8. In the second cycle, the treatment assignments will be reversed. Subsequent cycles will begin with 7 days of oral olaparib with intravenous carboplatin administered on the first or second day. Carboplatin will be stopped after the eighth cycle and olaparib therapy will continue until disease progression or unacceptable toxicity occurs. Doctors will test blood samples for differences in drug pharmacokinetics and pharmacodynamics (effects of the drugs on the body) between the administration schedules and will monitor the patients for any differences in safety.
Patients eligible for the trial include women with gynecologic cancers (ovarian, fallopian tube, primary peritoneal, uterine, or cervical) that have not responded to or recurred after previous treatment, women with any type of breast cancer that is metastatic or unresectable and for which curative therapies do not exist, and men with BRCA-mutation-positive metastatic breast cancer.
“This trial is testing in patients the hypothesis generated by our preclinical work that administering carboplatin followed by olaparib will cause greater DNA damage than olaparib presensitization of carboplatin,” said Dr. Lee, whose work on this study is supported in part by a 2011 ASCO Jane C. Wright MD Young Investigator Award. “Currently, most studies of PARP inhibitors and chemotherapy give the PARP inhibitor first or at the same time, but there’s really no published data to support that.”