A new oral tablet formulation of olaparib, a PARP inhibitor (poly (ADP-ribose) polymerase), is safe when combined with chemotherapy in advanced ovarian cancer patients previously treated with other agents. Those patients harboring a BRCA mutation in the phase 1b/II clinical trial may have a better response to olaparib compared to patients whose tumors do not have a BRCA mutation--although the patient sample size thus far is relatively small.
The results of the clinical trial (which has so far enrolled 14 patients), was presented at the Marsha Rivkin Center for Ovarian Cancer Research and the American Association for Cancer Research 10th Biennial Ovarian Cancer Research Symposium, held September 8-9, 2014, in Seattle.
The investigator-initiated academic study is among the first to test the new formulation of olaparib, which is being developed by UK-based AstraZeneca.
The overall response rate was 66% among 12 patients who had been previously treated with three to eight prior therapies for their advanced ovarian cancer. The complete response rate was 33% (4 patients). Two patients (16%) had stable disease and two (16%) had disease progression.
Three of the complete responders had tumors with a BRCA mutation, as did three of the four partial responders, and one patient with stable disease. One patient who progressed while on trial also had a BRCA mutation in her tumors.
The maximum tolerated dose in the phase 1b portion of the trial was found to be 150 mg twice daily. Patients received olaparib for three consecutive days, along with weekly metronomic AUC 2 intravenous carboplatin and 60 mg/m2 intravenous paclitaxel in each weekly cycle. Patients were treated for 3 weekly cycles followed by one off-therapy week. Olaparib tablets were started at 50 mg twice daily.
Patients were between 42 and 77 years of age (median age of 58), and had a median of four prior therapies. The patients have remained on study for a median of 9.3 cycles thus far.
Saul Rivkin, MD, founder and chairman of the Marsha Rivkin Center for Ovarian Cancer Research, and research scientist at the Swedish Cancer Institute (both in Seattle) and colleagues, are now enrolling 40 patients onto phase II of the clinical trial.
“The 150 mg tablet is about the size of an aspirin and is relatively easy for patients to take,” said Dr. Rivkin. In prior olaparib clinical trials, patients had to take five to six of the older capsule formulation of olaparib twice daily.
No grade 4 toxicities were documented on study. “There were no hospitalizations and no patients had to drop out of the study,” said Dr. Rivkin. The most common grade 3 toxicities included neutropenia, leukopenia, lymphopenia, and anemia. Patients had no evidence of gastrointestinal, renal, cardiac, hepatic, pulmonary, or dermatologic toxicities in those patients who had a toxicity of grade 3 or greater.
According to Rivkin, the patients whose tumors did not harbor a BRCA mutation may have responded because they have other mutations in genes that function in the double-stranded repair pathway. As a class, PARP inhibitors have been shown to be effective in treating BRCA-deficient breast and ovarian cancers. The PARP enzyme is necessary to repair single-strand DNA breaks. By inhibiting PARP, these single-stranded breaks can become even more deleterious double-stranded breaks that require homologous recombination to be repaired-repair that requires the BRCA proteins. By inhibiting the PARP enzyme in the presence of non-functioning BRCA proteins, cells acquire double-stranded breaks which are lethal to the cell. The addition of chemotherapy may further contribute to breaks in the DNA of these cells.
The newer olaparib tablet formulation is currently being tested in phase 3 clinical trials including for patients with BRCA-mutated, advanced ovarian cancer that have had a partial or complete response to platinum-based chemotherapy. Olaparib may also be indicated for patients with metastatic breast cancer patients who have germline BRCA1 or BRCA2 mutations.