Ovarian Cancer

Rucaparib in BRCA 1–2 Mutated Advanced Ovarian Cancer with Platinum Chemotherapy Exposure

Rucaparib in BRCA 1–2 Mutated Advanced Ovarian Cancer with Platinum Chemotherapy Exposure

Patients with advanced ovarian cancer, with underlying BRCA 1/ 2 mutations, have limited treatment options, after progression on chemotherapy. Rucaparib is a PARP inhibitor with significant activity in BRCA mutated ovarian cancer as well as prostate cancer. The ARIEL-4 trial was designed test the efficacy of rucaparib in BRCA 1 / 2 mutated advanced ovarian cancer patients who had progressed on 2 or more prior lines of chemotherapy.

The ARIEL-4 clinical trial involved 349 patients, with high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer.  Patients had either BRCA1 or BRCA2 germline mutations or somatic mutations.  These were seen in 84% and 16%, respectively.  Patients had to have received 2 or more prior chemotherapy regimens but no PARP inhibitor.  51% of patients were platinum resistant.  28% were “partially platinum sensitive” while 21% were fully platinum sensitive.  The definition of fully platinum sensitive was more than 12 months of a platinum free interval while partial was between 6 and 12 months.  6.6% of patients, n=23 patients, were found to have BRCA reversion mutations.  Reversion mutations are thought to convey platinum resistance and PARP inhibitors in BRCA mutant cancers.

Patients were randomized to either rucaparib 600 mg twice daily or weekly paclitaxel 60-80 mg/m² with platinum resistant or partially platinum sensitive disease.  Platinum sensitive patients were given investigators choice of platinum-based chemo or a platinum doublet.  The primary endpoint was investigator assessed progression free survival.  Overall survival data was not mature yet.  In both efficacy and the intent to treat populations, median progression free survival was significantly longer with rucaparib than with chemotherapy.  Investigator assessed progression free survival in the efficacy population with 7.4 months with rucaparib and 5.7 months with chemotherapy, hazard ratio 0.64, p=0.001.  The median progression free survival was 7.4 months versus 5.7 months, hazard ratio 0.67, P = 0.002 in the intent to treat population.  In an exploratory analysis of 23 patients with BRCA reversion mutations, median progression free survival was shorter with rucaparib than with chemotherapy, 2.9 months versus 5.5 months, HR = 2.77.  The objective response rate in the efficacy population with similar, 40.3% versus 32.3%, P = 0.13.