Initial PARP Inhibitor Use for Ovarian Cancer May Not Lead to Resistance in Secondary Use

Prior exposure to PARP inhibitor treatment may not lead to resistance in future use with these agents in women with recurrent epithelial ovarian cancer, meaning repeat use could become more common, according to results from a multi-institutional study presented at the 50th SGO Annual Meeting, held March 16-19 in Honolulu, Hawaii.

“This is the first effort to report on patients who have received more than one PARP inhibitor. PARP inhibitors are now indicated in the frontline setting and BRCA patients are going to be exposed to PARP inhibitors in the frontline and may progress or recur. We need to know more about who we rechallenge,” said Kathleen G. Essel, MD, gynecologic oncology fellow, Stephenson Cancer Center, University of Oklahoma.

Following a retrospective review of 22 patients with epithelial ovarian cancer who received at least two lines of therapy containing a PARP inhibitor, there were 10 complete responses (45.5 percent), three partial responses (13.6 percent), four with stable disease (18.2 percent), and two with progressive disease (13.6 percent).

For initial PARP inhibitor use, 12 patients (54.5 percent) received veliparib (ABT-888); seven patients (31.8 percent) with Lynparza (olaparib), three patients (13.6 percent) with Rubraca (rucaparib), and none with Zejula (niraparib). PARPi1 was used as maintenance in two patients (13.6 percent).

Among patients treated with initial PARP inhibitor use, treatment was discontinued because the planned number of cycles was reached (10 patient; 45.5 percent), progression (eight patients; 36.4 percent), toxicity (two patients; 9.1 percent), and side effects from other chemotherapy or patient choice (two patients; 9.1 percent).

“Despite the fact that eight patients discontinued initial PARP due to progression of disease, five of eight may have experienced clinical benefit in the form of stable disease before progressing,” Essel said.

Of the patients treated with a second PARP inhibitor, 10 patients (45.4 percent) received Zejula; six patients (27.3%) with Lynparza; six patients (27.3 percent) with Rubraca, and none with veliparib. Three patients used the agent as maintenance therapy.

Best responses in this group included three patients who experienced partial response (13.6 percent), three with progressive disease (13.6 percent), and 13 with stable disease (59.1 percent). Of note, the three patients who experienced a partial to a secondary PARP inhibitor had a BRCA mutation and had all experienced a complete response to initial PARP inhibitor therapy. “There does seem to be a signal for rechallenge with a PARP inhibitor in this population,” Essel said.

Secondary PARP inhibitor use was discontinued because of progression (13 patients; 59.1 percent), toxicity (six patients; 27.3 percent), and financial reasons or provider choice (two patients; 9.1 percent). One patient currently remains on therapy with their secondary PARP inhibitor.

In both initial and secondary PARP inhibitor use, patients experienced grade 3/4 anemia (four patients vs. one patient, respectively), thrombocytopenia (five patients each), neutropenia (four patients vs. one patient), non-hematologic toxicities (three patients each), and any toxicity (10 patients vs. seven patients). Toxicity after initial PARP inhibitor use was not significantly associated with toxicity following second PARP inhibitor therapy, suggesting safety may be acceptable, Essel said.

She also acknowledged the study was limited due to its population size, and in turn, overall response to initial PARP inhibitor use did not predict overall response to second PARP inhibitor therapy.

“Repeat use of PARP inhibitors will likely become a big question as will sequencing,” Essel said. “Mechanisms of resistance to PARP inhibitors and prediction of resistance are important areas of research.”