Repeat Use of PARP Inhibitors Could Be Effective Strategy in Ovarian Cancer

Kathleen G. Essel, MD

Prior exposure to PARP inhibitor treatment may not lead to resistance in future use with these agents in women with recurrent epithelial ovarian cancer, suggesting that repeat use could become more common, according to results from a retrospective, multi-institutional study presented at the 2019 SGO Annual Meeting.

“Repeat use of PARP inhibitors will likely become a big question as will sequencing,” said Kathleen G. Essel, MD, gynecologic oncology fellow, Stephenson Cancer Center, University of Oklahoma. “Mechanisms of resistance to PARP inhibitors and prediction of resistance are important areas of research.”

In the small retrospective review of 22 patients with epithelial ovarian cancer, the median age was 54.5 years (range, 42-69); the majority of patients were Caucasian (n = 14; 63.6%). Half of patients had a germline BRCA mutation, 2 patients (n = 9.1%) had a somatic BRCA mutation, and 9 patients (40.9%) tested negative for both.

In these 22 patients who received ≥2 lines of therapy containing a PARP inhibitor, there were 10 complete responses (CR; 45.5%), 3 partial responses (PR; 13.6%), 4 cases of stable disease (SD; 18.2%), and 2 patients with progressive disease (PD; 13.6%).

For initial PARP inhibitor use (PARPi1), 12 patients (54.5%) received veliparib (ABT-888); 7 patients (31.8%) with olaparib; (Lynparza), 3 patients (13.6%) with rucaparib (Rubraca), and none with niraparib (Zejula). PARPi1 was used as maintenance in 2 patients (13.6%).

Among patients treated with PARPi1, treatment was discontinued because the planned number of cycles was reached (n = 10; 45.5%), disease progression (n = 8; 36.4%), toxicity (n = 2; 9.1%), and adverse events (AEs) of other chemotherapy and patient choice (n = 2; 9.1%).

“Despite the fact that 8 patients discontinued initial PARP [inhibition] due to progression of disease, 5 of 8 may have experienced clinical benefit in the form of stable disease before progressing,” Essel said.

Of the patients treated with a second PARP inhibitor (PARPi2), 10 patients (45.4%) received niraparib; 6 patients (27.3%) olaparib; 6 patients (27.3%) rucaparib, and none with veliparib. Three patients (13.6%) used PARPi2 as maintenance therapy.

Best responses in this group included 3 patients who experienced PR (13.6%), 3 with PD (13.6%), and 13 with SD (59.1%). Of note, the 3 patients who experienced a PR to PARPi2 had a BRCA mutation and had all experienced a CR to PARPi1. “There does seem to be a signal for rechallenge with a PARP inhibitor in this population,” Essel said.

PARPi2 was discontinued because of disease progression (n = 13; 59.1%), toxicity (n = 6; 27.3%), and financial reasons or provider choice (n = 2; 9.1%). One patient (4.5%) currently remains on therapy with PARPi2.

Regarding safety, in PARPi1 and PARPi2, patients experienced grade 3/4 anemia (4 vs 1, respectively), thrombocytopenia (5 each), neutropenia (4 vs 1), non-hematologic toxicities (3 each), and any toxicity (10 vs 7). Toxicity following 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 that 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.

“This is the first effort to report on patients who have received more than 1 PARP inhibitor” Essel said. “PARP inhibitors are now indicated in the frontline setting and BRCA[-mutant] 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.”

Essel KG, Behbakht K, Lai T, et al. PARPi after PARPi in epithelial ovarian cancer. Presented at: 2019 SGO Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract 7.

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