When PARP Inhibitors Fail in Ovarian Cancer

March 18, 2019 6:00 pm

The following article is provided by The Clearity Foundation to support women with ovarian cancer and their families. Learn more about The Clearity Foundation and the services we provide directly to women as they make treatment decisions and navigate emotional impacts of their diagnosis.

Dendritic Cell-Based Immunotherapy Appears Promising for Recurrent Ovarian Cancer

By Ian Ingram

Study identifies subgroup for whom another go could be worthwhile.

Lack of response to a PARP inhibitor in epithelial ovarian cancer didn’t necessarily mean patients were resistant to all such agents, a small retrospective study indicated.

Among a review of 22 women treated with PARP inhibitors in various settings, three had partial responses (PRs) and 13 achieved stable disease when rechallenged with a different PARP inhibitor, Kathleen Essel, MD, of the Stephenson Cancer Center in Oklahoma City, reported here.

“We did see patients benefit from retreatment,” she said during her presentation at the Society of Gynecologic Oncology (SGO) meeting. “Specifically, patients with BRCA mutations whose disease responded favorably to first PARP as part of frontline therapy.”

All three PRs on the second PARP inhibitor were among the 13 BRCA mutation carriers, and seven of these patients also achieved stable disease.

“There does seem to be a signal for a rechallenge with a PARP inhibitor in this population,” Essel said.

Veliparib was the most common initial PARP inhibitor (n=12), followed by olaparib (Lynparza) in seven patients, and rucaparib (Rubraca) in three. Ten patients subsequently had no evidence of disease, three achieved PRs, four had stable disease, with two using the therapy in a maintenance fashion. Essel noted that due to the wide variety of treatment settings, there was no clear way to classify best response.

Of the eight patients that discontinued the initial PARP inhibitor due to disease progression, five achieved stable disease when rechallenged.

Niraparib was the most common second PARP inhibitor (n=10), followed by olaparib and rucaparib in six patients each. Reasons for discontinuing a second PARP inhibitor was progressive disease in 13 patients, toxicity in six, and other reasons in two, with one patient still on therapy.

“Dr. Essel asked us the elephant-in-the-room question,” said SGO session discussant and co-author Kathleen Moore, MD, also of the Stephenson Cancer Center. “Now that PARP’s in the frontline, what are we going to do with those patients who recur, are we going to use PARP again and if so, in whom, and in what line of therapy?”

That some patients appeared to benefit from PARP inhibition even after prior exposure is encouraging, she said, despite the study’s small numbers.

“That gives us a road forward, which fortunately is already underway,” said Moore, pointing to the phase IIIb OREO trial, a randomized trial testing olaparib maintenance in patients with or without BRCA mutations with prior PARP inhibitor exposure in the maintenance setting who again respond to platinum induction following relapse.

“This will be an incredibly important study,” she said.

In the current study, median age at diagnosis was 54 and the majority of patients were white (63.6%). Initial PARP inhibitors were used in various ways, some as monotherapy, some in combination, and some as maintenance.

During the first round of PARP inhibition, grade 3/4 adverse events (AEs) included thrombocytopenia in five patients, anemia and neutropenia in four each, and non-hematologic toxicities in three patients. During the second round, grade 3/4 AEs included thrombocytopenia in five patients, non-hematologic toxicities in three, and anemia and neutropenia in one patient each. There were no cases of myelodysplastic syndromes or acute myeloid leukemia.

Toxicity with the first PARP inhibitor was not significantly associated with toxicity with the second PARP inhibitor, and toxicity did not appear additive, Essel noted. Her group sought to evaluate if response to initial PARP inhibitor correlated with response to the second therapy, but 12 patients had received their first PARP inhibitor in combination with chemotherapy, making it difficult to indicate whether these patients were responders or non-responders to PARP inhibition.

This article was published by Medpage Today.

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