PARP Inhibitor-Resistant Ovarian Cancer Responds to PARP Plus ATR Inhibitors

Stephanie L. Wethington, MD, MSc, director of the Susan L. Burgert M.D. Gynecologic Oncology Survivorship Program and assistant professor of Gynecology and Obstetrics at Johns Hopkins Medicine, discusses results of a study of olaparib (Lynparza) plus ceralasertib (AZD6738) for overcoming resistance to PARP inhibition.

PARP inhibitors are an important treatment for high-grade serous ovarian cancer (HGSOC), but PARP inhibitor resistance makes them less effective against tumors. This resistance develops through several mechanisms including reversion mutations. Preclinical data from the Simpkins Lab at the University of Pennsylvania’s Perelman School of Medicine indicated that ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors can be combined with PARP inhibitors to overcome PARP inhibitor resistance.

The non-randomized phase 2 CAPRI trial (NCT03462342) investigators administered the PARP inhibitor olaparib 300 mg orally twice daily with the addition of ATR inhibitor ceralasertib 160 mg orally once daily on for the first 7 days of a 28-day cycle in 13 patients with HGSOC. The patients who were selected were platinum sensitive and had shown benefit from prior PARP inhibitors, but their disease had progressed. They may have been given PARP inhibitors during prior treatment or maintenance.

The primary end points were the overall response rate (ORR) and the incidence of treatment-related adverse events (TRAEs). According to Wethington, there was a 46% ORR with the combination based on 6 partial responses and 0 complete responses. In terms of toxicity, there was a 31% rate of grade 3 or 4 TRAEs, but no patients needed to stop therapy due to toxicity, suggesting that the combination is well tolerated.

TRANSCRIPTION:

0:08 | Our 2 primary results were about the response rates. We found a 46% ORR. This consisted of 6 partial responses, and we found that it was a well-tolerated regimen. So, it was a well-tolerated regimen in that, although we did see a 31% rate of grade 3 or grade 4 toxicities and 4 dose reductions, no patient had to come off of therapy as a result of toxicity. So the 46% response rate is actually, when you look at the details, a very small series, but intriguing. We see responses in patients who received a PARP inhibitor as part of maintenance. We see responses in patients who receive a PARP inhibitor as part of their treatment. And there doesn't seem to be a distinction in this and those, clinically. Whether you're using it in maintenance or in a treatment setting are important.

So the responses, that 46% response rate is [from] a heterogeneous group of patients within our very narrowly-defined population of patients who are platinum sensitive, and have received prior PARP inhibitor and progressed with that prior PARP inhibitor. The 2 primary outcomes we see here are the excellent tolerability with no patients having had to come off of therapy due to toxicity, and a quite remarkable 46% ORR, which supports the preclinical data that Dr Simpkins's lab developed.