ATR/PARP Inhibition May Overcome PARP Resistance in High-Grade Serous Ovarian Cancer

Stephanie L. Wethington, MD, MSc

Treating high-grade serous ovarian cancer means working against the inevitable resistance to PARP inhibitors in patients. Preclinical research conducted by researchers in the Simpkins Lab at the Perelman School of Medicine at the University of Pennsylvania suggests that adding an ATR inhibitor to a PARP inhibitor may overcome resistance.

A non-randomized study of olaparib (Lynparza) 300 mg orally twice daily plus ceralasertib (AZD6738) 160 mg orally once daily on days 1 through 7 set out to test the hypothesis in 13 patients. the population studied had a median age of 60 years (range, 43-78). Notably, 69% had germline BRCA mutations, and 23% had somatic BRCA mutations. Eight percent of the population was positive for homologous recombination deficiency (HRD).

According to the study results, the theory posed by the Simpkins lad about combination ATR and PARP, may be accurate.

In an interview with Targeted Oncology™, Stephanie L. Wethington, MD, MSc, the director, The Susan L. Burgert M.D. Gynecologic Oncology Survivorship Program and assistant professor of Gynecology and Obstetrics, at Johns Hopkins Medicine, discussed the modern treatment of high-grade serous ovarian cancer and the study of olaparib plus ceralasertib as a strategy for overcoming resistance to PARP inhibition.

TARGETED ONCOLOGY™: What is unique about treating high-grade serous ovarian cancer today?

Wethington: We've seen is that over the course of the last decade, there's been a complete transformation and how we think about ovarian cancer. Most remarkably, in 2021, there is this focus and emphasis on HRD, and how that should or shouldn't, in different moments guide our therapeutic approaches. I think that the idea of HRD as a key discriminator in the management of high grade serous ovarian cancers has been one of the real revolutionary changes that we are currently experiencing and practicing within.

What are the key challenges oncologists face with treating this patient population?

I think the high grade serous ovarian cancer patients face the sort of that first challenge of how do we assess HRD? Which of the many different assays do we use? What sequence do we complete the testing in? How do we then interpret the test results and counsel our patients based on those results?

So, I think probably the first challenge we face is just simply in that assessment of HRD. And then as treatment paradigms have shifted over time, we have a growing patient population that has received a PARP inhibitor in the past. PARP inhibitors are those therapeutic approaches that really target HRD as their primary mechanism.

Can you discuss PARP inhibitor resistance in this population? What is the best next line of therapy?

PARP inhibitor resistance is not a single entity. There are many mechanisms of PARP inhibitor resistance and increasing papers and publications on additional mechanisms over time. Probably the 1 that most people hear about, and we think about the most is reversion mutations, because this is one that's somewhat easier to assay for using available commercial tests. Certainly, the idea of PARP inhibitor resistance as the clinical concept or the phenotype of someone no longer responding to a PARP inhibitor is what we mean when we talk about PARP inhibitor resistance and in the laboratory. We are really meaning those specific mechanisms.

What Dr. Fiona Simpkins lab at the Perelman School of Medicine has elegantly demonstrated is that ATR inhibitors are 1 potential avenue to re-sensitize cells, mouse PDX models, and maybe even people with high grade serous ovarian cancers to PARP inhibitor. This may introduce the option or possibility of another therapeutic approach, and that therapeutic approach may be a combination of a PARP inhibitor and an ATR inhibitor.

Can discuss the design of the study of the combination of olaparib and ceralasertib in acquired PARP inhibitor-resistant recurrent ovarian cancer?

This was a small 13-patient, single-arm study looking at the combination of ceralasertib and olaparib. Patients in our study all were platinum-sensitive. They had all received a prior PARP inhibitor, and there's variability in that prior PARP inhibitor meaning they could have received the PARP inhibitor in the upfront maintenance setting, or in the platinum sensitive recurrent setting.

We similarly defined that differently for each of those categories, but each patient must have received a benefit from the PARP inhibitor and then experienced progression. So, it's this very specific detailed patient population. The majority of the patients had progressed while on the PARP inhibitor, and so we studied in this patient population, the combination of ceralasertib and PARP inhibitor. And in this way, we took Dr. Simpkins laboratory data and are first translating it into a study in the clinical setting to establish the overall response rates and the tolerability of this regimen.

What were the results of this study?

in line with that our 2 primary results were about the response rates, we found a 46% overall response rate. This consisted of 5 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 three or grade four toxicities and four dose reductions, no patient had to come off of therapy as a result of toxicity.

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 PARP inhibitor as part of maintenance. We see responses in patients who receive PARP inhibitor as part of their treatment. 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. This is a heterogeneous group of patients within our very narrowly defined population of patients who are platinum-sensitive and have received prior PARP inhibitor and progress with that prior PARP inhibitor. So, 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 overall response rate, which supports the preclinical data that Dr. Simpkins lab developed.

What are you keep takeaways from this research?

What we have is intriguingly, a well-tolerated regimen with a response rate worthy of further investigation. This is a small series by no means is a definitive series. But I think the takeaway message in this case is that additional research is needed a larger patient population, and some comparison to what would be the standard of care if someone didn't go on trial and a platinum-sensitive patient, which is a platinum-based chemotherapy regimen. I think the takeaway is the excellent tolerability, and the excellent response rate that lend themselves to the need for further research.

_Reference:

_{Wethington SL, Shah PD, Martin LP, et al. Combination of PARP and ATR inhibitors (olaparib and ceralasertib) shows clinical activity in acquired PARP inhibitor-resistant recurrent ovarian cancer. J Clin Oncol. 2021; 39 (suppl 15: abstr 5516. doi: 10.1200/JCO.2021.39.15_suppl.5516}