ATR / PARP inhibition may overcome PARP resistance in high-grade serous ovarian cancer


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

According to the results of the study, the theory posed by the boy Simpkins on the combination of ATR and PARP, may be correct.

In an interview with Targeted Oncology â„¢, Stephanie L. Wethington, MD, MSc, Director of the Susan L. Burgert MD Gynecologic Oncology Survival Program and Assistant Professor of Gynecology and Obstetrics, at Johns Hopkins Medicine, discussed modern treatment serous hyper-ovarian cancer and the study of olaparib plus ceralasertib as a strategy to overcome resistance to PARP inhibition.

TARGETED ONCOLOGY â„¢: What is unique in the treatment of high grade serous ovarian cancer today?

Wethington: We have seen that over the last decade there has been a complete transformation and the way we think about ovarian cancer. More remarkably, in 2021 there is this focus and emphasis on HRD, and how it should or should not, at different times, guide our therapeutic approaches. I think the idea of ​​HRD as a key discriminator in the management of high grade serous ovarian cancer has been one of the truly revolutionary changes that we are experiencing and practicing now.

What are the main challenges that oncologists face in treating this patient population?

I think that patients with high grade serous ovarian cancer face this first challenge: how to assess HRD? Which of the many different tests do we use? In what order do we perform the tests? How then to interpret the test results and advise our patients based on these results?

So I think probably the first challenge we face is just in this HRD assessment. And then, as the treatment paradigms have changed over time, we have a growing population of patients who have received a PARP inhibitor in the past. PARP inhibitors are those therapeutic approaches that truly target HRD as the primary mechanism.

Can you discuss resistance to PARP inhibitors in this population? What’s the best next line of therapy?

Resistance to PARP inhibitors is not a single entity. There are many mechanisms of resistance to PARP inhibitors and a growing body of articles and publications on additional mechanisms over time. Probably the 1 that most people hear about, and think about it the most, is reversion mutations, as this is the one that is a bit easier to assay using the commercial tests available. Certainly, the idea of ​​resistance to PARP inhibitors as a clinical concept or phenotype of a person no longer responding to a PARP inhibitor is what we mean when we talk about resistance to PARP inhibitors and in the laboratory. We really mean those specific mechanisms.

What the lab of Dr Fiona Simpkins at the Perelman School of Medicine has elegantly demonstrated is that ATR inhibitors are a potential pathway to resensitize cells, PDX models of mice, and perhaps even people. with high-grade serous ovarian cancer with the PARP inhibitor. This can introduce the option or possibility of another therapeutic approach, and this therapeutic approach can be a combination of a PARP inhibitor and an ATR inhibitor.

Can we discuss the design of the study of the combination of olaparib and ceralasertib in acquired relapsed ovarian cancer resistant to PARP inhibitors?

This was a small, single-arm study of 13 patients of the combination of ceralasertib and olaparib. The patients in our study were all sensitive to platinum. They had all received a prior PARP inhibitor, and there is variability in this prior PARP inhibitor, meaning they could have received the PARP inhibitor in the initial maintenance setting or in the recurrent platinum sensitive setting.

We also defined this differently for each of these categories, but each patient should have received a benefit from the PARP inhibitor and then experienced progression. So this is this very specific detailed patient population. The majority of patients had progressed on a PARP inhibitor, and we therefore studied in this patient population the combination of ceralasertib and a PARP inhibitor. And in this way, we took the data from Dr. Simpkins’ lab and first translated it into a clinical study to establish the overall response rates and tolerability of this diet.

What were the results of this study?

In keeping with the fact that our 2 main results were about response rates, we found an overall response rate of 46%. It consisted of 5 partial responses, and we found it to be a well-tolerated diet. It was therefore a well-tolerated regimen in that although we saw a 31% rate of grade three or four toxicities and four dose reductions, no patient had to stop treatment due to ‘toxicity.

The response rate of 46% is actually, when you look at the details, a very small, but intriguing series. We are seeing responses in patients who received a PARP inhibitor as part of the interview. We are seeing responses in patients who receive a PARP inhibitor as part of their treatment. There doesn’t seem to be any distinction there and those clinically, whether you use it in maintenance or in a treatment setting, are important. This is a heterogeneous group of patients within our very narrowly defined population of platinum sensitive patients who received a prior PARP inhibitor and progressing with that prior PARP inhibitor. Thus, the 2 main results that we see here are the excellent tolerance, no patient having had to stop the treatment due to the toxicity and a rather remarkable overall response rate, which supports the preclinical data developed by the laboratory of Dr. Simpkins.

What do you take away from this research?

What we have is oddly, a well-tolerated diet with a response rate worthy of further investigation. This is a small series by no means a definitive series. But I think the take-home message in this case is that more research is needed for a larger patient population, and a comparison to what the standard of care would be if someone didn’t go to the trial and a patient sensitive to platinum, which is a chemotherapeutic platinum. I think the takeaway is the excellent tolerability and excellent response rate which lends itself to the need for further research.

Reference:

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

About Hector Hedgepeth

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